molecules demonstrate a high affinity for human PD-L1, potently disrupt the PD-L1:PD-1 interaction, and inhibit Src homology region 2 domain-containing phosphatase (SHP2) recruitment to PD-1. More than 50 molecules from the pyrazolone family have been synthesized and a dozen highly potent "PD-L1 silencing compounds" have been identified, based on in vitro measurements. Structure-activity relationships have been defined and an in silico drug-target model supporting the mechanism of action has been built (Figure 31).

<figure><img src="image_35.png" /><figcaption>**Figure 31.** Example of one of the lead molecules of the pyrazolone series and its in silico drug-target model.</figcaption></figure>

4.29. Benzo[D]Thiazol-2(3h)-Ones as New Potent Selective Cb2 Agonists with Anti-Inflammatory Properties (P29)

Natascha Leleu-Chavain ¹, Davy Baudelet ¹, Valéria Moas Heloire ¹, Diana Escalante Rochas ¹, Madjid Djouina ², Amélie Barczyk ¹, Mathilde Body-Malapel ², Pascal Carato ³, Régis Millet ¹

¹ Univ. Lille, Inserm, ICPAL, U995-LIRIC-Lille Inflammation Research International Center, F-59000 Lille

² Univ. Lille, Inserm, CHU Lille, U995-LIRIC-Lille Inflammation Research International Center, F-59000 Lille

³ Université de Poitiers, UFR de Médecine et de Pharmacie, IC2MP-CNRS 7285, 6 rue de la Milétrie Bât D1-TSA 5115 86073 Poitiers; natascha.leleu@univ-lille.fr

The high distribution of CB₂ receptors in immune cells [132] suggests their important role in the control of inflammation [133]. CB₂ selective agonists have the capability to modulate inflammation without triggering psychotropic effects due to the activation of CB₁ receptors [134,135]. Therefore, there is growing evidence to consider this receptor as an attractive therapeutic target. More specifically, CB₂ receptors' activation represents a very promising strategy to treat gastrointestinal inflammatory diseases. In this work, we designed new selective CB₂ agonists based on a 2-oxo-2,3-dihydro-1,3-benzothiazolinone scaffold [136]. Structure-activity relationships were studied from a series of 22 compounds. From these pharmacomodulations, we identified the importance of having both a bulky aliphatic group attached to the ketone at position 6 and an alkyl chain at N3 position of the heterocycle. This drug design project led to the discovery of a very potent and selective CB₂ agonist in the nanomolar range (compound 1, Figure 32) able to counteract colon inflammation in vivo.

<figure><img src="image_36.png" /><figcaption>**Figure 32.** Chemical structure of compound 1.</figcaption></figure>
### 4.30. Synthesis and Antipseudomonal Activities of New Iron Chelator–Ciprofloxacin Conjugates (P30)

Pauline Loupias¹, Nicolas Taudon², Alexandra Dassonville-Klimpt¹, Pascal Sonnet²

¹ AGIR, UR 4294, UFR de Pharmacie, UPJV, 1 rue des Louvels, 80037 Amiens, France

² Unité de Toxicologie Analytique, IRBA, 91223 Brétigny-sur-Orge, France; pauline.loupias@u-picardie.fr

Each year, antibiotic-resistant germs cause at least 700,000 deaths worldwide. Among them, the Gram-negative bacterium *P. aeruginosa* has the highest burden of healthcare-acquired infections in intensive care units and belongs to the first list of antibiotic-resistant "priority pathogens" described by the WHO [137]. In Europe, 31.8% of the cases reported to EARS-Net in 2019 were resistant to at least one antimicrobial group [138]. Alarmingly, the number of pan-drug-resistant specimens, untreatable with any of the antipseudomonal antibiotics available in the clinic, has increased [139]. The double-layered cell envelope of *P. aeruginosa* is responsible for a decreased penetration and low activity of many antibiotics. An innovative idea to bypass this barrier and restore the activity of conventional antibiotics, such as β-lactams or fluoroquinolones, is the exploitation of the siderophore-dependent active iron uptake with a "Trojan horse" strategy. In this approach, an antibiotic is chemically coupled to a natural or synthetic siderophore molecule, which forms an iron complex, thereby enhancing its active transport through bacteria outer membrane receptors (OMR). Cefiderocol, a catecholate cephalosporin conjugate using the "Trojan horse" strategy was recently approved in the USA (2019) and in Europe (2020) and is indicated for the treatment of MDR Gram-negative bacteria including *P. aeruginosa* (Figure 33) [140]. Herein, we will describe the synthesis and the antipseudomonal activities of ciprofloxacin-based conjugates bearing iron chelator moieties (catechol or hydroxypyridinone), via a linker, cleavable or not.

<figure><img src="image_35.png" /><figcaption>**Figure 33.** Structures of cefiderocol and ciprofloxacin-based conjugates.</figcaption></figure>

### 4.31. Investigation of CA-4 Metabolism and Related β-Lactam Analogues in Chemoresistant HT-29 Colon Cancer Cells (P31)

Azizah M. Malebari¹,², Mary J. Meegan²

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia

² School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2 DO2R590, Ireland; amelibary @kau.edu.sa

Drug resistance is a common cause of the failure of chemotherapeutic agents to achieve cytotoxicity responses in human malignant disease. Drug inactivation by metabolism within tumor cells is recognized as an important mechanism of drug resistance [141]. Glucuronidation is a major route for the metabolic inactivation of many drugs and also endogenous substances. Combretastatin-A4 (CA-4) undergoes direct glucuronidation in the presence of UGTs at the meta-hydroxy group of the B-ring and could cause an inherent resistance in HT-29 colon cancer cells [60,142]. Here, we assessed the strategic deletion of the ring B hydroxyl group to produce CA-4 analogues that are equally effective in cancer cells expressing UGTs as compared to those expressing little or undetectable levels of UGTs, offering a simple solution to overcoming resistance associated with glucuronidation of CA-4 (Figure 34). These compounds play a dual role by improving the stability by blocking the isomerization of the CA-4 olefin bridge and overcoming the resistance in HT-29 colon cancer cells by improving the metabolic stability. The stability of CA-4 and its
### 4.30. Synthesis and Antipseudomonal Activities of New Iron Chelator–Ciprofloxacin Conjugates (P30)

Pauline Loupias<fnref n="1" />, Nicolas Taudon<fnref n="2" />, Alexandra Dassonville-Klimpt<fnref n="1" />, Pascal Sonnet<fnref n="2" />

Each year, antibiotic-resistant germs cause at least 700,000 deaths worldwide. Among them, the Gram-negative bacterium *P. aeruginosa* has the highest burden of healthcare-acquired infections in intensive care units and belongs to the first list of antibiotic-resistant “priority pathogens” described by the WHO [137]. In Europe, 31.8% of the cases reported to EARS-Net in 2019 were resistant to at least one antimicrobial group [138]. Alarmingly, the number of pan-drug-resistant specimens, untreatable with any of the antipseudomonal antibiotics available in the clinic, has increased [139]. The double-layered cell envelope of *P. aeruginosa* is responsible for a decreased penetration and low activity of many antibiotics. An innovative idea to bypass this barrier and restore the activity of conventional antibiotics, such as β-lactams or fluoroquinolones, is the exploitation of the siderophore-dependent active iron uptake with a “Trojan horse” strategy. In this approach, an antibiotic is chemically coupled to a natural or synthetic siderophore molecule, which forms an iron complex, thereby enhancing its active transport through bacteria outer membrane receptors (OMR). Cefiderocol, a catecholate cephalosporin conjugate using the “Trojan horse” strategy was recently approved in the USA (2019) and in Europe (2020) and is indicated for the treatment of MDR Gram-negative bacteria including *P. aeruginosa* (Figure 33) [140]. Herein, we will describe the synthesis and the antipseudomonal activities of ciprofloxacin-based conjugates bearing iron chelator moieties (catechol or hydroxypyridinone), via a linker, cleavable or not.

<figure><img src="image_37.png" /><figcaption>**Figure 33.** Structures of cefiderocol and ciprofloxacin-based conjugates.</figcaption></figure>

### 4.31. Investigation of CA-4 Metabolism and Related β-Lactam Analogues in Chemoresistant HT-29 Colon Cancer Cells (P31)

Azizah M. Malebari<fnref n="1" />,<fnref n="2" />, Mary J. Meegan<fnref n="2" />

Drug resistance is a common cause of the failure of chemotherapeutic agents to achieve cytotoxicity responses in human malignant disease. Drug inactivation by metabolism within tumor cells is recognized as an important mechanism of drug resistance [141]. Glucuronidation is a major route for the metabolic inactivation of many drugs and also endogenous substances. Combretastatin-A4 (CA-4) undergoes direct glucuronidation in the presence of UGTs at the meta-hydroxy group of the B-ring and could cause an inherent resistance in HT-29 colon cancer cells [60,142]. Here, we assessed the strategic deletion of the ring B hydroxyl group to produce CA-4 analogues that are equally effective in cancer cells expressing UGTs as compared to those expressing little or undetectable levels of UGTs, offering a simple solution to overcoming resistance associated with glucuronidation of CA-4 (Figure 34). These compounds play a dual role by improving the stability by blocking the isomerization of the CA-4 olefin bridge and overcoming the resistance in HT-29 colon cancer cells by improving the metabolic stability. The stability of CA-4 and its

<footnote n="1">¹ AGIR, UR 4294, UFR de Pharmacie, UPJV, 1 rue des Louvels, 80037 Amiens, France</footnote>

<footnote n="2">² Unité de Toxicologie Analytique, IRBA, 91223 Brétigny-sur-Orge, France; pauline.loupias@u-picardie.fr</footnote>

<footnote n="1">¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia</footnote>

<footnote n="2">² School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2 DO2R590, Ireland; amelibary@kau.edu.sa</footnote>
β-lactam analogue in HT-29 cells in the absence and presence of many different inhibitors of UGT enzymes (propofol, Borneol, bile acids, U0126 and 4-nitrophenol) was examined. Collectively, these data suggest a key role of UGT in mediating the resistance effect of CA-4 in HT-29 cells and provides a rationale to improve the therapeutic efficacy of CA-4 and its related analogues.

<figure><img src="image_36.png" /><figcaption>**Figure 34.** Metabolic stability in HT-29 cells of CA-4 and its representative β-lactam analogues.</figcaption></figure>

## 4.32. Using Metabolic Glycoengineering for Targeted Treatment of Cancer (P32)

Madonna Mitry<fnref n="1" />,<fnref n="2" />, Francesca Greco<fnref n="1" />, Helen Osborn<fnref n="1" />

The main limitation of conventional chemotherapies is the poor selectivity to cancer cells, which leads to serious side effects. We aim to develop a novel selective targeting method to address this challenge. This will exploit a specific property of cancer cells, namely the overexpression of certain surface glycans called tumor-associated carbohydrate antigens, or “TACAs” [143]. The biosynthesis of these surface glycans can be intercepted through the exposure of cells to unnatural monosaccharide precursors in order to engineer unnatural functionalities on the cancer cells’ surfaces in a process called metabolic glycoengineering [144]. Hence, by using azide-modified monosaccharides, the azide functionality will be expressed on the surface of the cancer cells. This can then act as a bio-orthogonal label that can be subsequently targeted by phosphine-modified prodrugs. The bio-orthogonal Staudinger ligation reaction between the azide on the tumor cell and the phosphine in the prodrug will lead to the prodrug activation specifically at the tumor site.

As a proof of concept, we have investigated the feasibility of the Staudinger ligation reaction for prodrug activation through an HPLC-monitored release study. This involved 9-azido-N-acetyl neuraminic acid (as an example of an azide-modified sialic acid that will be expressed on the surface of the cancer cells after the metabolic glycoengineering) and 4-nitrophenyl 2-(diphenylphosphino) benzoate (as an example of a phosphine-modified prodrug) in an aqueous environment at 37 °C. Release of 4-nitrophenol (our model ‘drug’) reached 80% over 72 h, which confirms the potential of our proposed strategy.

## 4.33. Synthesis and Biological Evaluation of Covalent Inhibitors of Focal Adhesion Kinase against Human Malignant Glioblastoma (P33)

Louna Mossino Diaz<fnref n="1" />, Bo Li<fnref n="1" />, Céline Tomkiewicz-Raulet<fnref n="2" />, Xavier Coumoul<fnref n="2" />, Christiane Garbay<fnref n="1" />, Mélanie Etheve-Quelquejeu<fnref n="1" />, Huixiong Chen<fnref n="1" />

Human malignant glioblastomas (GBM), which carry a poor prognosis, are highly aggressive and lethal brain cancers, with significant invasive and infiltrative features,

<footnote n="1">¹ School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK</footnote>

<footnote n="2">² Dept of Pharmaceutical chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; m.m.adeebmitry@pgr.reading.ac.uk</footnote>

<footnote n="1">¹ Chemistry of RNA, nucleosides, peptides and heterocycles, CNRS UMR8601, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France</footnote>

<footnote n="2">² Laboratoire Molécules de Communication et Adaptation des Micro-organismes, CNRS, Muséum National d'Histoire Naturelle, 63 rue Buffon 75005-Paris, France; louna.mossino@etu.u-paris.fr</footnote>
β-lactam analogue in HT-29 cells in the absence and presence of many different inhibitors of UGT enzymes (propofol, Borneol, bile acids, U0126 and 4-nitrophenol) was examined. Collectively, these data suggest a key role of UGT in mediating the resistance effect of CA-4 in HT-29 cells and provides a rationale to improve the therapeutic efficacy of CA-4 and its related analogues.

<figure><img src="image_38.png" /><figcaption>**Figure 34.** Metabolic stability in HT-29 cells of CA-4 and its representative β-lactam analogues.</figcaption></figure>

## 4.32. Using Metabolic Glycoengineering for Targeted Treatment of Cancer (P32)

Madonna Mitry¹,², Francesca Greco¹, Helen Osborn¹

¹ School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AD, UK

² Dept of Pharmaceutical chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; m.m.adeebmitry@pgr.reading.ac.uk

The main limitation of conventional chemotherapies is the poor selectivity to cancer cells, which leads to serious side effects. We aim to develop a novel selective targeting method to address this challenge. This will exploit a specific property of cancer cells, namely the overexpression of certain surface glycans called tumor-associated carbohydrate antigens, or "TACAs" [143]. The biosynthesis of these surface glycans can be intercepted through the exposure of cells to unnatural monosaccharide precursors in order to engineer unnatural functionalities on the cancer cells' surfaces in a process called metabolic glycoengineering [144]. Hence, by using azide-modified monosaccharides, the azide functionality will be expressed on the surface of the cancer cells. This can then act as a bio-orthogonal label that can be subsequently targeted by phosphine-modified prodrugs. The bio-orthogonal Staudinger ligation reaction between the azide on the tumor cell and the phosphine in the prodrug will lead to the prodrug activation specifically at the tumor site.

As a proof of concept, we have investigated the feasibility of the Staudinger ligation reaction for prodrug activation through an HPLC-monitored release study. This involved 9-azido-N-acetyl neuraminic acid (as an example of an azide-modified sialic acid that will be expressed on the surface of the cancer cells after the metabolic glycoengineering) and 4-nitrophenyl 2-(diphenylphosphino) benzoate (as an example of a phosphine-modified prodrug) in an aqueous environment at 37 °C. Release of 4-nitrophenol (our model 'drug') reached 80% over 72 h, which confirms the potential of our proposed strategy.

## 4.33. Synthesis and Biological Evaluation of Covalent Inhibitors of Focal Adhesion Kinase against Human Malignant Glioblastoma (P33)

Louna Mossino Diaz¹, Bo Li¹, Céline Tomkiewicz-Raulet², Xavier Coumoul², Christiane Garbay¹, Mélanie Etheve-Quelquejeu¹, Huixiong Chen¹

¹ Chemistry of RNA, nucleosides, peptides and heterocycles, CNRS UMR8601, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France

² Laboratoire Molécules de Communication et Adaptation des Micro-organismes, CNRS, Muséum National d'Histoire Naturelle, 63 rue Buffon 75005-Paris, France; louna.mossino@etu.u-paris.fr

Human malignant glioblastomas (GBM), which carry a poor prognosis, are highly aggressive and lethal brain cancers, with significant invasive and infiltrative features,
resulting in a strong resistance to conventional treatments and high recurrence rates [145]. Current therapies such as surgical resection, radiation, and temozolomide chemotherapy remain mostly palliative because of their limited efficacy. Consequently, the survival rate of glioblastoma patients has still not improved in the last few decades. Thus, there is a necessity to find new and more efficient therapeutic solutions for malignant glioblastomas.

The focal adhesion kinase (FAK), an integrin downstream signaling mediator, is highly overexpressed in glioblastomas, thereby promoting tumor growth and invasion, and offering a promising target for novel glioblastoma therapy. Therefore, several ATP-competitive FAK inhibitors have been recently developed and their early clinical studies have shown encouraging results [146].

Here, we present the structure-based design and synthesis of a series of novel covalent inhibitors of FAK [147,148]. A cocrystal structure of the FAK kinase domain in complex with our compound revealed the inhibitor binding mode within the ATP binding site and confirmed the covalent linkage between the targeted Cys427 of the protein and the inhibitor. Biochemical characterization of our inhibitors showed a time-dependent inhibition of FAK kinase in vitro and a reversible/irreversible inhibition of the autophosphorylation of FAK. The biological evaluation of these compounds has proven their inhibitory potency against FAK enzymatic activity with IC₅₀ values in the nanomolar range and anti-proliferative effects on several glioblastoma cell lines. These results exhibit the potential therapeutic benefits of covalent inhibitors of FAK for the treatment of human malignant gliomas and may offer a promising new targeted therapy for human glioblastomas.

### 4.34. Optimization of a Novel Fast-Acting Transmission-Blocking Antimalarial Agent (P34)

**Laura Mourot**¹, **Marjorie Schmitt**¹, **Elisabeth Mouray**², **Isabelle Florent**², **Sébastien Albrecht**¹

¹ Laboratoire d'Innovation Moléculaire et Applications, Université de Haute-Alsace, Université de Strasbourg, CNRS, 3bis rue Alfred Werner, 68093-Mulhouse, France

² Toxicologie, Pharmacologie et Signalisation Cellulaire, INSERM UMR S 1124, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France; laura.mourot@uha.fr

Despite significant progress in the control of malaria with a net reduction of morbidity and mortality over the past years, it remains one of the deadliest infectious diseases in the world. New drugs with broad therapeutic potential and novel modes of action to overcome emerging drug resistances are urgently needed. Key features of the next-generation antimalarial, termed single-exposure radical cure and prophylaxis (SERCaP), have been rationalized and resulted in the recommendation of a series of target candidate profiles (TCPs). Notably, TCP1 requires rapid elimination of the initial parasite burden, at least as fast as chloroquine.

In this context, the quinazolinedione MMV665878, with its antimalarial activities against multiple life stages of Plasmodium and fast-acting and transmission-blocking activities, has great potential to deliver useful drugs for malaria parasite eradication. Moreover, this quinazolinedione-based scaffold shows a remarkable selectivity window with a low toxicity for human cells and no cardiotoxicity risk. However, pharmacokinetic issues are encountered and include moderate overall exposure and/or modest bioavailability [149], an issue probably caused by rapid metabolism and elimination. Herein, we report our progress towards the optimization of this quinazolinedione-based antimalarial series (Figure 35).
resulting in a strong resistance to conventional treatments and high recurrence rates [145]. Current therapies such as surgical resection, radiation, and temozolomide chemotherapy remain mostly palliative because of their limited efficacy. Consequently, the survival rate of glioblastoma patients has still not improved in the last few decades. Thus, there is a necessity to find new and more efficient therapeutic solutions for malignant glioblastomas.

The focal adhesion kinase (FAK), an integrin downstream signaling mediator, is highly overexpressed in glioblastomas, thereby promoting tumor growth and invasion, and offering a promising target for novel glioblastoma therapy. Therefore, several ATP-competitive FAK inhibitors have been recently developed and their early clinical studies have shown encouraging results [146].

Here, we present the structure-based design and synthesis of a series of novel covalent inhibitors of FAK [147,148]. A cocrystal structure of the FAK kinase domain in complex with our compound revealed the inhibitor binding mode within the ATP binding site and confirmed the covalent linkage between the targeted Cys427 of the protein and the inhibitor. Biochemical characterization of our inhibitors showed a time-dependent inhibition of FAK kinase in vitro and a reversible/irreversible inhibition of the autophosphorylation of FAK. The biological evaluation of these compounds has proven their inhibitory potency against FAK enzymatic activity with IC₅₀ values in the nanomolar range and anti-proliferative effects on several glioblastoma cell lines. These results exhibit the potential therapeutic benefits of covalent inhibitors of FAK for the treatment of human malignant gliomas and may offer a promising new targeted therapy for human glioblastomas.

### 4.34. Optimization of a Novel Fast-Acting Transmission-Blocking Antimalarial Agent (P34)

**Laura Mourot**¹, **Marjorie Schmitt**¹, **Elisabeth Mouray**², **Isabelle Florent**², **Sébastien Albrecht**¹

¹ Laboratoire d'Innovation Moléculaire et Applications, Université de Haute-Alsace, Université de Strasbourg, CNRS, 3bis rue Alfred Werner, 68093-Mulhouse, France

² Toxicologie, Pharmacologie et Signalisation Cellulaire, INSERM UMR S 1124, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France; laura.mourot@uha.fr

Despite significant progress in the control of malaria with a net reduction of morbidity and mortality over the past years, it remains one of the deadliest infectious diseases in the world. New drugs with broad therapeutic potential and novel modes of action to overcome emerging drug resistances are urgently needed. Key features of the next-generation antimalarial, termed single-exposure radical cure and prophylaxis (SERCaP), have been rationalized and resulted in the recommendation of a series of target candidate profiles (TCPs). Notably, TCP1 requires rapid elimination of the initial parasite burden, at least as fast as chloroquine.

In this context, the quinazolinedione MMV665878, with its antimalarial activities against multiple life stages of Plasmodium and fast-acting and transmission-blocking activities, has great potential to deliver useful drugs for malaria parasite eradication. Moreover, this quinazolinedione-based scaffold shows a remarkable selectivity window with a low toxicity for human cells and no cardiotoxicity risk. However, pharmacokinetic issues are encountered and include moderate overall exposure and/or modest bioavailability [149], an issue probably caused by rapid metabolism and elimination. Herein, we report our progress towards the optimization of this quinazolinedione-based antimalarial series (Figure 35).
<figure><img src="image_37.png" /><figcaption>**Figure 35.** Pharmacological profile of MMV665878.</figcaption></figure>

4.35. *Ruthenium* (Ii) Octahedral Complexes Featuring Pyrimidine-Like Ligands: Cytotoxicity and DNA/Protein Interaction Studies (P35)

Alexandra-Cristina Munteanu ¹, Mirela Mihaila ², George Mihai Nitulescu ³, Valentina Uivarosi ¹

¹ Department of General and Inorganic Chemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 6 Traian Vuia Str., 020956 Bucharest, Romania

² Center of Immunology, Stefan S. Nicolau Institute of Virology, 285 Mihai Bravu Ave, 030304 Bucharest, Romania

³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 6 Traian Vuia Str., 020956 Bucharest, Romania; alexandra.ticea@umfcd.ro

Two pyrimidine-like ligands, namely orotic acid (6-carboxyuracil, H₃Or) (Figure 1) and isoorotic acid (5-carboxyuracil, H₃Or) (Figure 36), have been bound to rigid octahedral Ru(N,N)₂ scaffolds, where (N,N) stands for 2,2'-bipyridine and 1,10-phenanthroline, respectively. H₃Or is a key compound involved in the de nuovo biosynthesis of pyrimidine bases of nucleic acids in living organisms, which displays bacteriostatic and cytostatic properties, while its isomer, H₃Or, exerts anticancer, antibacterial, and antihypertensive properties [150]. Moreover, the clinical efficacy of the Ru(II)-polypyridyl scaffold has been recently proven by TLD-1433, which has entered pivotal phase II clinical studies as a photosensitizer for intravesical photodynamic therapy against bladder cancer [151]. The physico-chemical properties and structural features of these four complexes have been investigated by spectroscopic techniques (FT-IR, UV-Vis, mass spectrometry, ¹H and ¹³C NMR), and elemental analysis. Their cytotoxicity was tested against several cancer (breast, liver, colon, pharynx) and healthy cell lines. As a means of studying the mechanism underlying the cytotoxic effects of the complexes, interactions with calf thymus DNA were also carried out. Moreover, drug binding to serum proteins plays a very important role in drug pharmacokinetics and pharmacology, with a strong impact on absorption, distribution, metabolism, and excretion. Therefore, the binding properties of the complexes with human serum albumin and transferrin have been investigated by means of spectrophotometric studies.

<figure><img src="image_38.png" /><figcaption>**Figure 36.** Chemical structures of orotic acid (left) and isoorotic acid (right).</figcaption></figure>
<figure><img src="image_39.png" /><figcaption>**Figure 35.** Pharmacological profile of MMV665878.</figcaption></figure>

4.35. *Ruthenium* (Ii) *Octahedral Complexes Featuring Pyrimidine-Like Ligands: Cytotoxicity and DNA/Protein Interaction Studies* (P35)

Alexandra-Cristina Munteanu ¹, Mirela Mihaila ², George Mihai Nitulescu ³, Valentina Uivarosi ¹

¹ Department of General and Inorganic Chemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 6 Traian Vuia Str., 020956 Bucharest, Romania

² Center of Immunology, Stefan S. Nicolau Institute of Virology, 285 Mihai Bravu Ave, 030304 Bucharest, Romania

³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, 6 Traian Vuia Str., 020956 Bucharest, Romania; alexandra.ticea@umfcd.ro

Two pyrimidine-like ligands, namely orotic acid (6-carboxyuracil, H₃Or) (Figure 1) and isoorotic acid (5-carboxyuracil, H₃Or) (Figure 36), have been bound to rigid octahedral Ru(N,N)₂ scaffolds, where (N,N) stands for 2,2'-bipyridine and 1,10-phenanthroline, respectively. H₃Or is a key compound involved in the de nuovo biosynthesis of pyrimidine bases of nucleic acids in living organisms, which displays bacteriostatic and cytostatic properties, while its isomer, H₃Or, exerts anticancer, antibacterial, and antihypertensive properties [150]. Moreover, the clinical efficacy of the Ru(II)-polypyridyl scaffold has been recently proven by TLD-1433, which has entered pivotal phase II clinical studies as a photosensitizer for intravesical photodynamic therapy against bladder cancer [151]. The physico-chemical properties and structural features of these four complexes have been investigated by spectroscopic techniques (FT-IR, UV-Vis, mass spectrometry, ¹H and ¹³C NMR), and elemental analysis. Their cytotoxicity was tested against several cancer (breast, liver, colon, pharynx) and healthy cell lines. As a means of studying the mechanism underlying the cytotoxic effects of the complexes, interactions with calf thymus DNA were also carried out. Moreover, drug binding to serum proteins plays a very important role in drug pharmacokinetics and pharmacology, with a strong impact on absorption, distribution, metabolism, and excretion. Therefore, the binding properties of the complexes with human serum albumin and transferrin have been investigated by means of spectrophotometric studies.

<figure><img src="image_40.png" /><figcaption>**Figure 36.** Chemical structures of orotic acid (left) and isoorotic acid (right).</figcaption></figure>
### 4.36. Samarium-Doped Anatase TiO2 Nanoparticles: Synthesis, Characterization, and Synergy between Sm Rare Earth Doping and Oxygen Vacancies (P36)

Chaima Ouled Amor¹, Kais Elghniji¹, Clarence Charnay², Elimame Elaloui¹

¹ Dept of Chemistry, Faculty of sciences of Gafsa, Gafsa, Tunisia

² Institut Charles Gerhardt de Montpellier Equipe IMNO, Montpellier, France; amor-chaima92@gmail.com

Semiconductor nanoparticles can absorb the entire incident light whose photon energy is greater than the band gap of semiconductor, which belongs to a broadband absorption. When rare earth ions are doped into semiconductor nanoparticles, some impurity energy levels could be formed in the host's band structure. If there exists a certain energy transfer channel between the impurity energy levels and host's band structure, the conduction band electrons or valence band holes that are excited by the incident light could relax to the impurity energy levels of the dopants. Then, the incident energy will be released in the form of radiative relaxation, resulting in light emission. Because rare earth ions have a wealth of energy levels of 4f-states, so the effective energy transfer between semiconductor nanoparticles and rare earth ion dopants can achieve multi-wavelength light emission. In the research field regarding RE³⁺-doped TiO₂, the role of trivalent samarium ions (Sm³+) has attracted wide attention because of its good fluorescence efficiency in the visible and infrared region [152].

In order to obtain deeper information about the luminescence properties of Sm³⁺ ions in TiO₂ nanoparticles, we systematically investigated the effects of samarium concentration on the nanoparticles' structure and the luminescence properties of Sm³⁺, using a simple preparation method of sol-gel [153]. The materials were characterized by XRD, SEM, FTIR, TEM, and UV. The emissions of ⁴G₅/₂ → ⁶HJ (J = 5/2, 7/2, 9/2 and 11/2) transitions of Sm³⁺ ions were observed under the excitation wavelength at 350 nm, and the emission intensity depended strongly on the doping concentration. It has been found that samarium addition into the TiO₂ system leads to crystal expansion and matrix distortion, which indicates that some Sm³⁺ ions have entered into the matrix of TiO₂ to replace Ti⁴⁺ ions. Due to substitution of Sm³⁺ ions in the Ti⁴⁺, oxygen vacancies are created, which generates shallow energy states which serve as electron traps in the bottom of conduction band and suppresses the recombination of excited electrons and holes.

### 4.37. Copper-Catalyzed C-H Arylation of Fused Pyrimidinones Using Diaryliodonium Salts under Microwave Irradiation (P37)

Alexandra Pacheco-Benichou, Corinne Fruit, Thierry Besson

Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France; alexandra.benichou@univ-rouen.fr

Late-stage C-H arylation of heteroarenes is a powerful tool for the synthesis of valuable scaffolds used in drug discovery. Previously, our group developed mono and bis-arylation reactions of pyrimidinones including thiazolo[5,4-f]quinazolin-9-(8H)-ones, mainly conceived as potential kinase inhibitors [154–156]. During the last decade, diaryliodonium salts appeared as efficient electrophilic and non-toxic reagents for late-stage arylation [157,158]. In this context, a Cu-catalyzed C-H arylation process using diaryliodonium salts was investigated under microwave irradiation. This sustainable methodology, allowing the introduction of (het)aryl groups on the C2 atom of the thiazole moiety, was successfully extended to various fused pyrimidinones (Figure 37).

<figure><img src="image_39.png" /><figcaption>**Figure 37.** Cu-catalyzed C-H arylation process using diaryliodonium salts.</figcaption></figure>
### 4.36. Samarium-Doped Anatase TiO2 Nanoparticles: Synthesis, Characterization, and Synergy between Sm Rare Earth Doping and Oxygen Vacancies (P36)

Chaima Ouled Amor¹, Kais Elghniji¹, Clarence Charnay², Elimame Elaloui¹

¹ Dept of Chemistry, Faculty of sciences of Gafsa, Gafsa, Tunisia

² Institut Charles Gerhardt de Montpellier Equipe IMNO, Montpellier, France; amor-chaima92@gmail.com

Semiconductor nanoparticles can absorb the entire incident light whose photon energy is greater than the band gap of semiconductor, which belongs to a broadband absorption. When rare earth ions are doped into semiconductor nanoparticles, some impurity energy levels could be formed in the host's band structure. If there exists a certain energy transfer channel between the impurity energy levels and host's band structure, the conduction band electrons or valence band holes that are excited by the incident light could relax to the impurity energy levels of the dopants. Then, the incident energy will be released in the form of radiative relaxation, resulting in light emission. Because rare earth ions have a wealth of energy levels of 4f-states, so the effective energy transfer between semiconductor nanoparticles and rare earth ion dopants can achieve multi-wavelength light emission. In the research field regarding RE³⁺-doped TiO₂, the role of trivalent samarium ions (Sm³+) has attracted wide attention because of its good fluorescence efficiency in the visible and infrared region [152].

In order to obtain deeper information about the luminescence properties of Sm³⁺ ions in TiO₂ nanoparticles, we systematically investigated the effects of samarium concentration on the nanoparticles' structure and the luminescence properties of Sm³⁺, using a simple preparation method of sol-gel [153]. The materials were characterized by XRD, SEM, FTIR, TEM, and UV. The emissions of ⁴G₅/₂ → ⁶HJ (J = 5/2, 7/2, 9/2 and 11/2) transitions of Sm³⁺ ions were observed under the excitation wavelength at 350 nm, and the emission intensity depended strongly on the doping concentration. It has been found that samarium addition into the TiO₂ system leads to crystal expansion and matrix distortion, which indicates that some Sm³⁺ ions have entered into the matrix of TiO₂ to replace Ti⁴⁺ ions. Due to substitution of Sm³⁺ ions in the Ti⁴⁺, oxygen vacancies are created, which generates shallow energy states which serve as electron traps in the bottom of conduction band and suppresses the recombination of excited electrons and holes.

### 4.37. Copper-Catalyzed C-H Arylation of Fused Pyrimidinones Using Diaryliodonium Salts under Microwave Irradiation (P37)

Alexandra Pacheco-Benichou, Corinne Fruit, Thierry Besson

Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA UMR 6014, 76000 Rouen, France; alexandra.benichou@univ-rouen.fr

Late-stage C-H arylation of heteroarenes is a powerful tool for the synthesis of valuable scaffolds used in drug discovery. Previously, our group developed mono and bis-arylation reactions of pyrimidinones including thiazolo[5,4-f]quinazolin-9-(8H)-ones, mainly conceived as potential kinase inhibitors [154–156]. During the last decade, diaryliodonium salts appeared as efficient electrophilic and non-toxic reagents for late-stage arylation [157,158]. In this context, a Cu-catalyzed C-H arylation process using diaryliodonium salts was investigated under microwave irradiation. This sustainable methodology, allowing the introduction of (het)aryl groups on the C2 atom of the thiazole moiety, was successfully extended to various fused pyrimidinones (Figure 37).

<figure><img src="image_41.png" /><figcaption>**Figure 37.** Cu-catalyzed C-H arylation process using diaryliodonium salts.</figcaption></figure>
4.38. *Sar Study of New Antikinetoplastid 3-Nitroimidazo[1,2-A]Pyridines* (P38)

Romain Paoli-Lombardo <fnref n="1" />, Nicolas Primas <fnref n="1" />, Sébastien Hutter <fnref n="2" />, Emilie Brenot <fnref n="3" />, Clotilde Boudot <fnref n="3" />, Caroline Castera-Ducros <fnref n="1" />, Sandra Bourgeade-Delmas <fnref n="4" />, Alix Sournia-Saquet <fnref n="5" />, Alexis Valentin <fnref n="4" />, Nadine Azas <fnref n="2" />, Bertrand Courtioux <fnref n="3" />, Pierre Verhaeghe <fnref n="5" />, Pascal Rathelot <fnref n="1" />, Patrice Vanelle <fnref n="1" />

Kinetoplastids are flagellated protozoans responsible for parasitic diseases in humans, including *Leishmania* spp. (leishmaniasis), *Trypanosoma brucei* (sleeping sickness), and *Trypanosoma cruzi* (Chagas disease). Nearly 20 million people are infected by one of these neglected tropical diseases (NTDs) per year, causing up to 50,000 deaths. Moreover, currently available treatments have major limitations. In this context, our laboratory previously described two 3-nitroimidazo[1,2-a]pyridine lead compounds selectively activated by the parasitic type 1 NTR: one active in vitro against Leishmania [159], and the other against Trypanosoma [160]. However, these compounds have low solubility and poor mouse microsomal stability. Among the probable metabolites, oxidized metabolites were synthetized and confirmed to be the result of the metabolism of the lead compounds. In order to improve microsomal stability, analogues with metabolic blockers were obtained. Finally, pharmacomodulation works at the C2 position were carried out, and new molecules of therapeutic interest were synthesized [161]. The synthesis pathway and biological results of these new compounds will be presented in the communication (Figure 38).

<figure><img src="image_40.png" /><figcaption>**Figure 38.** Lead compounds and new designed antikinetoplastid 3-nitroimidazo[1,2-a]pyridines.</figcaption></figure>

4.39. *New Nitric-Oxide-Releasing Indomethacin Derivatives: Synthesis and Biological Evaluation* (P39)

Lenuța Profire <fnref n="1" />, Alexandru Sava <fnref n="1" />, Frédéric Buron <fnref n="2" />, Sylvain Routier <fnref n="2" />

Nitric-oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) are a new class of anti-inflammatory drugs consisting of a traditional NSAID to which an NO-releasing moiety has been covalently attached by a spacer [162,163]. NO is an endogenous short-lived free radical, produced in mammalian cells through nitric-oxide-synthase-mediated conversion of L-arginine to L-citruline [164]. It is known that NO has a key role

<footnote n="1">¹ Aix Marseille Univ, CNRS, ICR UMR 7273, PCR, 13385 Marseille, France</footnote>

<footnote n="2">² Aix Marseille Univ, IHU Méditerranée Infection, UMR VITROME, 13005 Marseille, France</footnote>

<footnote n="3">³ Université de Limoges, UMR Inserm 1094, NET, 87025 Limoges, France</footnote>

<footnote n="4">⁴ Université Paul Sabatier, UMR 152 PharmaDev, 31062 Toulouse, France</footnote>

<footnote n="5">5 Université Paul Sabatier, CNRS UPR 8241, LCC, 31077 Toulouse, France; romain.paoli-lombardo@etu.univ-amu.fr</footnote>

<footnote n="1">¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy of Iași, 16 University Street, Iasi, Romania</footnote>

<footnote n="2">² Institut de Chimie Organique et Analytique ICOA, CNRS UMR 7311, Université d'Orléans, Orléans, France; lenuta.profire@umfiasi.ro</footnote>
4.38. *Sar Study of New Antikinetoplastid 3-Nitroimidazo[1,2-A]Pyridines* (P38)

Romain Paoli-Lombardo <fnref n="1" />, Nicolas Primas <fnref n="1" />, Sébastien Hutter <fnref n="2" />, Emilie Brenot <fnref n="3" />, Clotilde Boudot <fnref n="3" />, Caroline Castera-Ducros <fnref n="1" />, Sandra Bourgeade-Delmas <fnref n="4" />, Alix Sournia-Saquet <fnref n="5" />, Alexis Valentin <fnref n="4" />, Nadine Azas <fnref n="2" />, Bertrand Courtioux <fnref n="3" />, Pierre Verhaeghe <fnref n="5" />, Pascal Rathelot <fnref n="1" />, Patrice Vanelle <fnref n="1" />

Kinetoplastids are flagellated protozoans responsible for parasitic diseases in humans, including *Leishmania* spp. (leishmaniasis), *Trypanosoma brucei* (sleeping sickness), and *Trypanosoma cruzi* (Chagas disease). Nearly 20 million people are infected by one of these neglected tropical diseases (NTDs) per year, causing up to 50,000 deaths. Moreover, currently available treatments have major limitations. In this context, our laboratory previously described two 3-nitroimidazo[1,2-a]pyridine lead compounds selectively activated by the parasitic type 1 NTR: one active in vitro against Leishmania [159], and the other against Trypanosoma [160]. However, these compounds have low solubility and poor mouse microsomal stability. Among the probable metabolites, oxidized metabolites were synthetized and confirmed to be the result of the metabolism of the lead compounds. In order to improve microsomal stability, analogues with metabolic blockers were obtained. Finally, pharmacomodulation works at the C2 position were carried out, and new molecules of therapeutic interest were synthesized [161]. The synthesis pathway and biological results of these new compounds will be presented in the communication (Figure 38).

<figure><img src="image_42.png" /><figcaption>**Figure 38.** Lead compounds and new designed antikinetoplastid 3-nitroimidazo[1,2-a]pyridines.</figcaption></figure>

4.39. *New Nitric-Oxide-Releasing Indomethacin Derivatives: Synthesis and Biological Evaluation* (P39)

Lenuța Profire <fnref n="1" />, Alexandru Sava <fnref n="1" />, Frédéric Buron <fnref n="2" />, Sylvain Routier <fnref n="2" />

Nitric-oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) are a new class of anti-inflammatory drugs consisting of a traditional NSAID to which an NO-releasing moiety has been covalently attached by a spacer [162,163]. NO is an endogenous short-lived free radical, produced in mammalian cells through nitric-oxide-synthase-mediated conversion of L-arginine to L-citruline [164]. It is known that NO has a key role

<footnote n="1">¹ Aix Marseille Univ, CNRS, ICR UMR 7273, PCR, 13385 Marseille, France</footnote>

<footnote n="2">² Aix Marseille Univ, IHU Méditerranée Infection, UMR VITROME, 13005 Marseille, France</footnote>

<footnote n="3">³ Université de Limoges, UMR Inserm 1094, NET, 87025 Limoges, France</footnote>

<footnote n="4">⁴ Université Paul Sabatier, UMR 152 PharmaDev, 31062 Toulouse, France</footnote>

<footnote n="5">5 Université Paul Sabatier, CNRS UPR 8241, LCC, 31077 Toulouse, France; romain.paoli-lombardo@etu.univ-amu.fr</footnote>

<footnote n="1">¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy of Iași, 16 University Street, Iasi, Romania</footnote>

<footnote n="2">² Institut de Chimie Organique et Analytique ICOA, CNRS UMR 7311, Université d'Orléans, Orléans, France; lenuta.profire@umfiasi.ro</footnote>
in a wide variety of physiological and pathophysiological processes, such as inflammation, vasodilatation, platelet adhesion, thrombosis neurotransmission, neuronal communication, and wound healing [165,166]. In this study, we present the design and synthesis of new nitric-oxide-releasing indomethacin derivatives with 1,3-thiazolidine-4-one scaffold (NO-IND-TZDs), as a new safer and efficient multi-target strategy for inflammatory diseases. The chemical structure of synthesized derivatives was proven by NMR and mass spectroscopic analysis. The synthesized compounds were evaluated in terms of anti-inflammatory and antioxidant effects, using in vitro assays, as well as the nitric oxide (NO) release. The tested compounds showed improved radical-scavenging effects, the highest radical-scavenging effect being noted for 6n, which contains a 2-(4-nitro-phenoxy)ethyl nitrate moiety. For this compound, the highest NO release capacity was also noted, which means it could have reduced side effects on the GI level, such as irritation, bleeding, or ulceration. Moreover, the best predicted anti-inflammatory effect, measured as BSA denaturation, was showed by 6i, which contains a (2,6-dichloro-phenoxy)ethylnitrate moiety, which supports the good influence of chloro substituent for anti-inflammatory effects. The results of our study strongly support the potential effect of NO-IND-TZDs as a multi-target strategy, targeting the inflammation, oxidative stress, and NO release.

### 4.40. Fishing Potent Epac2 Inhibitors: An Interdisciplinary Approach (P40)

Urooj Qureshi<fnref n="1" />, Israr Khan<fnref n="2" />, Sajda Ashraf<fnref n="1" />, Abdul Hameed<fnref n="2" />, M. Hafizur Rahman<fnref n="2" />, Zaheer Ul-Haq<fnref n="1" />,<fnref n="2" />

¹ H.E.J. Research Institute of Chemistry, International Center of Chemical and Biological Sciences, University of Karachi, Karachi-75210, Pakistan

² Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi-75210, Pakistan; uroojquareshi@ymail.com; zaheer.qasmi@iccs.edu

Exchange protein activated by cAMP 2 (EPAC2) is a direct target of 3'-5'-cyclic adenosine monophosphate (cAMP), which is involved in cAMP-mediated signal transduction through activation of the Ras-like small GTPase Rap. EPAC signals play crucial roles in almost every disease related to dysfunctional signaling pathways. Therefore, EPAC represents an excellent drug target against various diseases as a signal transduction component. To date, very few EPAC inhibitors are available; however, there is still a lack of isoform-selective inhibitors due to off-target effects. Selective inhibition of one isoform leads to work on the allosteric site in EPAC2 that is distinct from the active site shared by EPAC variants [167,168]. Here, we present a site-directed approach, specifically targeting the EPAC2 isoform.

To explore the allosteric site, we applied multiple pharmacophore modeling, molecular docking, and molecular dynamics simulation techniques. Primarily, the commercially available databases NCI and Maybridge and an in-house database were screened against validated pharmacophore models. Molecules obtained were scrutinized by molecular docking to predict their binding affinities. In step-wise screening, four compounds were short-listed for stability dynamics to get deep insight into their binding mechanism. Simultaneously, inhibitory activities of these compounds were investigated to validate their effect on mice pancreatic islets. The results highlighted the efficiency of pharmacophores to access diverse chemical classes that can contribute to designing selective probes for EPAC2-associated pathologies.

### 4.41. New Mononuclear Gold(iii) Complexes—Study of the DNA/HSA/BSA-Binding Properties (P41)

Snežana Radisavljević<fnref n="1" />, Milica Međedović<fnref n="1" />, Ana Rilak<fnref n="2" />, Dušan Ćoćić<fnref n="1" />, Biljana Petrović<fnref n="1" />

<footnote n="1">¹ University of Kragujevac, Faculty of Science, R. Domanovića 12, Kragujevac</footnote>

<footnote n="2">² University of Kragujevac, Institute for Information Technologies, J. Cvijica bb, Kragujevac; snezana.radisavljevic@pmf.kg.ac.rs</footnote>
in a wide variety of physiological and pathophysiological processes, such as inflammation, vasodilatation, platelet adhesion, thrombosis neurotransmission, neuronal communication, and wound healing [165,166]. In this study, we present the design and synthesis of new nitric-oxide-releasing indomethacin derivatives with 1,3-thiazolidine-4-one scaffold (NO-IND-TZDs), as a new safer and efficient multi-target strategy for inflammatory diseases. The chemical structure of synthesized derivatives was proven by NMR and mass spectroscopic analysis. The synthesized compounds were evaluated in terms of anti-inflammatory and antioxidant effects, using in vitro assays, as well as the nitric oxide (NO) release. The tested compounds showed improved radical-scavenging effects, the highest radical-scavenging effect being noted for 6n, which contains a 2-(4-nitro-phenoxy)ethyl nitrate moiety. For this compound, the highest NO release capacity was also noted, which means it could have reduced side effects on the GI level, such as irritation, bleeding, or ulceration. Moreover, the best predicted anti-inflammatory effect, measured as BSA denaturation, was showed by 6i, which contains a (2,6-dichloro-phenoxy)ethylnitrate moiety, which supports the good influence of chloro substituent for anti-inflammatory effects. The results of our study strongly support the potential effect of NO-IND-TZDs as a multi-target strategy, targeting the inflammation, oxidative stress, and NO release.

### 4.40. Fishing Potent Epac2 Inhibitors: An Interdisciplinary Approach (P40)

Urooj Qureshi<fnref n="1" />, Israr Khan<fnref n="2" />, Sajda Ashraf<fnref n="1" />, Abdul Hameed<fnref n="2" />, M. Hafizur Rahman<fnref n="2" />, Zaheer Ul-Haq<fnref n="1" />,<fnref n="2" />

¹ H.E.J. Research Institute of Chemistry, International Center of Chemical and Biological Sciences, University of Karachi, Karachi-75210, Pakistan

² Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi-75210, Pakistan; uroojquareshi@ymail.com; zaheer.qasmi@iccs.edu

Exchange protein activated by cAMP 2 (EPAC2) is a direct target of 3'-5'-cyclic adenosine monophosphate (cAMP), which is involved in cAMP-mediated signal transduction through activation of the Ras-like small GTPase Rap. EPAC signals play crucial roles in almost every disease related to dysfunctional signaling pathways. Therefore, EPAC represents an excellent drug target against various diseases as a signal transduction component. To date, very few EPAC inhibitors are available; however, there is still a lack of isoform-selective inhibitors due to off-target effects. Selective inhibition of one isoform leads to work on the allosteric site in EPAC2 that is distinct from the active site shared by EPAC variants [167,168]. Here, we present a site-directed approach, specifically targeting the EPAC2 isoform.

To explore the allosteric site, we applied multiple pharmacophore modeling, molecular docking, and molecular dynamics simulation techniques. Primarily, the commercially available databases NCI and Maybridge and an in-house database were screened against validated pharmacophore models. Molecules obtained were scrutinized by molecular docking to predict their binding affinities. In step-wise screening, four compounds were short-listed for stability dynamics to get deep insight into their binding mechanism. Simultaneously, inhibitory activities of these compounds were investigated to validate their effect on mice pancreatic islets. The results highlighted the efficiency of pharmacophores to access diverse chemical classes that can contribute to designing selective probes for EPAC2-associated pathologies.

### 4.41. New Mononuclear Gold(Iii) Complexes—Study of the DNA/HSA/BSA-Binding Properties (P41)

Snežana Radisavljević<fnref n="1" />, Milica Međedović<fnref n="1" />, Ana Rilak<fnref n="2" />, Dušan Ćoćić<fnref n="1" />, Biljana Petrović<fnref n="1" />

<footnote n="1">¹ University of Kragujevac, Faculty of Science, R. Domanovića 12, Kragujevac</footnote>

<footnote n="2">² University of Kragujevac, Institute for Information Technologies, J. Cvijica bb, Kragujevac; snezana.radisavljevic@pmf.kg.ac.rs</footnote>
Considering that cancer is one of the major human problems, the discovery of metal-
based drugs which can be used as anticancer agents represents the most important field
of investigation [169]. It is already known that platinum(II) complexes have shown great
impact on the treatment of different cancers, but scientists continue to make efforts to
develop new drugs. The most promising new metal-based drugs are gold(III) complexes,
due to their similarities with platinum(II) complexes. The main problem for usage of
gold(III) complexes is their reduction to gold(I) or gold(0), but this can usually be solved
with the right choice of ligands [170]. DNA is the main target for many metal-based
antitumor drugs, and interactions with DNA have a major role in the development of new
drugs. In addition, serum proteins are important for the regulation of osmotic pressure as
well as blood pH. Consequently, interaction between human serum albumin (HSA)/bovine
serum albumin (BSA) and drugs have a big impact on the development of potential drugs.

New gold(III) complexes with the general formula [Au(N-N)Cl₂]⁺ for complexes **1–3** (where N-N is **L1**, **L2** or **L3**), and [Au(N-N)₂]³⁺ for complexes **4–5** (where N-N is **L1** or **L2**) were synthesized (Figure 39). The interactions of these complexes and CT-DNA were evaluated by different methods: UV–Vis spectroscopy, fluorescence spectrometry, and viscosity measurements, while interactions with HSA/BSA were investigated by fluorescence spectroscopy. The binding of all complexes with CT-DNA was confirmed with the high values of intrinsic binding constant (Kb), while further examinations confirmed that the mode of binding is groove binding. The performed experiments have shown a good ability of complexes for binding to serum albumins, especially BSA, with the value of binding constants in the optimal range.

<figure><img src="image_41.png" /><figcaption>**Figure 39.** Structures of ligands.</figcaption></figure>

4.42. *Aralkylpyrimidinetriones as Growth Inhibitors of Clostridioides Difficile* (P42)

Bassant Rateb, Tony Worthington, William Fraser

College of Health and Life Sciences, Aston University, Aston Triangle, B4 7ET Birm-
ingham, UK; Bassant Rateb

There is a pressing clinical need for effective new antimicrobial agents against *Clostridioides difficile*, one of the UK's leading nosocomial healthcare-associated infection pathogens. Strains of *C. difficile* have become less sensitive to the current frontline therapies metronidazole and vancomycin, with growing resistance to many other antibiotics [171]. We have prepared aralkylpyrimidinetriones (APTs), some of which are active against *C. difficile* but inactive against *Escherichia coli* and *Staphylococcus aureus*. Selective targeting of *C. difficile* would provide a significant advantage over current antibiotic treatments that also destroy various gut-colonizing bacteria and exacerbate life-threatening *C. difficile*-associated diarrhea.

Dihydroorotate dehydrogenase (DHODase) catalyzes the reversible and rate-determining fourth step of de novo pyrimidine biosynthesis. Arylidene barbiturates are known to inhibit purified DHODase from the organism *Clostridioides oroticum*, with the rate of inhibition being strongly dependent upon the electronic properties of the aryl substitutents [172,173]. Indiscriminate reactivity towards nucleophiles, poor aqueous solubility, and the risk of unwanted anxiolytic, hypnotic, and sedative properties associated with uncharged CNS-active barbiturate drugs render arylidene barbiturates poor candidates as potential anti-infective agents. We considered APTs to be surrogate substrates with potential as novel pro-drug inhibitors of DHODase that exploit the enzyme's ability to create C=C bonds [174]. Once bound at the DHODase active site, the benzylic C-C bond in the APT prodrug may conceivably be oxidized to give an exocyclic C=C bond, generating the reactive arylidene at the
Considering that cancer is one of the major human problems, the discovery of metal-
based drugs which can be used as anticancer agents represents the most important field
of investigation [169]. It is already known that platinum(II) complexes have shown great
impact on the treatment of different cancers, but scientists continue to make efforts to
develop new drugs. The most promising new metal-based drugs are gold(III) complexes,
due to their similarities with platinum(II) complexes. The main problem for usage of
gold(III) complexes is their reduction to gold(I) or gold(0), but this can usually be solved
with the right choice of ligands [170]. DNA is the main target for many metal-based
antitumor drugs, and interactions with DNA have a major role in the development of new
drugs. In addition, serum proteins are important for the regulation of osmotic pressure as
well as blood pH. Consequently, interaction between human serum albumin (HSA)/bovine
serum albumin (BSA) and drugs have a big impact on the development of potential drugs.

New gold(III) complexes with the general formula [Au(N-N)Cl₂]⁺ for complexes **1–3** (where N-N is **L1**, **L2** or **L3**), and [Au(N-N)₂]³⁺ for complexes **4–5** (where N-N is **L1** or **L2**) were synthesized (Figure 39). The interactions of these complexes and CT-DNA were evaluated by different methods: UV–Vis spectroscopy, fluorescence spectrometry, and viscosity measurements, while interactions with HSA/BSA were investigated by fluorescence spectroscopy. The binding of all complexes with CT-DNA was confirmed with the high values of intrinsic binding constant (Kb), while further examinations confirmed that the mode of binding is groove binding. The performed experiments have shown a good ability of complexes for binding to serum albumins, especially BSA, with the value of binding constants in the optimal range.

<figure><img src="image_43.png" /><figcaption>**Figure 39.** Structures of ligands.</figcaption></figure>

4.42. *Aralkylpyrimidinetriones as Growth Inhibitors of Clostridioides Difficile* (P42)

Bassant Rateb, Tony Worthington, William Fraser

College of Health and Life Sciences, Aston University, Aston Triangle, B4 7ET Birm-
ingham, UK; Bassant Rateb

There is a pressing clinical need for effective new antimicrobial agents against *Clostridioides difficile*, one of the UK's leading nosocomial healthcare-associated infection pathogens. Strains of *C. difficile* have become less sensitive to the current frontline therapies metronidazole and vancomycin, with growing resistance to many other antibiotics [171]. We have prepared aralkylpyrimidinetriones (APTs), some of which are active against *C. difficile* but inactive against *Escherichia coli* and *Staphylococcus aureus*. Selective targeting of *C. difficile* would provide a significant advantage over current antibiotic treatments that also destroy various gut-colonizing bacteria and exacerbate life-threatening *C. difficile*-associated diarrhea.

Dihydroorotate dehydrogenase (DHODase) catalyzes the reversible and rate-determining fourth step of de novo pyrimidine biosynthesis. Arylidene barbiturates are known to inhibit purified DHODase from the organism *Clostridioides oroticum*, with the rate of inhibition being strongly dependent upon the electronic properties of the aryl substitutents [172,173]. Indiscriminate reactivity towards nucleophiles, poor aqueous solubility, and the risk of unwanted anxiolytic, hypnotic, and sedative properties associated with uncharged CNS-active barbiturate drugs render arylidene barbiturates poor candidates as potential anti-infective agents. We considered APTs to be surrogate substrates with potential as novel pro-drug inhibitors of DHODase that exploit the enzyme's ability to create C=C bonds [174]. Once bound at the DHODase active site, the benzylic C-C bond in the APT prodrug may conceivably be oxidized to give an exocyclic C=C bond, generating the reactive arylidene at the
DHODase active site, to which a proximal nucleophile can attach followed by deactivating protonation, leading to irreversible inhibition of the enzyme. Better aqueous solubility and closer resemblance to the enzyme's natural substrate is predicted for the APT derivatives were ionization to generally occur at C5 (pKₐ = 3.9) [175] under physiological conditions.

We demonstrated success in the use of uncatalyzed Knoevenagel condensation between barbituric acid and various 2-aryl-substituted acrylaldehydes in ethanol (1 h, reflux) to give moderate to good yields of diene derivatives of barbituric acid, from which APT analogues were readily prepared by reduction using sodium borohydride or palladium on charcoal. We achieved regiospecific reduction of the exocyclic double bond using sodium borohydride, whereas reduction of both double bonds to give a saturated propyl linkage resulted from use of palladium on charcoal (1 h, sonication, 2-3 atm). Representative compounds in the arylidene and APT series were evaluated and shown to have C. difficile growth inhibitory properties, but with reduced or no activity against E. coli and S. aureus.

### 4.43. 1,3- Dipolar Cycloaddition of Diazo Compounds to Activated Enynes (P43)

Sergey A. Sokov ¹,², Simon S. Zlotskii ¹, Ivan S. Odin ², Alexander A. Golovanov ²

¹ Ufa State Petroleum Technological University, Ufa, Russia

² Togliatti State University, Togliatti, Russia; s.a.sokov.tltsu@gmail.com

The reactions of 1,3-dipolar cycloaddition of diazo compounds to unsaturated compounds, such as enynones, is of great interest. As shown earlier, such interaction in the presence of catalysts can lead to the formation of furan derivatives [176]. The interaction of activated enyne structures is poorly studied. We have studied the 1,3-dipolar cycloaddition of diazomethane to the enyne derivatives of Meldrum acid **1** and dimethylmalonate **2** (Figure 40).

<figure><img src="image_42.png" /><figcaption>**Figure 40.** Reaction of enynes with diazomethane solution.</figcaption></figure>

It was shown that compounds **1** and **2**, due to the polarization effect of CO groups, easily react with diazo compounds, specifically at double C=C bonds. In the case of the Meldrum acid derivative **1**, the reaction with an ether solution of diazomethane gives the cyclopropane derivative **3** with a yield of 80%. The reaction of compounds **2** with an ether solution of diazomethane proceeds with the formation of pyrazolines **4** and **5** in high yields (>95%). Structures **5** are minor isomers, the content of which does not exceed 10%. It should be noted that for products **4** and **5**, it is not possible to register high-resolution mass spectra, since under electrospray conditions, they decompose with the evolution of nitrogen; in this case, a peak corresponding to the molecular ion of cyclopropane is recorded. Nevertheless, the composition of these products is reliably confirmed by quantitative elemental microanalysis for carbon and hydrogen. The structure was confirmed by NMR spectroscopy.

Thus, we have shown that electron-deficient 1,3-enynes containing in the first position one or two electron-withdrawing groups react with diazomethane on a double carbon-carbon bond in the absence of a catalyst. The data obtained can further serve as the basis for the development of methods for the synthesis of polyfunctional compounds containing structural elements of nitrogen-containing heterocycles and cyclopropane.
DHODase active site, to which a proximal nucleophile can attach followed by deactivating protonation, leading to irreversible inhibition of the enzyme. Better aqueous solubility and closer resemblance to the enzyme's natural substrate is predicted for the APT derivatives were ionization to generally occur at C5 (pKₐ = 3.9) [175] under physiological conditions.

We demonstrated success in the use of uncatalyzed Knoevenagel condensation between barbituric acid and various 2-aryl-substituted acrylaldehydes in ethanol (1 h, reflux) to give moderate to good yields of diene derivatives of barbituric acid, from which APT analogues were readily prepared by reduction using sodium borohydride or palladium on charcoal. We achieved regiospecific reduction of the exocyclic double bond using sodium borohydride, whereas reduction of both double bonds to give a saturated propyl linkage resulted from use of palladium on charcoal (1 h, sonication, 2-3 atm). Representative compounds in the arylidene and APT series were evaluated and shown to have C. difficile growth inhibitory properties, but with reduced or no activity against E. coli and S. aureus.

### 4.43. 1,3- Dipolar Cycloaddition of Diazo Compounds to Activated Enynes (P43)

Sergey A. Sokov ¹,², Simon S. Zlotskii ¹, Ivan S. Odin ², Alexander A. Golovanov ²

1. Ufa State Petroleum Technological University, Ufa, Russia

2. Togliatti State University, Togliatti, Russia; s.a.sokov.tltsu@gmail.com

The reactions of 1,3-dipolar cycloaddition of diazo compounds to unsaturated compounds, such as enynones, is of great interest. As shown earlier, such interaction in the presence of catalysts can lead to the formation of furan derivatives [176]. The interaction of activated enyne structures is poorly studied. We have studied the 1,3-dipolar cycloaddition of diazomethane to the enyne derivatives of Meldrum acid **1** and dimethylmalonate **2** (Figure 40).

<figure><img src="image_44.png" /><figcaption>**Figure 40.** Reaction of enynes with diazomethane solution.</figcaption></figure>

It was shown that compounds **1** and **2**, due to the polarization effect of CO groups, easily react with diazo compounds, specifically at double C=C bonds. In the case of the Meldrum acid derivative **1**, the reaction with an ether solution of diazomethane gives the cyclopropane derivative **3** with a yield of 80%. The reaction of compounds **2** with an ether solution of diazomethane proceeds with the formation of pyrazolines **4** and **5** in high yields (>95%). Structures **5** are minor isomers, the content of which does not exceed 10%. It should be noted that for products **4** and **5**, it is not possible to register high-resolution mass spectra, since under electrospray conditions, they decompose with the evolution of nitrogen; in this case, a peak corresponding to the molecular ion of cyclopropane is recorded. Nevertheless, the composition of these products is reliably confirmed by quantitative elemental microanalysis for carbon and hydrogen. The structure was confirmed by NMR spectroscopy.

Thus, we have shown that electron-deficient 1,3-enynes containing in the first position one or two electron-withdrawing groups react with diazomethane on a double carbon-carbon bond in the absence of a catalyst. The data obtained can further serve as the basis for the development of methods for the synthesis of polyfunctional compounds containing structural elements of nitrogen-containing heterocycles and cyclopropane.
### 4.44. Torquoselective Nazarov Cyclization Mediated by a Chiral Sulfoxide (P44)

Xavier J. Salom-Roig, Erwann Grenet, Jean Martinez

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, ENSCM, Place Eugène Bataillon, 34095 Montpellier, France; xavier.salom-roig@umontpellier.fr

We report here a Nazarov cyclization reaction of activated dienones that contain an aromatic moiety as an electron-donating group and a chiral sulfoxide that act as both an electron-withdrawing group and a chiral auxiliary. The sulfinyl group directed the torqueselectivity and AlCl₃ was used as a promoter. Only the *trans* stereoisomers were observed. Substrates that contained activated aromatic moieties, including phenyl and aromatic heterocycles, led to the desired cyclopentenones. The potential use of this method was highlighted in the first enantioselective synthesis of the two anticancer agents **1** and **2** (Figure 41) [177,178].

<figure><img src="image_43.png" /><figcaption>**Figure 41.** Torquoselective Nazarov cyclization and anticancer agents 1 and 2.</figcaption></figure>

### 4.45. Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 (P45)

Sonam Roy ¹, Amarjyoti Das Mahapatra ², Taj Mohammad ¹, Preeti Gupta ¹, Mohamed F. Alajmi ³, Afzal Hussain ³, Md. Tabish Rehman ³, Bhaskar Datta ², Md. Imtaiyaz Hassan ¹

¹ Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, 110025 New Delhi, India

² Department of Chemistry, Indian Institute of Technology, Palaj, Gandhinagar, 382355 Gujarat, India

³ Department of Pharmacognosy, College of Pharmacy, King Saud University, 11451 Riyadh, Saudi Arabia; roysonam12@gmail.com

SphK1 promotes fundamental cellular processes including cell survival, proliferation, migration, and immune function. SphK1 inhibition is considered as an attractive strategy for cancer therapeutics [179,180]. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, the selectivity and potency of first-generation inhibitors are a great challenge [181,182]. In search of effective SphK1 inhibitors, a set of 11 novel small molecules were designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups and screened for their inhibitory activity against SphK1. Fluorescence binding studies, isothermal titration calorimetry (ITC), enzyme inhibition assay, and molecular docking were performed to gain insights into the binding and inhibition mechanism (Figure 42).

Compounds **1**, **5**, and **7** bound to the SphK1 with a higher affinity in the sub-micromolar range and significantly inhibited its activity with IC₅₀ values in the micromolar range. Molecular docking studies revealed that these compounds fit well into the sphingosine-binding pocket of SphK1 and formed a significant number of hydrogen bonds and van der Waals interactions. While urea and sulfonylurea derivatives have been reported as
4.44. Torquoselective Nazarov Cyclization Mediated by a Chiral Sulfoxide (P44)

Xavier J. Salom-Roig, Erwann Grenet, Jean Martinez

Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Mont-
pellier, CNRS, ENSCM, Place Eugène Bataillon, 34095 Montpellier, France; xavier.salom-
roig@umontpellier.fr

We report here a Nazarov cyclization reaction of activated dienones that contain an aromatic moiety as an electron-donating group and a chiral sulfoxide that act as both an electron-withdrawing group and a chiral auxiliary. The sulfinyl group directed the torqueselectivity and AlCl₃ was used as a promoter. Only the *trans* stereoisomers were observed. Substrates that contained activated aromatic moieties, including phenyl and aromatic heterocycles, led to the desired cyclopentenones. The potential use of this method was highlighted in the first enantioselective synthesis of the two anticancer agents **1** and **2** (Figure 41) [177,178].

<figure><img src="image_45.png" /><figcaption>**Figure 41.** Torquoselective Nazarov cyclization and anticancer agents 1 and 2.</figcaption></figure>

4.45. Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1 (P45)

Sonam Roy ¹, Amarjyoti Das Mahapatra ², Taj Mohammad ¹, Preeti Gupta ¹, Mohamed F. Alajmi ³, Afzal Hussain ³, Md. Tabish Rehman ³, Bhaskar Datta ², Md. Imtaiyaz Hassan ¹

¹ Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, 110025 New Delhi, India

² Department of Chemistry, Indian Institute of Technology, Palaj, Gandhinagar, 382355 Gujarat, India

³ Department of Pharmacognosy, College of Pharmacy, King Saud University, 11451 Riyadh, Saudi Arabia; roysonam12@gmail.com

SphK1 promotes fundamental cellular processes including cell survival, proliferation, migration, and immune function. SphK1 inhibition is considered as an attractive strategy for cancer therapeutics [179,180]. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, the selectivity and potency of first-generation inhibitors are a great challenge [181,182]. In search of effective SphK1 inhibitors, a set of 11 novel small molecules were designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups and screened for their inhibitory activity against SphK1. Fluorescence binding studies, isothermal titration calorimetry (ITC), enzyme inhibition assay, and molecular docking were performed to gain insights into the binding and inhibition mechanism (Figure 42).

Compounds 1, 5, and 7 bound to the SphK1 with a higher affinity in the sub-micromolar range and significantly inhibited its activity with IC₅₀ values in the micromolar range. Molecular docking studies revealed that these compounds fit well into the sphingosine-binding pocket of SphK1 and formed a significant number of hydrogen bonds and van der Waals interactions. While urea and sulfonylurea derivatives have been reported as
SphK1 inhibitors, this is the first report of a sulfonyltriurea providing the scope of SphK1 inhibition. Henceforth, compounds **1**, **5**, and **7** might be exploited as novel scaffolds for the generation of potent and selective SphK1 inhibitors that could be implicated in cancer therapeutics after the required in vivo validation.

<figure><img src="image_44.png" /><figcaption>**Figure 42.** Structural representation of the binding pattern of Compounds **1**, **5**, and **7** along with PF-543 in the substrate-binding site cavity of SphK1. (A) Cartoon representation of SphK1 showing ligands bound to the active site cavity. (B) Interaction of Compounds **1**, **5**, and **7** with the SphK1 residues. (C) Surface model highlighting the active site pocket of SphK1.</figcaption></figure>

### 4.46. Development of Chromone Carboxamides as Quorum-Sensing Inhibitors for the Treatment of Cf-Related Multi-Species Biofilms (P46)

Jeanne Trognon¹, Maya Rima¹, Gonzalo Vera¹, Jean-Luc Stigliani², Barbora Lajoie¹, Salomé El Hage¹, Christine Roques¹, Fatima El Garah¹

¹ Laboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, Toulouse, France

² Laboratoire de Chimie de Coordination, CNRS, INPT, UPS, Toulouse, France; jeanne.trognon@univ-tlse3.fr

Cystic fibrosis (CF) patients often suffer from chronic pulmonary infections caused by bacterial strains, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia, known to grow in patients' lungs as biofilms, a more virulent and antibiotic-resistant bacterial lifestyle. A major mechanism behind biofilm formation is quorum sensing (QS), a communication system where bacterial cells produce, detect, and respond to auto-inducers, such as acyl homoserine lactones (AHLs) and alkylquinolones (AQs) in Gram-negative bacteria [183,184]. QS inhibition has been proven to be a promising strategy to control biofilms. Our group has identified an AHL analog capable of inhibiting the formation of P. aeruginosa biofilm in vitro [185,186] and reduce its virulence in vivo [187]. QS inhibition within multi-species biofilms has been less studied so far.

In view of this, we investigated the ability of the chromone scaffold to serve for the design of structural analogs and potential inhibitors of the PQS auto-inducer. We used molecular docking to predict their binding affinity with the active site of the PqsR receptor protein. Chromone carboxamides with the best binding affinity for PqsR were synthesized via straightforward routes and in goods yields. Their ability to inhibit the formation of biofilms was first evaluated on P. aeruginosa PAO1. Several compounds showed a promising anti-biofilm activity, with a significant decrease of the total adherent biomass. In parallel, we also developed a 3-species biofilm inhibition assay for the evaluation of active compounds selected on PAO1. The design, synthesis, biological evaluation on PAO1, and setup of the three-species anti-biofilm assay will be presented. Overall, results showed chromones carboxamides are a promising series for the selection of a lead compound for further development in view of improving the prevention and treatment of CF-related multi-species infections.

### 4.47. Removing Cancer's Immortality: Targeting Telomerase (P47)

Suzanne van Wier, Mark Searcey, Andrew Beekman
SphK1 inhibitors, this is the first report of a sulfonyltriurea providing the scope of SphK1 inhibition. Henceforth, compounds **1**, **5**, and **7** might be exploited as novel scaffolds for the generation of potent and selective SphK1 inhibitors that could be implicated in cancer therapeutics after the required in vivo validation.

<figure><img src="image_46.png" /><figcaption>**Figure 42.** Structural representation of the binding pattern of Compounds **1**, **5**, and **7** along with PF-543 in the substrate-binding site cavity of SphK1. (A) Cartoon representation of SphK1 showing ligands bound to the active site cavity. (B) Interaction of Compounds **1**, **5**, and **7** with the SphK1 residues. (C) Surface model highlighting the active site pocket of SphK1.</figcaption></figure>

### 4.46. Development of Chromone Carboxamides as Quorum-Sensing Inhibitors for the Treatment of Cf-Related Multi-Species Biofilms (P46)

Jeanne Trognon¹, Maya Rima¹, Gonzalo Vera¹, Jean-Luc Stigliani², Barbora Lajoie¹, Salomé El Hage¹, Christine Roques¹, Fatima El Garah¹

¹ Laboratoire de Génie Chimique, Université de Toulouse, CNRS, INPT, UPS, Toulouse, France

² Laboratoire de Chimie de Coordination, CNRS, INPT, UPS, Toulouse, France; jeanne.trognon@univ-tlse3.fr

Cystic fibrosis (CF) patients often suffer from chronic pulmonary infections caused by bacterial strains, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia, known to grow in patients' lungs as biofilms, a more virulent and antibiotic-resistant bacterial lifestyle. A major mechanism behind biofilm formation is quorum sensing (QS), a communication system where bacterial cells produce, detect, and respond to auto-inducers, such as acyl homoserine lactones (AHLs) and alkylquinolones (AQs) in Gram-negative bacteria [183,184]. QS inhibition has been proven to be a promising strategy to control biofilms. Our group has identified an AHL analog capable of inhibiting the formation of P. aeruginosa biofilm in vitro [185,186] and reduce its virulence in vivo [187]. QS inhibition within multi-species biofilms has been less studied so far.

In view of this, we investigated the ability of the chromone scaffold to serve for the design of structural analogs and potential inhibitors of the PQS auto-inducer. We used molecular docking to predict their binding affinity with the active site of the PqsR receptor protein. Chromone carboxamides with the best binding affinity for PqsR were synthesized via straightforward routes and in goods yields. Their ability to inhibit the formation of biofilms was first evaluated on P. aeruginosa PAO1. Several compounds showed a promising anti-biofilm activity, with a significant decrease of the total adherent biomass. In parallel, we also developed a 3-species biofilm inhibition assay for the evaluation of active compounds selected on PAO1. The design, synthesis, biological evaluation on PAO1, and setup of the three-species anti-biofilm assay will be presented. Overall, results showed chromones carboxamides are a promising series for the selection of a lead compound for further development in view of improving the prevention and treatment of CF-related multi-species infections.

### 4.47. Removing Cancer's Immortality: Targeting Telomerase (P47)

Suzanne van Wier, Mark Searcey, Andrew Beekman
School of pharmacy, University of East Anglia, Norwich research park, NR4 7TJ, Norwich, Norfolk, UK; s.van-wier@uea.ac.uk

One of the hallmarks of cancers is their ability to replicate limitlessly, making them immortal. In 80–90% of cancer cells this is due to the reactivation of telomerase, a protein complex which elongates telomeres at the end of chromosomes, protecting the chromosomes from degradation and preventing cell senescence.

The Cryo-EM structure of telomerase published in 2018 provided an opportunity to identify new ways to target telomerase [188]. In patients with dyskeratosis congenita, a disease characterized by shortened telomeres, the structure showed that genetic mutations are transcribed to the dyskerin-dyskerin protein-protein interaction (PPI) in telomerase. In this project, we aim to target this PPI, inhibiting the telomerase activity of cancer cells and thus removing cancer's immortality.

We will describe the design and synthesis of a peptide derived from the dyskerin sequence at this PPI and an alanine scan of this peptide to identify the amino acids most important for binding. These peptides will be assessed for their binding affinity towards dyskerin, their α-helicity and their effect on telomerase activity.

When compared to small-molecule drugs, peptide therapeutics can have drawbacks, such as their limited stability and cell permeability. Therefore, peptide-directed binding will be used to go from peptide to small molecule inhibitor by computationally identifying fragments able to replace parts of the peptide. This method has previously been applied successfully to quickly identify hit compounds for PPIs whilst minimizing the organic synthesis and biological screening needed [189].

### 4.48. An Artemisinin-Derivative-(Nhc) Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of Nrf2 Transcriptional Activity (P48)

Xing Wang<fnref n="1" />, Catherine Hemmert<fnref n="1" />, Olivier Cuvillier<fnref n="2" />, Heinz Gornitzka<fnref n="1" />

A family of hybrid complexes combining two biologically active motifs, an artemisinin derivative and a cationic bis(NHC)-gold(I) unit, has been synthesized. One of these complexes, **2a**, has been analyzed by single-crystal X-ray diffraction (Figure 43). **2a** shows strong anticancer activities on a large panel of human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI50 values in the nm range, together with a high selectivity. An original and distinctive mechanism of action, that is, through inhibition of the redox antioxidant NRF2 transcription factor (strongly associated with aggressiveness and resistance to cancer therapies), has been evidenced. **2a** could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. **2a** also inhibited NF-κB and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) compounds represent a new class of organometallic hybrid molecules that may yield new therapeutic agents [190].

<figure><img src="image_45.png" /><figcaption>**Figure 43.** Structure of the cationic part of the complexe **2a** in the solid state. One bisNHC-gold unit looking along the C-Au-C axis on the left and dimeric arrangement on the right.</figcaption></figure>

<footnote n="1">¹ LCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, France</footnote>

<footnote n="2">² Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France; xing.wang@lcc-toulouse.fr</footnote>
School of pharmacy, University of East Anglia, Norwich research park, NR4 7TJ, Norwich, Norfolk, UK; s.van-wier@uea.ac.uk

One of the hallmarks of cancers is their ability to replicate limitlessly, making them immortal. In 80–90% of cancer cells this is due to the reactivation of telomerase, a protein complex which elongates telomeres at the end of chromosomes, protecting the chromosomes from degradation and preventing cell senescence.

The Cryo-EM structure of telomerase published in 2018 provided an opportunity to identify new ways to target telomerase [188]. In patients with dyskeratosis congenita, a disease characterized by shortened telomeres, the structure showed that genetic mutations are transcribed to the dyskerin-dyskerin protein-protein interaction (PPI) in telomerase. In this project, we aim to target this PPI, inhibiting the telomerase activity of cancer cells and thus removing cancer's immortality.

We will describe the design and synthesis of a peptide derived from the dyskerin sequence at this PPI and an alanine scan of this peptide to identify the amino acids most important for binding. These peptides will be assessed for their binding affinity towards dyskerin, their α-helicity and their effect on telomerase activity.

When compared to small-molecule drugs, peptide therapeutics can have drawbacks, such as their limited stability and cell permeability. Therefore, peptide-directed binding will be used to go from peptide to small molecule inhibitor by computationally identifying fragments able to replace parts of the peptide. This method has previously been applied successfully to quickly identify hit compounds for PPIs whilst minimizing the organic synthesis and biological screening needed [189].

### 4.48. An Artemisinin-Derivative-(Nhc) Gold(I) Hybrid with Enhanced Cytotoxicity through Inhibition of Nrf2 Transcriptional Activity (P48)

Xing Wang<fnref n="1" />, Catherine Hemmert<fnref n="1" />, Olivier Cuvillier<fnref n="2" />, Heinz Gornitzka<fnref n="1" />

A family of hybrid complexes combining two biologically active motifs, an artemisinin derivative and a cationic bis(NHC)-gold(I) unit, has been synthesized. One of these complexes, **2a**, has been analyzed by single-crystal X-ray diffraction (Figure 43). **2a** shows strong anticancer activities on a large panel of human cancer cell models (prostate, breast, lung, liver, bladder, bone, acute and chronic myeloid leukemias) with GI50 values in the nm range, together with a high selectivity. An original and distinctive mechanism of action, that is, through inhibition of the redox antioxidant NRF2 transcription factor (strongly associated with aggressiveness and resistance to cancer therapies), has been evidenced. **2a** could remarkably sensitize to sorafenib in HepG2 liver cells, in which dysregulated NRF2 signaling is linked to primary and acquired drug resistance. **2a** also inhibited NF-κB and HIF transcriptional activities, which are also associated with progression and resistance in cancer. Our findings provide evidence that hybrid (NHC)gold(I) compounds represent a new class of organometallic hybrid molecules that may yield new therapeutic agents [190].

<figure><img src="image_47.png" /><figcaption>**Figure 43.** Structure of the cationic part of the complexe **2a** in the solid state. One bisNHC-gold unit looking along the C-Au-C axis on the left and dimeric arrangement on the right.</figcaption></figure>

<footnote n="1">¹ LCC-CNRS, Université de Toulouse, CNRS, UPS, Toulouse, France</footnote>

<footnote n="2">² Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France; xing.wang@lcc-toulouse.fr</footnote>
4.49. *New Approaches to the Synthesis of Pyoverdine D* (P49)

Tianzhu Zhang ¹,², Albert Bolhuis ¹,², Ian M. Eggleston ¹,²

¹ Department of Pharmacy & Pharmacology, University of Bath, Bath, BA2 7AY, UK

² Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK; tz496@bath.ac.uk

Pseudomonas aeruginosa is a clinically opportunistic pathogen and a major threat to patients with compromised immune systems and cystic fibrosis. Iron is an essential nutrient for virtually all microbes, including P. aeruginosa, which acquires iron by the secretion of certain iron-chelating siderophores [191]. The most important of these siderophores is the cyclic peptide derivative pyoverdine D. As an endogenous siderophore, pyoverdine D is of considerable interest as it could provide a starting point for new ways to deliver toxic materials to P. aeruginosa, for instance by linking with antibiotics [192]. This requires an efficient and flexible synthetic route to be developed for this natural product. We will present our studies towards an improved modular synthesis of pyoverdine D, with a focus on the preparation of three important components—the novel amino acid, formylhydroxyornithine, which occurs twice in the pyoverdine D structure; the solid phase synthesis of the cyclic peptide unit; and the synthesis of the tricyclic “chromophore” unit (Figure 44).

<figure><img src="image_46.png" /><figcaption>**Figure 44.** Structure of pyoverdine D. The chromophore unit is shown in red. The formylhydroxyornithine residues are highlighted by an asterisk (*).</figcaption></figure>

4.50. *Commercialization of Small Fluorinated Hydrophobic Groups for Lipophilicity Tuning in Drug Development* (P50)

Mariana Manso ¹, Bruno Linclau ¹, Steve Brough ²

¹ Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK

² Key Organics, Camelford, Cornwall PL32 9RA, UK; m.g.manso@soton.ac.uk

Next to bioactivity, optimization of lipophilicity is crucial in drug development. Here, we describe the changes in lipophilicity using a selection of different internal and terminal fluorination patterns, motif rearrangements, and vicinal and skipped patterns on a linear alkanol and on a cyclopropylmethyl scaffold (Figure 45) [193,194]. The comparison with the corresponding non-fluorinated parents 1-butanol and cyclopropylmethanol is also shown. These trends can be replicated when these motifs are introduced in a pharmaceutical drug candidate as part of an aromatic butoxy chain [195]. The coupling reactions between these small fluorinated hydrophobic groups and the aromatic groups is typically achieved with a tosylate or triflate functional group. Hence, we offer a stock of different fluorinated 1-butanols and cyclopropylmethanols, some already activated as tosylate (which has the added benefit of reducing compound volatility).
4.49. *New Approaches to the Synthesis of Pyoverdine D* (P49)

Tianzhu Zhang ¹,², Albert Bolhuis ¹,², Ian M. Eggleston ¹,²

¹ Department of Pharmacy & Pharmacology, University of Bath, Bath, BA2 7AY, UK

² Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK; tz496@bath.ac.uk

Pseudomonas aeruginosa is a clinically opportunistic pathogen and a major threat to patients with compromised immune systems and cystic fibrosis. Iron is an essential nutrient for virtually all microbes, including P. aeruginosa, which acquires iron by the secretion of certain iron-chelating siderophores [191]. The most important of these siderophores is the cyclic peptide derivative pyoverdine D. As an endogenous siderophore, pyoverdine D is of considerable interest as it could provide a starting point for new ways to deliver toxic materials to P. aeruginosa, for instance by linking with antibiotics [192]. This requires an efficient and flexible synthetic route to be developed for this natural product. We will present our studies towards an improved modular synthesis of pyoverdine D, with a focus on the preparation of three important components—the novel amino acid, formylhydroxyornithine, which occurs twice in the pyoverdine D structure; the solid phase synthesis of the cyclic peptide unit; and the synthesis of the tricyclic “chromophore” unit (Figure 44).

<figure><img src="image_48.png" /><figcaption>**Figure 44.** Structure of pyoverdine D. The chromophore unit is shown in red. The formylhydroxyornithine residues are highlighted by an asterisk (*).</figcaption></figure>

4.50. *Commercialization of Small Fluorinated Hydrophobic Groups for Lipophilicity Tuning in Drug Development* (P50)

Mariana Manso ¹, Bruno Linclau ¹, Steve Brough ²

¹ Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK

² Key Organics, Camelford, Cornwall PL32 9RA, UK; m.g.manso@soton.ac.uk

Next to bioactivity, optimization of lipophilicity is crucial in drug development. Here, we describe the changes in lipophilicity using a selection of different internal and terminal fluorination patterns, motif rearrangements, and vicinal and skipped patterns on a linear alkanol and on a cyclopropylmethyl scaffold (Figure 45) [193,194]. The comparison with the corresponding non-fluorinated parents 1-butanol and cyclopropylmethanol is also shown. These trends can be replicated when these motifs are introduced in a pharmaceutical drug candidate as part of an aromatic butoxy chain [195]. The coupling reactions between these small fluorinated hydrophobic groups and the aromatic groups is typically achieved with a tosylate or triflate functional group. Hence, we offer a stock of different fluorinated 1-butanols and cyclopropylmethanols, some already activated as tosylate (which has the added benefit of reducing compound volatility).
<figure><img src="image_47.png" /><figcaption>**Figure 45.** Compounds available.</figcaption></figure>

**5. Conclusions**

The meeting attracted over 150 delegates, with remarkable growth of both the network membership and the geographical range of the attendees' home countries, which included France, Germany, the United Kingdom, Turkey, Spain, Portugal, Ireland, Italy and Romania, but also countries outside Europe. The program comprised a discipline-leading line-up of presenters from various universities, spanning a broad range of pharmaceutical-chemistry-related topics.

Louise Cooney (YRC02, University College of Cork, Ireland) received the award for the best presentation by an early-career researcher, sponsored by *RSC Medicinal Chemistry* journal. The runner-up prize went to Eavan McLoughlin (YRC05, Trinity College, University of Dublin, Ireland), sponsored by *Pharmaceuticals*, a journal published by MDPI.

The prize for the best poster presentation by a post-doctoral researcher was awarded to Dr. Pauline Loupias (P30, University of Amiens, France), sponsored by Teledyne ISCO, and the runner-up prize was given to Dr. Xavier Guillory (P18, University of Rennes 1, France and Eindhoven University of Technology, The Netherlands), sponsored by CEM.

Sébastien Depienne (P14, University of Nantes, France) received the prize for the best poster presentation by a PhD researcher from our sponsor Key Organics, and the two runner-up prizes, sponsored by Collaborative Drug Discovery, went to Louna Mossino Diaz (P33, University Paris-Descartes, France) and Jeanne Trognon (P46, University of Toulouse, France).

Congratulations to all the awardees!

The 30th Annual GP₂A Medicinal Chemistry Conference is scheduled to take place in person at Trinity College, Dublin, 24–26 August 2022. Our group will be delighted to welcome current and new members during this future event.

Both the GP2A and the organizing committees thank all the sponsors, namely *RSC Medicinal Chemistry, Pharmaceuticals* MDPI, Teledyne ISCO, CEM, Collaborative Drug Discovery, Key Organics, and Asynt, for supporting our 2021 annual conference.

**Author Contributions:** Writing—original draft preparation, P.M., J.-J.H. and L.C.; writing—review and editing, P.M., J.-J.H., L.C., F.O.M., V.M.M., F.G., N.O., S.E.M., G.B., S.B. and C.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data is contained in the article.

**Conflicts of Interest:** The authors declare no conflict of interest.
<figure><img src="image_49.png" /><figcaption>**Figure 45.** Compounds available.</figcaption></figure>

**5. Conclusions**

The meeting attracted over 150 delegates, with remarkable growth of both the network membership and the geographical range of the attendees' home countries, which included France, Germany, the United Kingdom, Turkey, Spain, Portugal, Ireland, Italy and Romania, but also countries outside Europe. The program comprised a discipline-leading line-up of presenters from various universities, spanning a broad range of pharmaceutical-chemistry-related topics.

Louise Cooney (YRC02, University College of Cork, Ireland) received the award for the best presentation by an early-career researcher, sponsored by *RSC Medicinal Chemistry* journal. The runner-up prize went to Eavan McLoughlin (YRC05, Trinity College, University of Dublin, Ireland), sponsored by *Pharmaceuticals*, a journal published by MDPI.

The prize for the best poster presentation by a post-doctoral researcher was awarded to Dr. Pauline Loupias (P30, University of Amiens, France), sponsored by Teledyne ISCO, and the runner-up prize was given to Dr. Xavier Guillory (P18, University of Rennes 1, France and Eindhoven University of Technology, The Netherlands), sponsored by CEM.

Sébastien Depienne (P14, University of Nantes, France) received the prize for the best poster presentation by a PhD researcher from our sponsor Key Organics, and the two runner-up prizes, sponsored by Collaborative Drug Discovery, went to Louna Mossino Diaz (P33, University Paris-Descartes, France) and Jeanne Trognon (P46, University of Toulouse, France).

Congratulations to all the awardees!

The 30th Annual GP₂A Medicinal Chemistry Conference is scheduled to take place in person at Trinity College, Dublin, 24–26 August 2022. Our group will be delighted to welcome current and new members during this future event.

Both the GP2A and the organizing committees thank all the sponsors, namely *RSC Medicinal Chemistry, Pharmaceuticals* MDPI, Teledyne ISCO, CEM, Collaborative Drug Discovery, Key Organics, and Asynt, for supporting our 2021 annual conference.

**Author Contributions:** Writing—original draft preparation, P.M., J.-J.H. and L.C.; writing—review and editing, P.M., J.-J.H., L.C., F.O.M., V.M.M., F.G., N.O., S.E.M., G.B., S.B. and C.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data is contained in the article.

**Conflicts of Interest:** The authors declare no conflict of interest.
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12. Noireau, A.; Lemasson, E.; Mauge, F.; Petit, A.M.; Bertin, S.; Hennig, P.; Lesellier, E.; West, C. Purification of drug degradation products supported by analytical and preparative supercritical fluid chromatography. *J. Pharm. Biomed. Anal.* **2019**, *170*, 40–47. [CrossRef]

13. Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering precision nanoparticles for drug delivery. *Nat. Rev. Drug Discov.* **2021**, *20*, 101–124. [CrossRef] [PubMed]

14. Li, B.; Li, Q.; Mo, J.; Dai, H. Drug-loaded polymeric nanoparticles for cancer stem cell targeting. *Front. Pharmacol.* **2017**, *8*, 51. [CrossRef]

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20. Faïon, L.; Djaout, K.; Frita, R.; Pintiala, C.; Cantrelle, F.X.; Moune, M.; Vandeputte, A.; Bourbiaux, K.; Piveteau, C.; Herledan, A.; et al. Discovery of the first *Mycobacterium tuberculosis* MabA (FabG1) inhibitors through a fragment-based screening. *Eur. J. Med. Chem.* **2020**, *200*, 112440. [CrossRef] [PubMed]

21. Villemagne, B.; Machelart, A.; Tran, N.C.; Flipo, M.; Moune, M.; Leroux, F.; Piveteau, C.; Wohlkönig, A.; Wintjens, R.; Li, X.; et al. Fragment-based optimized EthR inhibitors with in vivo ethionamide boosting activity. *ACS Infect. Dis.* **2020**, *6*, 366–378. [CrossRef] [PubMed]

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179. Truman, J.P.; García-Barros, M.; Obeid, L.M.; Hannun, Y.A. Evolving concepts in cancer therapy through targeting sphingolipid metabolism. *Biochim. Biophys. Acta* **2014**, *1841*, 1174–1188. [CrossRef]

180. Heffernan-Stroud, L.A.; Obeid, L.M. Sphingosine kinase 1 in cancer. *Adv. Cancer Res.* **2013**, *117*, 201–235. [CrossRef]

181. Kawamori, T.; Kaneshiro, T.; Okumura, M.; Maalouf, S.; Uflacker, A.; Bielawski, J.; Hannun, Y.A.; Obeid, L.M. Role for sphingosine kinase 1 in colon carcinogenesis. *FASEB J.* **2009**, *23*, 405–414. [CrossRef] [PubMed]

182. Shirai, K.; Kaneshiro, T.; Wada, M.; Furuya, H.; Bielawski, J.; Hannun, Y.A.; Obeid, L.M.; Ogretmen, B.; Kawamori, T. A role of sphingosine kinase 1 in head and neck carcinogenesis. *Cancer Prev. Res.* **2011**, *4*, 454–462. [CrossRef]

183. Davies, D.G.; Parsek, M.R.; Pearson, J.P.; Iglewski, B.H.; Costerton, J.W.; Greenberg, E.P. The involvement of cell-to-cell signals in the development of a bacterial biofilm. *Science* **1998**, *280*, 295–298. [CrossRef]

184. Pesci, E.C.; Milbank, J.B.J.; Pearson, J.P.; McKnight, S.; Kende, A.S.; Greenberg, E.P.; Iglewski, B.H. Quinolone signaling in the cell-to-cell communication system of *Pseudomonas aeruginosa*. *Proc. Natl. Acad. Sci. USA* **1999**, *96*, 11229–11234. [CrossRef] [PubMed]

185. Khalilzadeh, P.; Lajoie, B.; El Hage, S.; Furiga, A.; Baziard, G.; Berge, M.; Roques, C. Growth inhibition of adherent *Pseudomonas aeruginosa* by an N-butanoyl-L-homoserine lactone analog. *Can. J. Microbiol.* **2010**, *56*, 317–325. [CrossRef]

186. Furiga, A.; Lajoie, B.; El Hage, S.; Baziard, G.; Roques, C. Impairment of *Pseudomonas aeruginosa* biofilm resistance to antibiotics by combining the drugs with a new Quorum-Sensing Inhibitor. *Antimicrob. Agents Chemother.* **2016**, *60*, 1676–1686. [CrossRef] [PubMed]

187. Nogaret, P.; El Garah, F.; Blanc-Potard, A.-B. A Novel infection protocol in Zebrafish embryo to assess *Pseudomonas aeruginosa* virulence and validate efficacy of a quorum sensing inhibitor in vivo. *Pathogens* **2021**, *10*, 401. [CrossRef]

188. Nguyen, T.H.D.; Tam, J.; Wu, R.A.; Greber, B.J.; Toso, D.; Nogales, E.; Collins, K. Cryo-EM structure of substrate-bound human telomerase holoenzyme. *Nature* **2018**, *557*, 190–198. [CrossRef]

189. Beekman, A.M.; Cominetti, M.M.D.; Walpole, S.J.; Prabhu, S.; O'Connell, M.A.; Angulo, J.; Searcey, M. Identification of selective protein-protein interaction inhibitors using efficient in silico peptide-directed ligand design. *Chem. Sci.* **2019**, *10*, 4502–4508. [CrossRef]

190. Zhang, C.; Fortin, P.Y.; Barnoin, G.; Qin, X.; Wang, X.; Fernandez Alvarez, A.; Bijani, C.; Maddelein, M.L.; Hemmert, C.; Cuvillier, O.; et al. An artemisinin-derivative–(NHC) Gold (I) hybrid with enhanced cytotoxicity through inhibition of NRF2 transcriptional activity. *Angew. Chem. Int. Ed.* **2020**, *59*, 12062–12068. [CrossRef]

191. Al Shaer, D.; Al Musaimi, O.; de la Torre, B.G.; Albericio, F. Hydroxamate siderophores: Natural occurrence, chemical synthesis, iron binding affinity and use as trojan horses against pathogens. *Eur. J. Med. Chem.* **2020**, *208*, 112791–112819. [CrossRef] [PubMed]

192. Mashiach, R.; Meijler, M.M. Total synthesis of pyoverdin D. *Org. Lett.* **2013**, *15*, 1702–1705. [CrossRef] [PubMed]

193. Linclau, B.; Wang, Z.; Compain, G.; Paumelle, V.; Fontenelle, C.Q.; Wells, N.; Weymouth-Wilson, A. Investigating the influence of (deoxy)fluorination on the lipophilicity of non-UV-active fluorinated alkanols and carbohydrates by a new log P determination method. *Angew. Chem. Int. Ed.* **2016**, *55*, 674–6781. [CrossRef] [PubMed]

194. Jeffries, B.; Wang, Z.; Troup, R.I.; Goupille, A.; Le Questel, J.-Y.; Fallan, C.; Scott, J.S.; Chiarparin, E.; Graton, J.; Linclau, B. Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups. *Beilstein J. Org. Chem.* **2020**, *16*, 2141–2150. [CrossRef] [PubMed]

195. Jeffries, B.; Wang, Z.; Felstead, H.R.; Le Questel, J.-Y.; Scott, J.S.; Chiarparin, E.; Graton, J.; Linclau, B. Systematic investigation of lipophilicity modulation by aliphatic fluorination motifs. *J. Med. Chem.* **2020**, *63*, 1002–1031. [CrossRef]
176. Grennet, E.; Martinez, J.; Salom-Roig, X.J. Lewis acid induced switch of torqueselectivity in the Nazarov cyclization of activated dienones bearing a chiral sulfoxide. *Chem. Eur. J.* **2016**, *22*, 16770–16773. [CrossRef] [PubMed]

177. Grennet, E.; Martinez, J.; Salom-Roig, X.J. Torquoselective Nazarov cyclization mediated by a chiral sulfoxide: First enantioselec- tive synthesis of two known anticancer agents. *Asian J. Org. Chem.* **2017**, *6*, 189–198. [CrossRef]

178. Leong, W.I.; Saba, J.D. S1P metabolism in cancer and other pathological conditions. *Biochimie* **2010**, *92*, 716–723. [CrossRef] [PubMed]

179. Truman, J.P.; García-Barros, M.; Obeid, L.M.; Hannun, Y.A. Evolving concepts in cancer therapy through targeting sphingolipid metabolism. *Biochim. Biophys. Acta* **2014**, *1841*, 1174–1188. [CrossRef]

180. Heffernan-Stroud, L.A.; Obeid, L.M. Sphingosine kinase 1 in cancer. *Adv. Cancer Res.* **2013**, *117*, 201–235. [CrossRef]

181. Kawamori, T.; Kaneshiro, T.; Okumura, M.; Maalouf, S.; Uflacker, A.; Bielawski, J.; Hannun, Y.A.; Obeid, L.M. Role for sphingosine kinase 1 in colon carcinogenesis. *FASEB J.* **2009**, *23*, 405–414. [CrossRef] [PubMed]

182. Shirai, K.; Kaneshiro, T.; Wada, M.; Furuya, H.; Bielawski, J.; Hannun, Y.A.; Obeid, L.M.; Ogretmen, B.; Kawamori, T. A role of sphingosine kinase 1 in head and neck carcinogenesis. *Cancer Prev. Res.* **2011**, *4*, 454–462. [CrossRef]

183. Davies, D.G.; Parsek, M.R.; Pearson, J.P.; Iglewski, B.H.; Costerton, J.W.; Greenberg, E.P. The involvement of cell-to-cell signals in the development of a bacterial biofilm. *Science* **1998**, *280*, 295–298. [CrossRef]

184. Pesci, E.C.; Milbank, J.B.J.; Pearson, J.P.; McKnight, S.; Kende, A.S.; Greenberg, E.P.; Iglewski, B.H. Quinolone signaling in the cell-to-cell communication system of *Pseudomonas aeruginosa*. *Proc. Natl. Acad. Sci. USA* **1999**, *96*, 11229–11234. [CrossRef] [PubMed]

185. Khalilzadeh, P.; Lajoie, B.; El Hage, S.; Furiga, A.; Baziard, G.; Berge, M.; Roques, C. Growth inhibition of adherent *Pseudomonas aeruginosa* by an N-butanoyl-L-homoserine lactone analog. *Can. J. Microbiol.* **2010**, *56*, 317–325. [CrossRef]

186. Furiga, A.; Lajoie, B.; El Hage, S.; Baziard, G.; Roques, C. Impairment of *Pseudomonas aeruginosa* biofilm resistance to antibiotics by combining the drugs with a new Quorum-Sensing Inhibitor. *Antimicrob. Agents Chemother.* **2016**, *60*, 1676–1686. [CrossRef] [PubMed]

187. Nogaret, P.; El Garah, F.; Blanc-Potard, A.-B. A Novel infection protocol in Zebrafish embryo to assess *Pseudomonas aeruginosa* virulence and validate efficacy of a quorum sensing inhibitor in vivo. *Pathogens* **2021**, *10*, 401. [CrossRef]

188. Nguyen, T.H.D.; Tam, J.; Wu, R.A.; Greber, B.J.; Toso, D.; Nogales, E.; Collins, K. Cryo-EM structure of substrate-bound human telomerase holoenzyme. *Nature* **2018**, *557*, 190–198. [CrossRef]

189. Beekman, A.M.; Cominetti, M.M.D.; Walpole, S.J.; Prabhu, S.; O'Connell, M.A.; Angulo, J.; Searcey, M. Identification of selective protein-protein interaction inhibitors using efficient in silico peptide-directed ligand design. *Chem. Sci.* **2019**, *10*, 4502–4508. [CrossRef]

190. Zhang, C.; Fortin, P.Y.; Barnoin, G.; Qin, X.; Wang, X.; Fernandez Alvarez, A.; Bijani, C.; Maddelein, M.L.; Hemmert, C.; Cuvillier, O.; et al. An artemisinin-derivative-(NHC) Gold (I) hybrid with enhanced cytotoxicity through inhibition of NRF2 transcriptional activity. *Angew. Chem. Int. Ed.* **2020**, *59*, 12062–12068. [CrossRef]

191. Al Shaer, D.; Al Musaimi, O.; de la Torre, B.G.; Albericio, F. Hydroxamate siderophores: Natural occurrence, chemical synthesis, iron binding affinity and use as trojan horses against pathogens. *Eur. J. Med. Chem.* **2020**, *208*, 112791–112819. [CrossRef] [PubMed]

192. Mashiach, R.; Meijler, M.M. Total synthesis of pyoverdin D. *Org. Lett.* **2013**, *15*, 1702–1705. [CrossRef] [PubMed]

193. Linclau, B.; Wang, Z.; Compain, G.; Paumelle, V.; Fontenelle, C.Q.; Wells, N.; Weymouth-Wilson, A. Investigating the influence of (deoxy)fluorination on the lipophilicity of non-UV-active fluorinated alkanols and carbohydrates by a new log P determination method. *Angew. Chem. Int. Ed.* **2016**, *55*, 674–6781. [CrossRef] [PubMed]

194. Jeffries, B.; Wang, Z.; Troup, R.I.; Goupille, A.; Le Questel, J.-Y.; Fallan, C.; Scott, J.S.; Chiarparin, E.; Graton, J.; Linclau, B. Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups. *Beilstein J. Org. Chem.* **2020**, *16*, 2141–2150. [CrossRef] [PubMed]

195. Jeffries, B.; Wang, Z.; Felstead, H.R.; Le Questel, J.-Y.; Scott, J.S.; Chiarparin, E.; Graton, J.; Linclau, B. Systematic investigation of lipophilicity modulation by aliphatic fluorination motifs. *J. Med. Chem.* **2020**, *63*, 1002–1031. [CrossRef]