# Synthesis of 1,2,3-Triazole-Methyl-Menadione Derivatives: Evaluation of Electrochemical and Antiparasitic Properties against two Blood-Dwelling Parasites

Baptiste Dupouy, Tanja Karpstein, Cécile Häberli, Monica Cal, Matthias Rottmann, Pascal Mäser, Jennifer Keiser, Bogdan Cichocki, Mourad Elhabiri, Elisabeth Davioud-charvet

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Baptiste Dupouy, Tanja Karpstein, Cécile Häberli, Monica Cal, Matthias Rottmann, et al. Synthesis of 1,2,3-Triazole-Methyl-Menadione Derivatives: Evaluation of Electrochemical and Antiparasitic Properties against two Blood-Dwelling Parasites. ChemMedChem, 2025, 10.1002/cmdc.202400731. hal-04892049

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# Synthesis of 1,2,3-Triazole-Methyl-Menadione Derivatives: Evaluation of Electrochemical and Antiparasitic Properties against two Blood-Dwelling Parasites

Baptiste Dupouy,[a] Tanja Karpstein,[b, c] Cécile Häberli,[b, c] Monica Cal,[b, c] Matthias Rottmann,[b, c] Pascal Mäser,[b, c] Jennifer Keiser,[b, c] B. Cichocki,[a] Mourad Elhabiri,[a] and Elisabeth Davioud-Charvet*[a]

This study explores the synthesis and evaluation of novel 1,2,3-triazole-methyl-1,4-naphthoquinone hybrids, focusing on their electrochemical properties and antiparasitic efficacies against two human blood-dwelling parasites *Plasmodium falciparum* and *Schistosoma mansoni*. Using copper-catalyzed azide-alkyne cycloaddition (CuAAC), a well-established tool in click chemistry, two synthetic routes were assessed to develop *α*- and *β*-[triazole-methyl]-menadione derivatives. By optimizing the CuAAC reaction conditions, yields were significantly improved, reaching up to 94% for key intermediates and resulting in the formation of a library of approximately 30 compounds. Bio-

logical evaluation of the compounds in antiparasitic drug assays demonstrated notable antischistosomal potencies, while no significant activity was observed for the same series against *P. falciparum* parasites. Electrochemical and ‘benzylic’ oxidation studies confirmed that the active ‘benzoyl’ metabolite responsible for the antiplasmodial activity of plasmodione cannot be generated. These findings highlight the potential of triazole-linked menadione hybrids as promising early candidates for antischistosomal drug development, and provides insights into structure-activity relationships crucial for future therapeutic strategies.

## Introduction

Malaria is an infectious disease caused by the protozoan parasite *Plasmodium*, which is transmitted by the bite of an infected *Anopheles* mosquito. It is most prevalent in the Sub-Saharan Africa and in tropical and sub-tropical regions. In 2022, there was 249 million cases of malaria – well above the estimated number of cases before the COVID-19 pandemic, and an increase of five million over 2021, killing an estimated 608,000 people in 2022, mainly children under the age of five years in sub-Saharan Africa.[1] Five major species of the *Plasmodium* parasite – *P. falciparum*, *P. malariae*, *P. vivax*,

*P. ovale*, *P. knowlesi* – can infect humans; the most severe forms of the disease, leading to cerebral malaria, severe anaemia and ultimately death are largely caused by *P. falciparum*. However, most of the drugs among them chloroquine, atovaquone, or artemisinin available to treat these diseases are subject to resistance, which limit their effectiveness.[2]

Schistosomiasis is an acute and chronic neglected tropical disease caused by *Schistosoma* trematode worms. There are two major forms of schistosomiasis – intestinal and urogenital – caused by five main species of blood flukes that infect humans: *S. mansoni*, *S. japonicum*, *S. haematobium*, *S. intercalatum* and *S. mekongi*. The intermediate host of the parasite, various species of freshwater snails, transfer human infection through skin contact with infective cercariae.[3] According to the World Health Organization report published in 2023, 251.4 million people are infected, more than 700 million people are at risk of infection and currently estimated – but likely underestimated – 11,792 deaths globally per year.[4] The disease is often endemic with malaria and is found in most of Africa, Brazil, China, and the Philippines. In addition, urogenital schistosomiasis and genital schistosomiasis caused by *S. haematobium* increases the risk of HIV co-infection and cervical precancer lesions in women with a nearly four-fold higher susceptibility.[5]

Over the last decade, our team have invested much effort in a potent antiparasitic series of compounds known as 3-benzylmenadione (bMD) that target the redox homeostasis of two blood-feeding parasites, such as *P. falciparum* parasitizing human red blood cells (pRBC)[6,7] or the *S. mansoni* flatworms.[8] Most of the research was focused on medicinal chemistry of the antiplasmodial early lead plasmodione (PD)[9] (Figure 1), in particular on the understanding of its mode of action

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<footnote>[a] B. Dupouy, Dr. B. Cichocki, Dr. M. Elhabiri, Dr. E. Davioud-Charvet Laboratoire d'Innovation Moléculaire et Applications (LIMA), Team Bio(IN)organic & Medicinal Chemistry, UMR7042 CNRS-Université de Strasbourg-Université Haute-Alsace, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France
E-mail: elisabeth.davioud@unistra.fr</footnote>

<footnote>[b] T. Karpstein, C. Häberli, M. Cal, Dr. M. Rottmann, Prof. Dr. P. Mäser, Prof. Dr. J. Keiser
Swiss Tropical and Public Health Institute, Kreuzstrasse 2, CH-4123 Allschwil, Switzerland</footnote>

<footnote>[c] T. Karpstein, C. Häberli, M. Cal, Dr. M. Rottmann, Prof. Dr. P. Mäser, Prof. Dr. J. Keiser
University of Basel, Petersgraben 1, CH-4001 Basel, Switzerland</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cmdc.202400731</footnote>

<footnote>© 2024 The Author(s). ChemMedChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.</footnote>
<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /><figcaption>Figure 1. Work progress following introduction of *N*-heteroaromatics in the aromatic rings of 3-benzylmenadiones, from the eastern to the western part.</figcaption></figure>

(MoA)[10-12] and the optimization of its biological activity and pharmacokinetic (PK) properties.[13,14] Although its MoA has been partially deciphered in yeast,[15] we demonstrated that the 3-benzoylmenadione (PDO) (Figure 1) is a key metabolite generated from PD through a bioactivation process.[12,16] PDO is generated via a two steps sequence: reduction of the 1,4-naphthoquinone electrophore to semi-naphthoquinone[17] by flavoenzymes that thus enables oxidation of the benzylic position by insertion of O₂.[12] The resulting PDO then acts as a subversive substrate in a redox cycle involving an endogenous reductant, oxygen and/or methemoglobin.[6,10,15] This redox cycle not only slows down the process of methemoglobin catabolism (digestion through proteolysis and hemozoin formation), but also produces other harmful drug metabolites and reactive oxygen species (ROS) that ultimately leads to the death of the parasite.[10]

One of the main advantages that medicinal chemistry can bring to enhance the potency of a lead molecule is to bring subtle modifications of its physiochemical properties through introduction of chemical diversity in order to improve its PK properties. In particular the enhancement of the aqueous solubility and the decrease of the lipophilicity of derivatives based on a bMD scaffold is one of the target strategies in this work. We have therefore investigated the effect of introducing nitrogen-containing aromatics into the backbone of the lead molecule. A first step towards this goal has been achieved through the development of a series of aza-benzylmenadiones[8] (Figure 1) which, while improving the solubility properties, also increased the cytotoxicity towards human cells through their effects on electrochemical properties of the aza-menadione core. The chemical modifications on the west side of the molecule were therefore abandoned and efforts focused on the east side of the molecule.

Recently, we have shown that the introduction of various substituted pyridine (py) and pyrimidine (pyr) moieties on the eastern part (Figure 1) led to promising antimalarial activities without generating undesirable side effects (e.g. increased

cytotoxicity).[18] Following this concept, 1,2,3-triazole (TRZ) motifs were thus considered to improve the properties of the pharmacophore. TRZ rings, which are bioisosters of amide and ester functions, have indeed a high stability, dipole moment and hydrogen bonding ability that enhances their pharmacological properties, in particular their influence on target-drug interactions, metabolism and PK properties.[19] Over the last decade, advances in click chemistry (e.g. Cu-catalyzed azide-alkyne cycloaddition or CuAAC)[20] have not failed to stimulate interest in antiparasitic TRZs in medicinal chemistry of naphthoquinone moieties.[21-25] A recent review also describes the many developments in life sciences based on 1,4,5-trisubstituted halo-1,2,3-triazole scaffolds.[19] Therefore, we hypothesized that the introduction of α- or β-TRZ (Figure 1) could contribute to improve the antischistosomal and antimalarial activities of our substituted menadione series. In this work, we thus evaluated in depth the effect of the introduction of TRZ moieties on the antiparasitic activity against two different parasites and the consequences on the physico-chemical properties.

## Results and Discussion

### Synthesis of 1,2,3-[TRZ-Methyl]-Menadiones

Two different synthetic routes were initially considered to obtain the α- or β-[TRZ-methyl]-menadione derivatives (Scheme 1). Route (I) involves the use of a protected menadione as starting material, i.e., 1,4-dimethoxy-2-methylnaphthalene, functionalized with azide or alkyne groups to be engaged in a CuAAC reaction.

Since the carbonyls are protected, straightforward post-functionalization can be initiated, followed by deprotection to generate the α- or β-[TRZ-methyl]-menadione in three steps. Route (II) directly involves the unprotected menadione, generating [TRZ-methyl]-menadiones in only one step, but greatly
<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /><figcaption>**Scheme 1.** Accessibility of α- or β-[TRZ-methyl]-menadione through two different routes with their pros and cons.</figcaption></figure>

reduces the possibilities of post-functionalization and limits the accessibility to the desired product.

Our initial goal was to avoid limiting steps while introducing structural diversity into the TRZ in order to better understand the structure-activity relationships (SAR). Therefore, we first investigated the synthetic route (I). This route involved the synthesis of two menadione derivatives converted to 2-methyl-1,4-dimethoxynaphthalene homologues, the azide 1 and the alkyne 2 (Scheme 2). The azido derivative was obtained from the commercially available menadione through sequential reduction and protection (via the known intermediate 1,4-dimethoxy-2-methylnaphthalene), followed by chloromethylation (via the intermediate 2-(chloromethyl)-1,4-dimethoxy-3-methyl-naphthalene), and finally nucleophilic substitution with sodium azide producing 1 in three steps with a 74% overall yield. For the alkyne 2, the synthesis started with the starting intermediate 1,4-dimethoxy-2-methylnaphthalene, followed by formylation to give the 1,4-dimethoxy-3-methyl-2-naphthaldehyde 3. The latter was then alkynylated with acetylene-TMS (trimethylsilylacetylene) to afford the secondary alcohol 4, which was reduced to 5. The TMS protecting group was finally removed in the final step to produce the targeted terminal alkyne 2 in a five steps sequence in 53% overall yield.

The CuAAC click reaction[26-28] was then investigated using the azide 1 and a TMS-acetylene model to select the optimal

experimental conditions applicable to different alkynes (Table 1).

As the CuAAC reaction has been very popular since its discovery, a large number of experimental conditions are thus available in the literature. Inspired by the original review by Meldal and Tornøe,[29] we initially used copper iodide Cul as the catalyst. However, only 5% of the targeted α6 click product was obtained (Table 1, entry 1). Increasing the amount of catalyst and using DMSO as the solvent and triethylamine TEA as the amine base led to a significant improvement (Table 1, entry 2). In the proposed mechanism, the generation of Cu-acetylide from Cu(I) requires an amine base and/or a high temperature. However, in our case, increasing the temperature and reaction time led to degradation of the starting product (Table 1, entry 3). The use of other more classical conditions, such as a copper sulphate (CuSO₄) catalyst and sodium ascorbate as reductant, resulted in only 4% of the target product (Table 1, entry 4). Finally, we turned to the use of Cu(MeCN)₄BF₄ as the catalyst, as the latter has the advantage of being a source of Cu(I) soluble in organic solvents. These new conditions considerably improved the yield of the CuAAC reaction, giving α6 in 9% yield (Table 1, entry 5). Following the click reaction, the TMS group of α6 was deprotected with TBAF to give the compound α7 in 66% yield (Scheme 3). Finally, an oxidative demethylation reaction with BCl₃/TBAI afforded the first α-[TRZ-methyl]-menadione (α8) in moderate yield of 40% (Scheme 3).

<figure><img src="image_9.png" /><figcaption>**Scheme 2.** Access to azido substrates **1, 9** and alkyne substrates **2, 10**. Conditions: [a] 1. SnCl₂ (2.5 equiv.), HCl (4 equiv.), EtOH (0.2 M), r.t., 2 h, 2. Me₂SO₄ (5 equiv.), acetone (0.2 M), KOH (5 equiv.), MeOH (1 M), 60 °C, 4 h, 93%. [b] CH₂O (5 equiv.), HCl (0.4 M), 80 °C, 2 h, 81%. [c] NaN₃ (3 equiv.), DMF (0.2 M), 70 °C, 16 h, 98%. [d] CAN (2.2 equiv.), MeCN/H₂O (7/3, 0.06 M), r.t., 1 h, 94% for **9** and 95% for **10**. [e] TiCl₄ (1.1 equiv.), dichloromethyl methyl ether (1.1 equiv.), DCM (0.7 M), 0 °C, 2 h, 100%. [f] trimethylsilylacetylene (1.8 equiv.), n-BuLi (1.5 equiv.), THF (0.1 M), 0 °C to r.t., 3 h, 100%. [g] Et₃SiH (1.5 equiv.), BF₃.Et₂O (1.5 equiv.), DCM (0.05 M), 0 °C, 30 min, 89%. [h] K₂CO₃ (5 equiv.), MeOH (0.1 M), r.t., 3 h, 65%.</figcaption></figure>
<figure><img src="image_10.png" /></figure>

<table><caption>**Table 1.** Evaluation of the reactivity of 1 and 2 under different CuAAC reaction conditions.</caption><thead><tr><th>Entry</th><th>Cpnd</th><th>Catalyst/reductant or ligand</th><th>Solvent</th><th>Conditions<sup>[a]</sup></th><th>Yield<sup>[b]</sup> [%]</th></tr></thead><tbody><tr><td>1</td><td>1</td><td>Cul (0.3 equiv.)</td><td>MeCN (0.6 M)</td><td>r.t., 48 h</td><td>5<sup>[c]</sup></td></tr><tr><td>2</td><td>1</td><td>Cul (0.75 equiv.), TEA</td><td>DMSO (0.2 M)</td><td>r.t., 48 h</td><td>39<sup>[c]</sup></td></tr><tr><td>3</td><td>1</td><td>Cul (0.5 equiv.), TEA</td><td>DMSO (0.2 M)</td><td>50 °C, 72 h</td><td>Degradation<sup>[c]</sup></td></tr><tr><td>4</td><td>1</td><td>CuSO<sub>4</sub> (0.15 equiv.)/Na ascorbate (0.8 equiv.)</td><td>DMF/H<sub>2</sub>O (9/1) (0.6 M)</td><td>r.t., 48 h</td><td>4<sup>[c]</sup></td></tr><tr><td>5</td><td>1</td><td>Cu(MeCN)<sub>4</sub>BF<sub>4</sub> (0.5 equiv.)</td><td>MeCN (0.1 M)</td><td>50 °C, 72 h</td><td>94<sup>[c]</sup></td></tr><tr><td>6</td><td>2</td><td>Cu(MeCN)<sub>4</sub>BF<sub>4</sub> (0.5 equiv.)</td><td>MeCN (0.1 M)</td><td>50 °C, 72 h</td><td>0<sup>[d]</sup></td></tr><tr><td>7</td><td>2</td><td>Cu(MeCN)<sub>4</sub>BF<sub>4</sub> (0.5 equiv.)/bathocuproine (0.5 equiv.)</td><td>DCM (0.1 M)</td><td>r.t., 72 h</td><td>0<sup>[d]</sup></td></tr></tbody></table>

[a] Under argon atmosphere. [b] Isolated yield. [c] 3 equiv. of alkyne used. [d] 2 equiv. of azide used.

<figure><img src="image_11.png" /><figcaption>**Scheme 3.** Synthesis of α-[TRZ-methyl]-menadione (α8). Conditions: [a] TBAF (3 equiv.), THF (0.05 M), r.t., 16 h, 66%. [b] TBAI (2 equiv.), BCl₃ (6 equiv.), DCM (6 mM), -78 °C to r.t., 16 h, 40%.</figcaption></figure>

The total yield for these three steps to afford α8 is about 25% (Scheme 3). Noteworthy is to mention that α8 could only be obtained by route (I), and not by route (II), as it will be discussed below.

The experimental conditions for the CuAAC reaction were then optimized (Table 1, entry 5) and subsequently applied to the alkyne 2 in combination with a model azide, the benzyl azide. However, no reaction occurred, even when a chelator of Cu(I) (i.e. bathocuproine[30]) was used to stabilize copper in its + I oxidation state, to improve its reactivity and prevent its oxidation (Table 1, entries 6 and 7).

In addition, the optimized condition from entry 5 (Table 1) was tested with three different alkynes. Starting with azido 1 (Table S1 in the SI), the reaction with propargyl bromide only led to the starting material, accompanied with an undetermined by-product, which could correspond to a stable intermediate of the CuAAC catalytic cycle.

Finally, when propargyl alcohol or 3-methylbutynol was used, the reaction quantitatively reduced the azide function of compound 1 (Table S1 in the SI). Taken together, these results suggest that the CuAAC reaction is highly dependent on the nature of the substrate when using the protected menadiones 1 and 2.

Following these first results, we then investigated the synthetic route (II). The corresponding alkyne- (10) and azido-functionalized (9) menadione derivatives were obtained from 1

and 2 by oxidative demethylation, achieving high yields (i.e. 95% and 94%, respectively. We selected the conditions from Table 1 and tested them to investigate the accessibility to [TRZ-methyl]-menadiones. To introduce substituents compatible with desired physico-chemical properties, we synthesized several non-commercial alkynes and azides. Alkynes were readily obtained by a one-step nucleophilic substitution from propargyl bromide (Scheme 4). As far as azide derivatives are concerned, a three steps sequence starting from ethanolamine allowed their access, first, with a diazo transfer reaction leading to compound 11, then a tosylation of the alcohol function allowing access to compound 12 and finally a nucleophilic substitution reaction carried out to introduce the desired group (Scheme 4).

The results indicated that the various functional groups were well tolerated under the CuAAC conditions, allowing access to the targeted α- and β-[TRZ-methyl]-menadiones in low to good yields (Scheme 5). Selected side-chains tethered on the alkyne or azide groups were inspired by the structures of antischistosomal drugs, e.g. nitro-, amino-, and methanol groups are found in oxamniquine, the piperidine ring is inspired

<figure><img src="image_12.png" /><figcaption>**Scheme 4.** Synthesis of alkyne and azide derivatives. Conditions: [a] Nu (2.5 equiv.), DCM (1.7 M), 30 °C, 16 h. [b] 1-(azidosulfonyl)-1H-imidazol-3-ium hydrogen sulfate (52) (1.2 equiv.), TEA (7 equiv.), MeOH (0.15 M), r.t., 16 h, 76%. [c] TsCl (2.5 equiv.), NaOH (5 equiv.), THF (1.15 M), H₂O (1.15 M), 0 °C to r.t., 3 h, 63%. [d] Nu (2 equiv.), K₂CO₃ (3 equiv.), MeCN (0.2 M), 80 °C, 20 h.</figcaption></figure>
<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /><figcaption>**Scheme 5.** Access to [TRZ-methyl]-menadiones from 9 or 10 by CuAAC reaction. Grey balls represents a C (sp²) atom and green balls represents a CH₂ (sp³) group. *Products obtained from corresponding alkyne or azide crude mixture (two-steps yield). All yields are isolated yields. [a] 1.2 equiv. of azide or alkyne, CuSO₄ (0.2 equiv.)/Na ascorbate (0.4 equiv.), THF/H₂O (7/3, 0.02 M), r.t., 16 h. [b] 1.5 equiv. of azide or alkyne, Cu(MeCN)₄BF₄ (0.1 equiv.), DCM (0.1 M), 40 °C, 16 h, under argon. [c] 1.5 equiv. of azide or 2 equiv. of alkyne, Cu(MeCN)₄BF₄ (0.4 equiv.)/bathocuproine (0.4 equiv.), DCM (0.1 M), 40 °C, 72 h, under argon. [d] 2 equiv. of alkyne, Cu(MeCN)₄BF₄ (0.1 equiv.)/bathocuproine (0.1 equiv.), MeCN (0.01 M), 80 °C, 72 h, under argon. [e] 32 equiv. of TFA, DCM (0.06 M), r.t., 1 h.</figcaption></figure>

by the quinolyl cycle of oxamniquine, oxopiperidinyl and piperazine cycles as similar to those found in praziquantel, and finally fluorine atoms and cyano groups have been observed in various antischistosomal derivatives described in literature.[31]

Despite successful synthesis of many [TRZ-methyl]-menadiones, challenges remained with the deprotection of the TRZ-substituted side-chain. We were unable to debenzylate β13 either by palladium-catalyzed hydrogenation or under the conditions (tert-butoxide/DMSO/O₂) described by Deaton-Rewolinski et al.[32] Similarly, deprotection of α14 only led to degradation, using either fluoride or methanolate conditions. This unusual low reactivity could be explained by the fact that the menadione core is an efficient electron acceptor, which, in reduced form, is very sensitive to nucleophiles and/or bases (Michael acceptor). Attempts were thus made to protect the [TRZ-methyl]-menadione under conditions used for 1,4-dimethoxy-2-methylnaphthalene (Scheme 1). However, this only led to the degradation of the starting material, highlighting the limitation of post-modifications in synthetic route (II) to access [TRZ-methyl]-menadione derivatives. As direct introduction of the amine was not tolerated by the CuAAC conditions (potential interaction with Cu(I)), the free amino-α-TRZ α15 was therefore obtained by TFA deprotection of the N-Boc protected amine

α16. In contrast, the use of hydroxyl or O-oxetanyl groups were well tolerated, affording the targeted products in moderate to excellent yields (Scheme 5). In addition, several six-membered aliphatic heterocycles diversely substituted were introduced without much difficulty, except for unsubstituted piperidine, which was not tolerated to access either α- or β-isomers, likely because of methyl deprotonation of the menadione core.[33] By TFA deprotection of α17 and α18, piperazine derivatives α19 and α20 were quantitatively obtained, respectively (Scheme 5). For five-membered heterocycles, only thiazolidine was tested, producing α21 in 22% yield, while β22 was formed in a small amount but degraded after a few hours (yield not quantified). Other functional groups of interest were also considered, e.g. Br or OTs (α23, α24). The bromo-α-TRZ α23 was obtained in very low yield. As observed for 1 (Table S1 in the SI) different by-products were generated (not isolated), which could be linked to the competition between the generation of Cu-acetylide, Glaser coupling[34] and oxidative coupling. The tosyl-β-TRZ β25 was obtained in moderate yield, but post-functionalization by nucleophilic substitution with morpholine in mild conditions led to the degradation of the starting material. In contrast, its isomer α24 was not obtained. For the electron-withdrawing
<figure><img src="image_15.png" /></figure>

substitution, only the cyano group was tested, giving the
desired derivative β26.

Although successful for a large number of substituents,
these results highlight the drawbacks of direct CuAAC click
chemistry with unprotected reactive menadiones or for their
post-functionalization. Nevertheless, through this proposed
methodological approach, we could demonstrate that the
synthetic route (II) (Scheme 1) allowed the preparation of a
series of [TRZ-methyl]-menadiones in one single step (i.e.
without protection/deprotection of the menadione core).

Synthesis of 1,2,4-Triazole-, 3-Nitro-1,2,4-Triazole- and 2-
Nitroimidazole-Menadiones

To introduce more compatible structural diversity within the α-
and β-[TRZ-methyl]-menadiones, other five-membered *N*-hetero-
aromatic groups of varying diversity (Scheme 6) were consid-
ered. For example, the 1,2,4-TRZ derivative (41) was obtained in
moderate yield and NMR data was studied in detail. The latter is
prepared from intermediate 2-(chloromethyl)-1,4-dimethoxy-3-
methylnaphthalene by nucleophilic substitution with the
commercially available secondary amine *N*-heteroaromatic fol-
lowed by an oxidative demethylation of 42. The importance of
a nitro group was also evaluated and the compounds 3-nitro-
1,2,4-TRZ (43) and 2-nitroimidazole (44) were prepared in
moderate yields using the same methodology as for other
triazoles.

Antiparasitic Activities and Toxicity against Mammalian Cells
of [TRZ-Methyl]-Menadiones

All [TRZ-methyl]-menadiones were tested for antimalarial and
antischistosomal activities using standard 72 h assays and for
cytotoxicity on L6 cells derived from rat skeletal myoblasts
(ATCC CRL-1458) (Table 2). Growth inhibition of *P. falciparum*

<figure><img src="image_16.png" /><figcaption>**Scheme 6.** Synthesis of menadione derivatives containing a five-membered *N*-heteroaromatic ring. Conditions: [a] 2.5 equiv. of the corresponding secondary amine, 3 equiv. TEA, MeCN (0.05 M), 80 °C, 16 h. [b] 2 equiv. TBAI, 6 equiv. BCl₃, DCM (0.01 M), -78 °C, 16 h.</figcaption></figure>

(NF54 strain) using the [³H]-hypoxanthine incorporation assay[35]
or *in vitro* drug efficacy testing on two different *S. mansoni* life
stages (newly transformed schistosomula (NTS))[36] and adult
worms. Assays were conducted as described by Lombardo and
colleagues.[36] IC₅₀ values of the compounds were determined
accordingly by measuring the concentration of the inhibitor
required to reduce the growth (*P. falciparum*) or the viability
(*S. mansoni*) of the parasites by 50%. In addition, the drug effect
on the viability of *S. mansoni* NTS was evaluated after a 72 h
exposure time, at a concentration of 10 µM for all our
compounds. If the compound showed significant activity
(> 70% drug effect), the same test was performed with a lower
concentration of 1 µM (Table 2). Regarding activity against
*P. falciparum*, the α-[TRZ-methyl]-menadione series (including
the other 5-membered-*N*-heteroaromatic isomers, Scheme 6)
clearly show no efficacy with IC₅₀ values far above 1 µM.
Interestingly, half of the β-[TRZ-methyl]-menadione series
showed promising antimalarial activity with IC₅₀ values in the
sub-micromole range. In particular, compounds β38 and β18
exhibited low IC₅₀ values of 0.332 and 0.465 µM, respectively.
Notably, the deprotected form of β18, compound β20, is
inactive, indicating the negative effect of the presence of an
ionisable free amine on the antiparasitic activity of the
molecule. Comparison of the β-[TRZ-methyl]-menadione series
with the pyridine- and pyrimidine-substituted menadiones
recently published by our team[18] clearly showed that the 6-
membered-*N*-heteroaromatics are generally more potent than
their 5-membered congeners, with IC₅₀ values below 1 µM for
most of them (Table 2). The data obtained allowed us to
demonstrate the absence of antimalarial activity for the α-TRZ
and a moderate activity for the β-isomers. These results could
be explained by alterations of the redox properties of the
naphthoquinone electrophore depending on the type of
heteroaromatic introduced and its nature (isomer). It should be
noted that 3-benzylmenadiones or their heteroaromatic ana-
logues were proposed to act as prodrugs and are prone to
benzylic oxidation within pRBCs, which can significantly alter
the reactivity and the electrochemical properties of the
generated metabolites, as well as the influence of these
substitutions on the menadione moiety (see below).[17,37,38]

Screening against NTS at 10 µM for 72 h revealed that approximately 80% of the 28 triazoles tested inhibited NTS viability by at least 70%, with IC50 values between 1.89 and 0.81 µM (Table 2). The most potent triazoles were then retested at a tenfold lower concentration. The results showed that α15, which bears a free amine, was the most active of the series, with an activity of almost 54% and an IC50 value of 0.81 µM. It is interesting to note that although the series of 5-membered heteroaromatics showed no or only moderate antimalarial activity, almost all these triazoles showed potent antischistosomal activity, with NTS activity in the order of 35–54% at 1 µM. To investigate this further, additional studies were carried out on S. mansoni adult worms at a concentration of 10 µM to 25 µM after 72 h exposure (Table 3). At a concentration of 25 µM, 85% of [TRZ-methyl]-menadiones showed an activity of over 50% and were therefore re-tested at a 2.5 times lower concentration. Most have antischistosomal activity in the 40–
<figure><img src="image_17.png" /></figure>

<table><caption>**Table 2.** Antimalarial activity against *P. falciparum* NF54 strain, antischistosomal activity against *S. mansoni* NTS<sup>[a]</sup> and cytotoxicity on L6 cells.</caption><thead><tr><th rowspan="2">Cpnd</th><th rowspan="2">Menadione-substituent</th><th rowspan="2">NF54 IC<sub>50</sub> (µM)</th><th rowspan="2">L6 CC<sub>50</sub> (µM)</th><th rowspan="2">si<sup>[c]</sup></th><th colspan="2">NTS activity<sup>[b]</sup> % (±), 72 h</th><th rowspan="2">NTS IC<sub>50</sub> µM, 72 h</th><th rowspan="2">si<sup>[d]</sup></th></tr><tr><th>10 µM</th><th>1 µM</th></tr></thead><tbody><tr><td colspan="9"><strong>α-1,2,3-triazole</strong></td></tr><tr><td>α8</td><td>α-TRZ</td><td>&gt; 10</td><td>6.24</td><td></td><td>100 (0)</td><td>34 (2)</td><td>1.05</td><td>5.9</td></tr><tr><td>α14</td><td>α-TRZ (TMS)</td><td>7.20</td><td>18.24</td><td>2.5</td><td>91.72 (2.1)</td><td>38 (2)</td><td>1.57</td><td>11.6</td></tr><tr><td>α15</td><td>α-TRZ (NH<sub>2</sub>)</td><td>&gt; 10</td><td>-</td><td></td><td>100 (0)</td><td>54.17 (0)</td><td>-</td><td></td></tr><tr><td>α16</td><td>α-TRZ (NHBoc)</td><td>&gt; 10</td><td>-</td><td></td><td>40.26 (5.6)</td><td>-</td><td>-</td><td></td></tr><tr><td>α17</td><td>α-TRZ (piperazine-Boc)</td><td>1.46</td><td>-</td><td></td><td>75.26 (0.3)</td><td>50 (0)</td><td>1.50</td><td></td></tr><tr><td>α19</td><td>α-TRZ (piperazine)</td><td>&gt; 10</td><td>-</td><td></td><td>100 (0)</td><td>43.75 (2.1)</td><td>0.93</td><td></td></tr><tr><td>α21</td><td>α-TRZ (thiazolidine)</td><td>&gt; 10</td><td>-</td><td></td><td>42.35 (7.7)</td><td>-</td><td>-</td><td></td></tr><tr><td>α23</td><td>α-TRZ (Br)</td><td>5.55</td><td>18.23</td><td>3.3</td><td>89.58 (2.1)</td><td>36 (4)</td><td>1.02</td><td>17.9</td></tr><tr><td>α27</td><td>α-TRZ (tBuOH)</td><td>&gt; 10</td><td>7.27</td><td></td><td>100 (0)</td><td>34 (4)</td><td>1.05</td><td>6.9</td></tr><tr><td>α28</td><td>α-TRZ (NBr<sub>2</sub>)</td><td>1.91</td><td>-</td><td></td><td>44.35 (1.5)</td><td>-</td><td>-</td><td></td></tr><tr><td>α29</td><td>α-TRZ (OH)</td><td>&gt; 10</td><td>6.69</td><td></td><td>100 (0)</td><td>34 (6)</td><td>1.05</td><td>6.4</td></tr><tr><td>α30</td><td>α-TRZ (O-Oxetane)</td><td>&gt; 10</td><td>7.10</td><td></td><td>100 (0)</td><td>32 (0)</td><td>1.08</td><td>6.6</td></tr><tr><td>α31</td><td>α-TRZ (morpholine)</td><td>&gt; 10</td><td>-</td><td></td><td>100 (0)</td><td>39.58 (2.1)</td><td>0.98</td><td></td></tr><tr><td>α32</td><td>α-TRZ (difluoropiperidine)</td><td>2.84</td><td>-</td><td></td><td>87.5 (12.5)</td><td>45.83 (4.2)</td><td>1.48</td><td></td></tr><tr><td>α34</td><td>α-TRZ (4-piperidone)</td><td>&gt; 10</td><td>-</td><td></td><td>100 (0)</td><td>41.67 (4.2)</td><td>0.95</td><td></td></tr><tr><td colspan="9"><strong>β-1,2,3-triazole</strong></td></tr><tr><td>β13</td><td>β-TRZ (Ar)</td><td>0.89</td><td>49.16</td><td>55.2</td><td>58.33 (4.2)</td><td>-</td><td>-</td><td></td></tr><tr><td>β18</td><td>β-TRZ (piperazine-Boc)</td><td>0.465</td><td>-</td><td></td><td>71.17 (3.8)</td><td>33.33 (0)</td><td>1.89</td><td></td></tr><tr><td>β20</td><td>β-TRZ (piperazine)</td><td>6.51</td><td>-</td><td></td><td>91.84 (8.2)</td><td>33.33 (4.2)</td><td>1.67</td><td></td></tr><tr><td>β25</td><td>β-TRZ (OTs)</td><td>0.77</td><td>44.41</td><td>57.7</td><td>41.47 (4.2)</td><td>-</td><td>-</td><td></td></tr><tr><td>β26</td><td>β-TRZ (CN)</td><td>1.89</td><td>-</td><td></td><td>85.46 (10.5)</td><td>43.75 (6.3)</td><td>1.54</td><td></td></tr><tr><td>β36</td><td>β-TRZ (OH)</td><td>1.847</td><td>17.55</td><td>9.5</td><td>97.92 (2.1)</td><td>36 (4)</td><td>1.44</td><td>12.2</td></tr><tr><td>β37</td><td>β-TRZ (morpholine)</td><td>5.95</td><td>-</td><td></td><td>50.51</td><td>-</td><td>-</td><td></td></tr><tr><td>β38</td><td>β-TRZ (difluoropiperidine)</td><td>0.332</td><td>-</td><td></td><td>83.42 (8.4)</td><td>41.67 (0)</td><td>1.60</td><td></td></tr><tr><td>β40</td><td>β-TRZ (4-piperidone)</td><td>2.07</td><td>-</td><td></td><td>100 (0)</td><td>35.42 (2.1)</td><td>-</td><td></td></tr><tr><td colspan="9"><strong>5-membered-N-heteroaromatic</strong></td></tr><tr><td>41</td><td>α-1,3,4-TRZ</td><td>7.48</td><td>-</td><td></td><td>100 (0)</td><td>45.83 (4.2)</td><td>0.90</td><td></td></tr><tr><td>43</td><td>α-3-nitro-1,2,4-TRZ</td><td>&gt; 10</td><td>-</td><td></td><td>100 (0)</td><td>50 (0)</td><td>0.86</td><td></td></tr><tr><td>44</td><td>α-2-nitroimidazole</td><td>&gt; 10</td><td>-</td><td></td><td>100 (0)</td><td>35.42 (2.1)</td><td>1.03</td><td></td></tr><tr><td colspan="9"><strong>6-membered-N-heteroaromatic (pyridine, pyrimidine) and reference drugs</strong></td></tr><tr><td>47<sup>[e]</sup></td><td>γ-py-CF<sub>3</sub></td><td>0.078 ± 0.024<sup>[e]</sup></td><td>50.9</td><td>652.6</td><td></td><td>-</td><td>-</td><td></td></tr><tr><td>48<sup>[e]</sup></td><td>β-py-CF<sub>3</sub></td><td>0.069 ± 0.024<sup>[e]</sup></td><td>8.82</td><td>127.8</td><td></td><td>-</td><td>-</td><td></td></tr><tr><td>49<sup>[e]</sup></td><td>γ-pyr-CF<sub>3</sub></td><td>0.194 ± 0.125<sup>[e]</sup></td><td>179.20</td><td>923.7</td><td></td><td>-</td><td>-</td><td></td></tr><tr><td>50<sup>[e]</sup></td><td>β-pyr-CF<sub>3</sub></td><td>0.414 ± 0.293<sup>[e]</sup></td><td>17.56</td><td>42.4</td><td></td><td>-</td><td>-</td><td></td></tr><tr><td>PD<sup>[f]</sup></td><td>benzyl-CF<sub>3</sub></td><td>0.043 ± 0.002<sup>[e]</sup></td><td>141.70</td><td>3295.3</td><td>46.43 (0)</td><td>-</td><td>11.3</td><td>12.5</td></tr><tr><td>CQ</td><td></td><td>0.004 ± 0.00037 µg/ml<sup>[e]</sup></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

50% mortality range. Two compounds in particular, β13 and β36 ($IC_{50}$ = 7.3 µM, 72 h), stand out with much higher mortality rate at 10 µM of 56.9% and 64.7%, respectively. By comparison, with 54.1% activity at 10 µM, PD (Table 3), one of our leading antimalarials, was already shown to be very potent against

adult worms.[39] With the exception of 43 (Table 3), a compound that is very active on the NTS is not necessarily very active on the adult worms (48.1% at 10 µM, $IC_{50}$ = 7.3 µM, 72 h), and vice versa, as has been demonstrated with our series of compounds here. No clear correlation between α- or β-substituted triazoles

<footnote>[a] Praziquantel displayed $CC_{50}$ and $IC_{50}$ values of 96 µM and 2.2 µM against *S. mansoni* NTS, respectively (data from ref. [44]). [b] Effect in percentage in NTS assays after 72 h. [c] Selectivity index for the anti-*P. falciparum* NF54 activity: $CC_{50}$ (L6)/$IC_{50}$ (NF54). [d] Selectivity index for the anti-*S. mansoni* NTS activity: $CC_{50}$ (L6)/$IC_{50}$ (NTS). [e] from ref. [18]. [f] PD displayed an $IC_{50}$ value of 11.3 µM in the NTS assay (data from ref. [39]). "-" means not tested.</footnote>
<figure><img src="image_18.png" /></figure>

<table><caption>**Table 3.** Antischistosomal activity against *S. mansoni* adult worms.[a]</caption><thead><tr><th rowspan="2">Cpnd</th><th colspan="3">Adult worms<sup>[b]</sup> % (±), 25 µM</th><th colspan="3">Adult worms<sup>[b]</sup> % (±), 10 µM</th></tr><tr><th>24 h</th><th>48 h</th><th>72 h</th><th>24 h</th><th>48 h</th><th>72 h</th></tr></thead><tbody><tr><td>α8</td><td>46 (1)</td><td>50 (0)</td><td>54.9 (2)</td><td>41.3 (1)</td><td>42.8 (0)</td><td>43.8 (5.1)</td></tr><tr><td>α14</td><td>50.9 (4)</td><td>51.05 (9.4)</td><td>70.55 (2)</td><td>39.37 (1)</td><td>39.75 (5.1)</td><td>43.8 (5.1)</td></tr><tr><td>α15</td><td>50.4 (2.5)</td><td>50 (0)</td><td>52.75 (4.6)</td><td>37 (3.7)</td><td>44.4 (0)</td><td>45.35 (0.9)</td></tr><tr><td>α16</td><td>54.25 (10.5)</td><td>54.55 (0.4)</td><td>55.55 (7.4)</td><td>–</td><td>–</td><td>–</td></tr><tr><td>α17</td><td>43.75 (4.2)</td><td>45.45 (0.4)</td><td>50.95 (0.9)</td><td>41.65 (2.8)</td><td>45.35 (0.9)</td><td>46.25 (1.9)</td></tr><tr><td>α19</td><td>43.8 (0)</td><td>48.45 (0.6)</td><td>62.5 (4.2)</td><td>43.55 (8.3)</td><td>46.25 (1.9)</td><td>46.25 (1.9)</td></tr><tr><td>α21</td><td>43.5 (2.3)</td><td>46.4 (2.6)</td><td>51.85 (3.7)</td><td>–</td><td>–</td><td>–</td></tr><tr><td>α23</td><td>39.95 (1.2)</td><td>50 (0)</td><td>50 (1)</td><td>38.4 (0)</td><td>44.85 (2)</td><td>44.85 (2)</td></tr><tr><td>α27</td><td>43.85 (5.1)</td><td>44.8 (1)</td><td>45.1 (2)</td><td>39.37 (1.9)</td><td>40.8 (0)</td><td>40.8 (0)</td></tr><tr><td>α28</td><td>45.2 (7.7)</td><td>46.45 (0.6)</td><td>48.1 (0)</td><td>–</td><td>–</td><td>–</td></tr><tr><td>α29</td><td>43.95 (1.1)</td><td>56.25 (4.2)</td><td>57.85 (1)</td><td>39.37 (1.9)</td><td>39.75 (1)</td><td>43.8 (5.1)</td></tr><tr><td>α30</td><td>47 (0.1)</td><td>51.05 (5.2)</td><td>52.9 (0)</td><td>46.9 (4.1)</td><td>47.9 (1)</td><td>48.05 (2.9)</td></tr><tr><td>α31</td><td>45.45 (0.4)</td><td>46.45 (0.6)</td><td>54.65 (0.9)</td><td>29.6 (3.7)</td><td>44.4 (0)</td><td>47.2 (2.8)</td></tr><tr><td>α32</td><td>43.15 (2)</td><td>44.65 (0.9)</td><td>51.85 (1.9)</td><td>40.7 (7.4)</td><td>40.7 (3.7)</td><td>43.5 (2.8)</td></tr><tr><td>α34</td><td>36.45 (1)</td><td>42.75 (1)</td><td>50 (0)</td><td>35.15 (1.9)</td><td>42.55 (1.9)</td><td>47.2 (2.8)</td></tr><tr><td>β13</td><td>53.95 (0.9)</td><td>56.3 (0)</td><td>58.8 (0)</td><td>49.95 (1)</td><td>55.1 (0)</td><td>56.9 (0)</td></tr><tr><td>β18</td><td>33.33 (0)</td><td>46.9 (3.1)</td><td>49.9 (0.9)</td><td>29.6 (3.7)</td><td>41.65 (2.8)</td><td>44.4 (0)</td></tr><tr><td>β20</td><td>48.35 (4.6)</td><td>48.45 (0.6)</td><td>50 (5.6)</td><td>34.25 (0.9)</td><td>50 (5.6)</td><td>50 (5.6)</td></tr><tr><td>β25</td><td>34.05 (4.7)</td><td>42.7 (3.1)</td><td>48.05 (1)</td><td>33.6 (1)</td><td>35.65 (1)</td><td>43.1 (0)</td></tr><tr><td>β26</td><td>38.55 (1)</td><td>44.8 (1)</td><td>46.95 (1.2)</td><td>37.95 (4.6)</td><td>43.5 (4.6)</td><td>45.35 (4.6)</td></tr><tr><td>β36</td><td>48.05 (2.9)</td><td>55.25 (1)</td><td>66.7 (0)</td><td>44.85 (6.1)</td><td>51 (0)</td><td>64.7 (0)</td></tr><tr><td>β37</td><td>40.3 (2.8)</td><td>43.5 (2.3)</td><td>49.05 (4.6)</td><td>–</td><td>–</td><td>–</td></tr><tr><td>β38</td><td>41.3 (3.8)</td><td>41.45 (0.2)</td><td>53.75 (1.9)</td><td>37 (3.7)</td><td>41.65 (2.8)</td><td>44.4 (0)</td></tr><tr><td>β40</td><td>46.45 (0.6)</td><td>47.4 (1.6)</td><td>55.55 (1.9)</td><td>45.4 (6.5)</td><td>47.2 (2.8)</td><td>49.05 (0.9)</td></tr><tr><td>41</td><td>41.7 (0)</td><td>45.8 (0)</td><td>54.65 (4.6)</td><td>40.75 (1.9)</td><td>44.4 (0)</td><td>50 (0)</td></tr><tr><td>43</td><td>41.7 (2.1)</td><td>45.85 (2.1)</td><td>51.85 (1.9)</td><td>37.95 (4.6)</td><td>40.7 (3.7)</td><td>48.15 (1.9)</td></tr><tr><td>44</td><td>48.55 (1.5)</td><td>56.85 (3.9)</td><td>71.3 (6.5)</td><td>42.55 (1.9)</td><td>43.5 (0.9)</td><td>44.4 (0)</td></tr><tr><td>PD<sup>[c]</sup></td><td>73.95 (0.5)</td><td>75 (0)</td><td>76.5 (0)</td><td>50 (1)</td><td>50 (0)</td><td>54.15 (4.2)</td></tr></tbody></table>

and *S. mansoni* antischistosomal activity could be observed. This suggests that [TRZ-methyl]- or 3-benzyl-menadiones have different penetration properties in *S. mansoni* compared to *P. falciparum*, and consequently, possible distinct targets/drug transports mechanisms in these two hemoglobin-feeding parasites. 1,2,3-TRZ are known to allow simultaneous metal coordination and hydrogen bond donation (through dipole-ion interaction), making a synergistic increase of both CH-acidity and N-donor strength.[40] Here, in our study and from others,[41] 1,2,3-TRZ exert – via their ambivalent character – excellent antischistosomal activities through better PK and penetration properties. Similarly to 1,2,3-triazoles, our previous study on 1,2,3,4-tetrazoles clearly highlighted the bioisosteric character of this heterocycle to mimic the negative charge of carboxylic acids.[42] Several works also reported the potent antischistosomal activities of carboxylic acids.[31,43]

## Physico-Chemical Properties of the Most Potent [TRZ-Methyl]-Menadiones

While it is essential to optimize the efficacy of our compounds against the target parasites, it is also important to characterize the pharmacological profile of these compounds. By introducing N-heteroaromatic groups, in particular triazoles, we aimed to improve the oral bioavailability and the physico-chemical properties of the 3-benzylmenadione series. Therefore, an *in silico* prediction of several key PK parameters was performed using the SwissADME[45] web tool for compounds β38, β18, β13, β36 and 47, 48, 49, 50, PD and CQ (used as reference) based on their antimalarial and antischistosomal activities. The Lipinski's and Veber's rules,[46,47] which are the most widely used drug-likeness filters, were used in this work. The physico-chemical properties of the selected compounds, including their molecular weight (MW), number of hydrogen bonds acceptors/donors

<footnote>[a] Praziquantel displayed an IC₅₀ value of 0.1 µM against adult worms (data from ref. [44]). [b] Effect in percentage on adult worms after 24 h, 48 h, and 72 h.</footnote>

<footnote>[c] PD displayed an IC₅₀ value of 8.6 µM in the adult worm assay (data from ref. [39]). “-” means not tested.</footnote>
<figure><img src="image_19.png" /></figure>

(HBA/HBD) and total polar surface area (tPSA) were calculated and are presented in Table 4.

In addition, Table 4 presented their predicted *n*-octanol/water partition coefficient (clog P), their solubility, their number of rotatable bonds and the number of violations of Lipinski's rules. All compounds studied fulfilled Lipinski's five rules and showed interesting predicted bioavailability properties. They also have acceptable tPSA[48] values below 140 Å², suggesting acceptable solubility values above 0.0001 mg/L. The lead antimalarial molecule, plasmodione PD, has a low aqueous solubility and a relatively high lipophilicity. By introducing *N*-heteroatomic moieties, we have attempted to improve these properties. Clear trends in lipophilicity were observed for the *N*-heteroaromatic series. Each addition of aromatic nitrogen tends to reduce the log P by about one unit, from benzyl to pyridine to pyrimidine and triazole. Compared to benzyl (PD) or pyridine (47, 48) or pyrimidine (49, 50) substitution, the introduction of a triazole significantly improved the aqueous solubility of the molecule. Despite improvements in these physico-chemical properties, there is no correlation with their ability to kill the *P. falciparum* parasite. Compounds with poor aqueous solubility and high lipophilic are most likely the most potent against *P. falciparum* (i.e. PD and neutral CQ). Whereas, for their antischistosomal potencies we can conclude that lipophilicity and aqueous solubility are not necessarily determinant in our case, as shown by the diverse physico-chemical profiles of PD (clog P: 4.4), β13 (clog P: 3.1), and β36 (clog P: 1.3), all of which demonstrate strong efficacy against *S. mansoni* adult worms (54.1%, 56.9% and 64.7%, respectively). While González *et al.*[49] suggested an optimal lipophilicity (clog P ≤ 2.5) for better aqueous solubility and parasite penetration to enhance antischistosomal potency, our compounds deviate from this trend, with PD and β13 exhibiting higher clog P values. Despite this, they remain highly effective, similar to praziquantel (clog P: 2.4), suggesting that in this case, the relationship between physico-chemical properties and antischistosomal activity may involve

other factors rather than just lipophilicity and aqueous solubility. The introduction of α- or β-TRZ into our pharmacophores has enabled us to make progress towards our goal of identifying more potent compounds with improved PK properties against various parasites of interest.

## Redox Properties of [TRZ-Methyl]-Menadiones

To provide a possible explanation for the lack of activity of this series against *P. falciparum* and the contrast that exists between the activities against *S. mansoni* worms and *P. falciparum* parasite, we investigated the redox properties of the menadione electrophore for α- or β-[TRZ-methyl]-menadiones (Figure 2). For the sake of comparison, β-[TRZ-methyl]-menadione β36 and α-[TRZ-methyl]-menadione α29 bearing a hydroxymethyl substituent on the TRZ moiety were studied and compared to PD used as reference (Figure S1–S10 in the SI). The typical electrochemical profile of menadione derivatives, including PD and PDO, has been already described in detail in previous studies.[17,37,38] It relies on two consecutive one-electron reversible waves, which correspond to the sequential reduction of the 1,4-naphthoquinone core leading to the semi-naphthoquinone and dihydro-naphthoquinone, respectively. In this work, we have not considered anode potentials greater than 0.1 V. The comparison of the redox properties of β36 (β-TRZ, (Figure S2 in the SI) with the benzylmenadione PD (Figure S1 in the SI) firstly shows a comparable electrochemical profile (Table 4), except for a third irreversible wave observed at a much more negative value of −1.88 V (vs. Ag/AgCl/3 M KCl), which could be attributed to the reduction of the triazole unit (Figure S3 in the SI).[50,51] While the methylene bridge is expected to act as an effective electronic insulator, the weak differences observed for the two redox waves can be explained by possible non-covalent interactions (e.g., hydrogen bond[52]

<table><caption>**Table 4.** Predicted physico-chemical parameters of the most potent compounds.</caption><thead><tr><th>Cpnd</th><th>MW<sup>[a]</sup></th><th>HBA/HBD<sup>[b]</sup></th><th>Number of rotatable bonds</th><th>tPSA<sup>[c]</sup></th><th>clog P<sup>[d]</sup></th><th>Solubility<sup>[e]</sup></th><th>Lipinski violations<sup>[f]</sup></th></tr></thead><tbody><tr><td>Ref values</td><td>≤ 500</td><td>≤ 10/≤ 5</td><td>≤ 10</td><td>≤ 140</td><td>≤ 5</td><td>> 0.0001</td><td>≤ 1</td></tr><tr><td>β13</td><td>343.38</td><td>4/0</td><td>4</td><td>64.85</td><td>3.09</td><td>23.0</td><td>0</td></tr><tr><td>β18</td><td>465.54</td><td>7/0</td><td>8</td><td>97.63</td><td>2.48</td><td>70.9</td><td>0</td></tr><tr><td>β36</td><td>297.31</td><td>5/1</td><td>4</td><td>85.08</td><td>1.35</td><td>1490</td><td>0</td></tr><tr><td>β38</td><td>400.42</td><td>7/0</td><td>5</td><td>68.09</td><td>2.69</td><td>43.1</td><td>0</td></tr><tr><td>47</td><td>331.29</td><td>6/0</td><td>3</td><td>47.03</td><td>3.79</td><td>15.4</td><td>0</td></tr><tr><td>48</td><td>331.29</td><td>6/0</td><td>3</td><td>47.03</td><td>3.77</td><td>15.4</td><td>0</td></tr><tr><td>49</td><td>332.28</td><td>7/0</td><td>3</td><td>59.92</td><td>3.28</td><td>39</td><td>0</td></tr><tr><td>50</td><td>332.28</td><td>7/0</td><td>3</td><td>59.92</td><td>3.26</td><td>39</td><td>0</td></tr><tr><td>PD</td><td>330.30</td><td>5/0</td><td>3</td><td>34.14</td><td>4.43</td><td>6.89</td><td>0</td></tr><tr><td>CQ</td><td>319.87</td><td>2/1</td><td>8</td><td>28.16</td><td>4.15</td><td>9.05</td><td>0</td></tr><tr><td>Praziquantel</td><td>312.41</td><td>2/0</td><td>2</td><td>40.62</td><td>2.4</td><td>94.3</td><td>0</td></tr></tbody></table>

<footnote>[a] Molecular weight (g/mol). [b] Number of hydrogen bond acceptors/number of hydrogen bond donors. [c] Total polar surface area (Å²). [d] Average of five predicted logarithm of compound's partition coefficient between n-octanol and water. [e] Solubility (mg/L). [f] Number of violations of Lipinski's rules.</footnote>
<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /><figcaption>**Figure 2.** Comparison of the CV spectra recorded for α29 (1.07 mM, blue curve) PD (1.13 mM, black curve) and β36 (0.93 mM, red curve). Solvent: DMSO; *I* = 0.1 M *n*-Bu₄NPF₆; *v* = 200 mV s⁻¹. Reference electrode = KCl(3 M)/Ag/AgCl; working electrode = glassy carbon disk of 0.07 cm² area; auxiliary electrode = Pt wire.</figcaption></figure>

between the triazole and the negatively charged semiquinone,[53,54] CH-π or dipole-dipole[37]).

The study of the electrochemical properties of the α-[TRZ-methyl]-menadione α29 is much more complex. Although it is characterized by two main redox waves separated by more than 600 mV comparable to β36 and PD, each of the main waves is composed of two reversible waves separated by about 170 mV for the first redox process and about 100 mV for the second one (Figure S4 in the SI). Similarly to β36, a third irreversible redox wave can be observed at more negative potentials (−1.63 V vs. Ag/AgCl/3 M KCl) that can be assigned to the TRZ unit. It is interesting to note that when the scanning potential is shifted to more negative values (down to −2.5 V, Figure S5 in the SI), a change in the intensity of each of the 2 waves corresponding to each 1-electron transfer process is observed, but without changing the global shape (i.e. position of each redox peaks) of the voltammogram. Regardless of the complexity of the α29 voltammogram, its CV and SWV profiles remain comparable to that of β36, with the first redox waves at the same potentials as PD and β36 and a second redox wave that is more oxidizing than that measured for PD and comparable to that of β36 (Table 5, Figure S6 in the SI). Note that the electronic UV-visible absorption spectra recorded for these three compounds (i.e. PD, β36 and α29) are comparable

indicating an unaffected 1,4-naphthoquinone core (π-π* transitions centered at about 330 nm, Figure S7 in the SI) by the benzyl or TRZ-methyl substitution. The main structural differences between β36 and α29 are: i) the position of the α- or β-TRZ-methyl relative to the menadione core and ii) the position of the substituent on the triazole. To first investigate the possible effect of the hydroxymethyl substituent, we performed the same electrochemical experiment on the unsubstituted α-[TRZ-methyl]-menadione α8 (Figures S8 and S9 in the SI). α8 displays exactly the same profile as α29 (when reduced to −2.0 V or to −2.5 V), implying that only the triazole position (α-TRZ vs. β-TRZ) relative to menadione alters the electrochemical profile without any influence of the hydroxymethyl substituent (Figure S10 in the SI). We therefore hypothesized that for α-[TRZ-methyl]-menadiones a new electroactive product is generated during the electrochemical process,[55] a product also characterized by two reversible redox waves shifted towards anodic currents of more than 100 mV. This new unidentified species most likely involves the α-[TRZ-methyl] unit, the intensity ratio of each of the redox waves being modified according to the potential window considered.

### ‘Benzylic’ Oxidation of [TRZ-Methyl]-Menadiones

Based on our previous work with PD and its analogues[6,12,16] (i.e. benzyl oxidation to produce a highly active metabolite), the biological activity of [TRZ-methyl]-menadiones in *P. falciparum* could be based on their ability to undergo oxidation at the same carbon position *in vivo* to produce an active metabolite. In the case of [TRZ-methyl]-menadiones, the phenyl group has been indeed replaced by a heteroaromatic fragment and the nitrogen atom substituted to the methylene bridge (oxidation position) could therefore have a significant effect on oxygen insertion and therefore menadione activity. Note that for triazoles in the α-position, oxidation of the methylene group would lead to an amide bond after oxidation, which could significantly alter the redox properties of the naphthoquinone electrophore. [TRZ-methyl]-menadiones have little or no activity against *P. falciparum* (Table 2) and this lack of activity may be related to the inability of these compounds to generate the oxidized metabolite.

To investigate this property further, we used the photo-redox conditions established by our team,[11,12] which allow the oxidation of 3-benzylmenadione (in the presence of O₂) under

<table><caption>**Table 5.** Electrochemical data measured using cyclic voltammetry (CV).</caption><thead><tr><th>Compound</th><th>E<sup>1</sup><sub>1/2</sub>(ΔE)<sup>[a]</sup>/E<sup>1/2</sup><sub>1/2</sub><sup>[b]</sup><br>[V(mV)]<sup>[a]</sup>/[V]<sup>[b]</sup></th><th>E<sup>1</sup><sub>1/2</sub>(ΔE)<sup>[a]</sup>/E<sup>1/2</sup><sub>1/2</sub><sup>[b]</sup><br>[V(mV)]<sup>[a]</sup>/[V]<sup>[b]</sup></th><th>E<sup>2</sup><sub>1/2</sub>(ΔE)<sup>[a]</sup>/E<sup>2</sup><sub>1/2</sub><sup>[b]</sup><br>[V(mV)]<sup>[a]</sup>/[V]<sup>[b]</sup></th><th>E<sup>2</sup><sub>1/2</sub>(ΔE)<sup>[a]</sup>/E<sup>2</sup><sub>1/2</sub><sup>[b]</sup><br>[V(mV)]<sup>[a]</sup>/[V]<sup>[b]</sup></th><th>E<sup>3</sup><sub>1/2</sub>(ΔE)<sup>[a]</sup>/E<sup>3</sup><sub>1/2</sub><sup>[b]</sup><br>[V(mV)]<sup>[a]</sup>/[V]<sup>[b]</sup></th></tr></thead><tbody><tr><td>PD<sup>[c]</sup></td><td>−0.63 (84)/−0.59</td><td>NA</td><td>−1.35 (88)/−1.32</td><td>NA</td><td>NA</td></tr><tr><td>β36</td><td>−0.64 (90)/−0.61</td><td>NA</td><td>−1.31 (164)/−1.28</td><td>NA</td><td>−1.88</td></tr><tr><td>α29</td><td>−0.67 (86)/−0.65</td><td>−0.50 (84)/−0.49</td><td>−1.41 (76)/−1.34</td><td>−1.26 (102)/−1.23</td><td>−1.63</td></tr><tr><td>α8</td><td>−0.68 (88)/−0.65</td><td>−0.52 (64)/−0.48</td><td>−1.39/−1.24<sup>[d]</sup></td><td></td><td>−1.62</td></tr></tbody></table>

<footnote>[a] and Square Wave Voltammetry (SWV). [b] Solvent: DMSO; *I* = 0.1 M *n*-Bu₄NPF₆, *v* = 200 mV s⁻¹. NA: not applicable. [c] PD data from ref. [12,37]. [d] blended signals.</footnote>
<figure><img src="image_22.png" /></figure>

reducing conditions (photoirradiation with a hydrogen donor). These conditions perfectly mimic the enzymatic catalytic conditions. Menadione is known to be reduced to dihydro-menadione via a semi-quinone by photoreduction in isopropanol,[56] and we have demonstrated that benzylic oxidation is possible by insertion of O₂ from the corresponding reduced species.[11,12] We therefore subjected two [TRZ-methyl]-menadiones bearing inert substituents to photo-oxidation conditions (UV irradiation for 72 h in an oxygen atmosphere), namely compounds α14 and β13 (Scheme 7). These experiments were performed in a dichloromethane/isopropanol (1/1) mixture to avoid solubility issues. As expected, only β51, the oxidized form of β13, was obtained in 27% yield, while α14 either remained intact or underwent degradation due to the high-energy excitation conditions. These data are in excellent agreement with the antiplasmodial activities (Table 2), which show that the α-[TRZ-methyl]-menadiones have little or no activity against this pathogen, while the β-analogues are moderately active compared to PD. This also suggests different action or drug transport mechanisms in S. mansoni, as we were able to clearly demonstrate that both α- and β-[TRZ-methyl]-menadiones were active on NTS and adult worms.

To go even further, 3-benzylmenadiones can be chemically oxidized to benzoyl derivatives under harsher conditions. Indeed, Baltas et al. have described[57] a method for the preparation of α-keto-1,2,3-triazoles from benzyl-triazoles in the presence of tert-butyl hydroperoxide (TBHP) and catalytic amounts of copper iodide (Scheme 7). However, neither α- nor β-[TRZ-methyl]-menadiones were found to be reactive under these experimental conditions. This may be explained by the fact that the 1,4-naphthoquinone is a very electron-deficient group, already highly oxidized and acting as a strong EWG presumably requiring much harsher conditions. Among the numerous systems considered by Baltas et al.,[57] only nitrobenzyl was tested (NO₂ is a potent EWG that can be reduced). In the same report, no oxidation of the N-substituted benzyl moiety of the triazole ring was described as possible, confirming our hypothesis that α-[TRZ-methyl]-menadiones cannot be oxidized. We thus confirm that oxidation of β-[TRZ-methyl]-menadiones is possible *in tubo* (27% for β51) and that this is similar to the conversion observed for PD (37%) under

comparable experimental conditions.[58] In the case of α-[TRZ-methyl]-menadiones or the various 5-membered-N-heteroaromatic menadiones, the presence of a nitrogen atom in the α-position significantly reduces this possibility, leading to compounds with little or no activity against P. falciparum.

## Conclusions

Our goal was to revisit and improve the antiparasitic bMD series with the introduction of a triazole as "MedChem friendly" moiety. In this study, we were able to synthesize a library of about 30 compounds distributed in two series of α- and β-[TRZ-methyl]-menadiones, through one single step using CuAAC click chemistry. This modification led to a clear increase of aqueous solubility while decreasing the lipophilicity of our compounds, which significantly improved their bioavailability. However, their antimalarial evaluation revealed that, 1,2,3-triazoles were not internalized/active in general. By contrast, β-[TRZ-methyl]-menadiones β13 and β36 were highly potent against *in vitro* adult S. mansoni worms. Therefore, this highlights that the introduction of α- or β-TRZ-methyl resulted in differential antimalarial *versus* antischistosomal activities of compounds. To explain this contrast, we evaluated their electrochemical properties and their ability to undergo benzylic oxidation via a photo-reduction process. We demonstrated that the 1,2,3-triazole moiety does not necessarily affect the redox properties of the menadione core, while the insertion of oxygen in the benzylic position was totally altered, making the generation of the active metabolite in *P. falciparum* impossible for an α-TRZ and not favored for a β-TRZ. This study clearly raises the question that 3-benzylmenadiones or [TRZ-methyl]-menadiones share different MoA/penetration processes in S. mansoni worms compared to those in *P. falciparum* parasite. Future studies will aim to continue the development of [TRZ-methyl]-menadione series for a better SAR comprehension as antischistosomal compounds while investigate their MoA and evaluate possible distinct biological targets or drug transport mechanisms.

## Experimental Section

### General

All reagents and solvents were purchased from commercial sources and used as received, unless otherwise stated. The ¹H, ¹⁹F {¹H} and, and ¹³C {¹H} NMR spectra were obtained with CDCl₃, MeOD or acetone-d₆ as deuterated solvents using a 400 MHz or a 500 MHz spectrometer. Chemical shifts were reported in parts per million (δ). ¹H NMR data were reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz) and integration). Multiplicities are reported as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, quintuplet, or their combinations. High resolution mass spectroscopy (HRMS) spectra were recorded using electron spray ionization (ESI).

<figure><img src="image_23.png" /><figcaption>**Scheme 7.** Oxidation of α- or β-[TRZ-methyl]-menadiones via UV-irradiation or chemical conditions. Conditions: [a] DCM/iPrOH (1/1, 0.01 M), under O₂ atmosphere and UV-irradiation 350 nm (i.e. a Rayonet photochemical reactor equipped with 16 UV lamps of 14 W), 15 °C, 72 h. [b] described from ref. [57]: TBHP (4 equiv.), Cul (0.1 equiv.), MeCN (0.1 M), r.t., 20 h.</figcaption></figure>
<figure><img src="image_24.png" /></figure>

## Synthesis of Precursors

Starting chemicals were purchased from commercial sources, such as Fluorochem, Sigma-Aldrich, BLDpharm or Alfa Aesar. 1,4-Dimethoxy-2-methylnaphthalene,[6] 2-(chloromethyl)-1,4-dimethoxy-3-methylnaphthalene,[18] 1,4-dimethoxy-3-methyl-2-naphthaldehyde 3[59] were synthesized according to previously published methods.

## Synthesis of 1,2,3-[TRZ-Methyl]-Menadiones

1-((1,4-Dimethoxy-3-methylnaphthalen-2-yl)methyl)-4-(trimethylsilyl-yl)-1H-1,2,3-triazole (α6). 1 (50 mg, 0.2 mmol, 1 equiv.) was solubilized in MeCN (2.3 mL). Trimethylsilylacetylene (55 µL, 0.4 mmol, 2 equiv.) was then added under argon. Finally, Cu(MeCN)₄BF₄ (30.5 mg, 0.1 mmol, 0.5 equiv.) was added and the mixture was stirred at 50°C under argon for 72 h. The conversion was monitored by TLC (CHX/EtOAc, 7/3, v/v, UV). The crude was then evaporated, extracted three times with ethyl acetate, dried over magnesium sulphate and the solvent was removed under vacuum. The crude was purified by silica gel chromatography (CHX/EtOAc, 7/3 to 0/10, v/v, UV) to afford 1-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-4-(trimethyl-silyl)-1H-1,2,3-triazole (α6) as a light yellow oil (65 mg, 94.1%). ¹H NMR (400 MHz, CDCl₃) δ 8.16–8.05 (m, 2H), 7.55 (dqd, J=9.7, 6.8, 1.6 Hz, 2H), 7.39 (s, 1H), 5.79 (s, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 2.37 (s, 3H), 0.25 (s, 9H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 151.9, 150.8, 146.7, 129.5, 128.7, 127.2, 126.6, 126.1, 123.5, 122.9, 122.6, 63.2, 61.6, 45.7, 12.3, –1.0. HRMS (ESI+) calcd. for C₁₉H₂₆N₃O₂Si: 356.1789. Found: 356.1794 (M + H⁺).

1-((1,4-Dimethoxy-3-methylnaphthalen-2-yl)methyl)-1H-1,2,3-triazole (α7). To a solution of α6 (63.4 mg, 0.2 mmol, 1 equiv.) in THF (3.5 mL) was added at r.t. a 1 M TBAF solution in THF (0.5 mL, 0.5 mmol, 3 equiv.). The crude mixture was stirred at r.t. for 16 h. The grey mixture was hydrolyzed with saturated aqueous ammonium chloride and extracted three times with ethyl acetate, dried over magnesium sulphate, and the solvent was removed under vacuum. The crude was purified by silica gel chromatography (CHX/EtOAc, 7/3 to 0/10, v/v, UV) to afford 1-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-1H-1,2,3-triazole (α7) as a light yellow solid (33.4 mg, 66.1%). M.p. 111–113 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.14–8.05 (m, 2H), 7.65 (s, 1H), 7.60–7.50 (m, 2H), 7.49 (s, 1H), 5.79 (s, 2H), 3.94 (s, 3H), 3.84 (s, 3H), 2.36 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 151.9, 150.9, 129.6, 127.3, 127.0, 126.4, 126.2, 123.2, 122.9, 122.6, 63.2, 61.6, 46.3, 12.3. HRMS (ESI+) calcd. for C₁₆H₁₈N₃O₂: 284.1393. Found: 284.1395 (M + H⁺).

2-((1H-1,2,3-triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione (α8). To a stirred solution of α7 (33.4 mg, 0.1 mmol, 1 equiv.) and tetrabutylammonium iodide (87.1 mg, 0.2 mmol, 2 equiv.) in dry DCM (17.4 mL) was added dropwise boron trichloride (0.7 mL, 0.7 mmol, 6 equiv.) at –78 °C. The reaction mixture was then allowed to reach r.t. and stirred for 16 h. The yellow reaction mixture was quenched with water and extracted three times with DCM, dried over magnesium sulphate, and the solvent was removed under vacuum. The crude was purified by silica gel chromatography (DCM, UV) to afford 2-((1H-1,2,3-triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione (α8) as an orange solid (12 mg, 40.2%). M.p. 79–81 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.22 (d, J=1.4 Hz, 1H), 8.16–8.05 (m, 2H), 7.82–7.77 (m, 2H), 5.77 (s, 2H), 2.51 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 183.89, 183.82, 150.6, 135.7, 134.9, 134.5, 132.1, 131.4, 131.1, 128.5, 127.3, 126.8, 48.4, 13.7. HRMS (ESI+) calcd. for C₁₄H₁₂N₃O₂: 254.0924. Found: 254.0923 (M + H⁺).

## General Procedure for CuAAC Click Reaction

### Procedure [a]

The azide 9 (1 equiv.) or the alkyne 10 (1 equiv.) was mixed with the corresponding crude of alkyne or azide (1.2 equiv.) in THF (70% of 0.02 M). A solution of sodium ascorbate (0.4 equiv.) and CuSO₄ (0.2 equiv.) prepared in water (30% of 0.02 M) was then added. The mixture was stirred at r.t. for 16 h. The organic solvent was removed under reduced pressure, extracted three times with DCM, washed with water, dried over magnesium sulphate, and the solvent was removed under vacuum. The crude was purified by silica gel chromatography using the appropriate eluent (see below). All the yields are calculated in two steps, since the alkyne or azide are not purified.

2-((3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)-1H-1,2,3-triazol-1-yl)ethyl 4-methylbenzenesulfonate (β25). With 12, eluent (CHX/EtOAc, 8/2 to 6/4, v/v, UV), yellow solid, 42.6% yield. M.p. 87–89 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.06 (dt, J=6.2, 3.3 Hz, 2H), 7.71–7.67 (m, 2H), 7.66–7.62 (m, 2H), 7.44 (s, 1H), 7.27 (d, J=8.1 Hz, 2H), 4.55 (t, J=5.2 Hz, 2H), 4.35 (t, J=5.2 Hz, 2H), 4.04 (s, 2H), 2.41 (s, 3H), 2.32 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃) δ 184.1, 183.3, 144.4, 143.9, 143.5, 142.3, 132.6, 132.5, 131.1, 131.0, 130.9, 129.0, 126.8, 125.4, 125.3, 122.1, 66.5, 47.9, 22.5, 20.6, 12.1. HRMS (ESI) calcd. for C₂₃H₂₂N₃O₅S: 452.1314. Found: 452.1275 (M + H⁺).

Tert-Butyl 4-((1-((3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)piperazine-1-carboxylate (α17). With 63, eluent (EtOAc/MeOH, 10/0 to 8/2, v/v, UV), orange solid, 61.6% yield. M.p. 97–99 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.13–8.06 (m, 2H), 7.76–7.72 (m, 2H), 7.66 (s, 1H), 5.54 (s, 2H), 3.64 (s, 2H), 3.40 (t, J=5.1 Hz, 4H), 2.45 (s, 3H), 1.42 (s, 9H). ¹³C {¹H} NMR (126 MHz, CDCl₃) δ 184.7, 184.0, 154.8, 148.7, 144.0, 138.2, 134.3, 134.2, 132.2, 131.5, 126.9, 126.7, 123.9, 79.8, 53.3, 52.7, 45.0, 28.5, 13.4. HRMS (ESI) calcd. for C₂₄H₃₀N₅O₄: 452.2292. Found: 452.2305 (M + H⁺).

2-Methyl-3-((4-((oxetan-3-yloxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (α30). With 67, eluent (EtOAc, v/v, UV), yellow solid, 51.7% yield. M.p. 122–124 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.12–8.05 (m, 2H), 7.76–7.71 (m, 3H), 5.55 (s, 2H), 4.73–4.65 (m, 3H), 4.56–4.53 (m, 2H), 4.52 (s, 2H), 2.45 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃) δ 184.6, 183.9, 148.6, 144.5, 138.1, 134.3, 134.2, 132.1, 131.4, 126.9, 126.6, 123.9, 78.7, 72.3, 62.4, 45.1, 13.3. HRMS (ESI) calcd. for C₁₈H₁₇N₃NaO₄: 362.1111. Found: 362.1106 (M + Na⁺).

2-Methyl-3-((4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (α31). With 62, eluent (EtOAc/MeOH, 10/0 to 8/2, v/v, UV), yellow solid, 29.9% yield. M.p. 127–129 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.09 (ddt, J=7.0, 5.5, 3.7 Hz, 2H), 7.74 (dd, J=5.8, 3.3 Hz, 2H), 7.67 (s, 1H), 5.54 (s, 2H), 3.71–3.65 (m, 4H), 3.63 (s, 2H), 2.57–2.46 (m, 4H), 2.44 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃) δ 184.7, 184.0, 148.6, 143.9, 138.2, 134.3, 134.1, 132.2, 131.5, 126.9, 126.6, 123.9, 66.8, 53.6, 53.4, 44.9, 13.3. HRMS (ESI) calcd. for C₁₉H₂₁N₄O₃: 353.1608. Found: 353.1611 (M + H⁺).

Tert-Butyl ((1-((3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate (α16). With 69, eluent (CHX/EtOAc, 2/8, v/v, UV), orange solid, 54% yield. M.p. 105–107 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.10–8.04 (m, 2H), 7.75–7.69 (m, 2H), 7.66 (s, 1H), 5.52 (s, 2H), 5.13 (s, 1H), 4.33 (d, J=5.8 Hz, 2H), 2.41 (s, 3H), 1.39 (s, 9H). ¹³C NMR (101 MHz, CDCl₃) δ 184.7, 183.8, 155.9, 148.5, 145.5, 138.2, 134.2, 134.1, 132.1, 131.4, 126.8, 126.6, 122.9, 44.9, 36.2, 28.4, 13.3. HRMS (ESI) calcd. for C₂₀H₂₂N₄NaO₄: 405.1533. Found: 405.1533 (M + Na⁺).

2-((4-((Dibenzylamino)methyl)-1H-1,2,3-triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione (α28). With 70, eluent (CHX/EtOAc, 7/3, v/v, UV), orange oil, 8.3% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.11–8.05 (m,
<figure><img src="image_25.png" /></figure>

2H), 7.75-7.69 (m, 2H), 7.62 (s, 1H), 7.39-7.36 (m, 4H), 7.32-7.27 (m, 4H), 7.22-7.18 (m, 2H), 5.53 (s, 2H), 3.72 (s, 2H), 3.59 (s, 4H), 2.45 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 184.7, 183.9, 184.8, 145.4, 139.3, 138.3, 134.2, 134.0, 132.1, 131.5, 128.9, 128.3, 127.0, 126.8, 126.6, 123.8, 57.8, 48.1, 44.9, 13.3. HRMS (ESI) calcd. for C₂₉H₂₇N₄O₂: 463.2128. Found: 463.2136 (M + H⁺).

**2-(4-((3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)-1H-1,2,3-triazol-1-yl)acetonitrile** (β26). With 60, eluent (CHX/EtOAc, 6/4, v/v, UV), orange solid, 26.8% yield. M.p. 112-114 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.11-7.96 (m, 2H), 7.70-7.65 (m, 2H), 7.64 (s, 1H), 5.27 (s, 2H), 4.08 (s, 2H), 2.34 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 185.1, 184.5, 145.9, 145.4, 142.9, 133.8, 133.7, 132.2, 131.9, 126.6, 126.4, 122.6, 112.7, 37.5, 23.7, 13.3. HRMS (ESI) calcd. for C₁₆H₁₃N₄O₂: 293.1033. Found: 293.1036 (M + H⁺).

**2-((4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione** (α32). With 64, eluent (EtOAc/MeOH, 95/5, v/v, UV), orange oil, 25.1% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (td, J=6.0, 3.3 Hz, 2H), 7.74 (dd, J=5.8, 3.3 Hz, 2H), 7.65 (s, 1H), 5.54 (s, 2H), 3.66 (s, 2H), 2.58 (t, J=5.8 Hz, 4H), 2.45 (s, 3H), 2.01-1.90 (m, 4H). ¹⁹F {¹H} NMR (377 MHz, CDCl₃) δ -98.13. ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 184.7, 184.0, 148.6, 144.5, 138.2, 134.3, 134.2, 132.2, 131.5, 126.9, 126.6, 123.8, 52.5, 49.9 (t, J=5.4 Hz), 45.0, 33.9 (t, J=23.1 Hz), 13.3. HRMS (ESI) calcd. for C₂₀H₂₁O₂N₄F₂: 387.1627. Found: 387.1635 (M + H⁺).

**Tert-Butyl 4-((1-((3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)piperazine-1-carboxylate** (α34). With 65, eluent (EtOAc/MeOH, 90/10, v/v, UV), orange oil, 16.9% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.14-8.06 (m, 2H), 7.75 (dd, J=5.8, 3.3 Hz, 2H), 7.70 (s, 1H), 5.56 (s, 2H), 3.76 (s, 2H), 2.80 (t, J=6.1 Hz, 4H), 2.46 (s, 3H), 2.44 (t, J=6.1 Hz, 4H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 208.8, 184.7, 184.1, 148.7, 144.4, 138.2, 134.3, 134.2, 132.2, 131.5, 126.9, 126.7, 123.9, 52.8, 52.4, 45.1, 41.2, 13.4. HRMS (ESI) calcd. for C₂₀H₂₁O₃N₄: 365.1608. Found: 365.1610 (M + H⁺).

**2-Methyl-3-((4-(thiazolidin-3-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione** (α21). With 66, eluent (EtOAc/MeOH, 9/1, v/v, UV), orange oil, 21.8% yield, contains a small impurity. ¹H NMR (400 MHz, CDCl₃) δ 8.10 (dt, J=5.8, 3.6 Hz, 2H), 7.75 (dd, J=5.8, 3.3 Hz, 2H), 7.71 (s, 1H), 5.56 (s, 2H), 4.07 (s, 2H), 3.65 (s, 2H), 3.09 (t, J=6.6 Hz, 2H), 2.95 (t, J=6.5 Hz, 2H), 2.46 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 184.8, 184.0, 148.7, 145.7, 138.2, 134.3, 134.2, 132.2, 131.5, 126.9, 126.7, 123.7, 60.5, 57.5, 48.0, 45.0, 29.5, 13.4. HRMS (ESI) calcd. for C₁₈H₁₉O₂N₄S: 355.1223. Found: 355.1230 (M + H⁺).

**2-Methyl-3-((1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)methyl)naphthalene-1,4-dione** (β37). With 53, eluent (EtOAc/MeOH, 9/1, v/v, UV), orange oil, 11.9% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.10-8.04 (m, 2H), 7.70 (dd, J=5.8, 3.3 Hz, 2H), 7.51 (s, 1H), 4.38 (t, J=6.4 Hz, 2H), 4.08 (s, 2H), 3.67-3.60 (t, 4H), 2.77 (t, J=6.4 Hz, 2H), 2.47-2.42 (t, 4H), 2.37 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 185.3, 184.7, 145.1, 144.3, 143.8, 133.7, 133.6, 132.3, 132.0, 126.6, 126.3, 122.9, 66.9, 57.9, 53.6, 47.5, 23.8, 13.3. HRMS (ESI) calcd. for C₂₀H₂₃O₃N₄: 367.1760. Found: 367.1764 (M + H⁺).

**2-Methyl-3-((1-(2-(thiazolidin-3-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)naphthalene-1,4-dione** (β22). With 55, eluent (EtOAc/MeOH, 9/1, v/v, UV), yellow solid, 5.7% yield, not stable leads to degradation after few hours. ¹H NMR (400 MHz, CDCl₃) δ 8.21-8.16 (m, 2H), 7.55-7.46 (m, 2H), 6.68 (s, 1H), 3.94 (s, 2H), 3.41-3.36 (m, 2H), 2.86-2.83 (m, 2H), 2.80-2.75 (m, 4H), 2.48 (s, 3H).

**2-Methyl-3-((1-(2-oxopiperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)naphthalene-1,4-dione** (β40). With 56, eluent (EtOAc/MeOH, 9/1, v/v, UV), orange solid, 35.7% yield. M.p. 109-111 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.08-7.97 (m, 2H), 7.70-7.64 (m, 2H), 7.53 (s, 1H), 4.42 (t, J=6.3 Hz, 2H), 4.07 (s, 2H), 2.90 (t, J=6.3 Hz, 2H), 2.75 (t, J=6.0 Hz, 4H), 2.37 (d, J=7.0 Hz, 7H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ

208.2, 185.2, 184.6, 145.0, 143.6, 133.7, 133.6, 132.2, 131.9, 126.5, 126.2, 56.5, 53.1, 48.3, 41.2, 23.8, 13.2. HRMS (ESI) calcd. for C₂₁H₂₂O₃N₄Na: 401.1584. Found: 401.1579 (M + Na⁺).

**2-((1-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-3-methylnaphthalene-1,4-dione** (β38). With 57, eluent (EtOAc/MeOH, 9/1, v/v, UV), orange solid, 49.1% yield. M.p. 110-112 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (ddd, J=9.3, 6.2, 3.3 Hz, 2H), 7.70-7.66 (m, 2H), 7.50 (s, 1H), 4.37 (t, J=6.3 Hz, 2H), 4.07 (s, 2H), 2.81 (t, J=6.2 Hz, 2H), 2.55 (t, J=5.7 Hz, 4H), 2.36 (s, 3H), 1.91 (tt, J=13.6, 5.7 Hz, 4H). ¹⁹F {¹H} NMR (377 MHz, CDCl₃) δ -98.08, -98.34. ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 185.3, 184.6, 145.0, 143.7, 133.7, 133.6, 132.2, 131.9, 126.5, 126.3, 56.6, 50.1, 50.1, 50.0, 48.1, 34.2, 34.0, 33.8, 23.8, 13.2. HRMS (ESI) calcd. for C₂₁H₂₃F₂O₂N₄: 401.1779. Found: 401.1783 (M + H⁺).

**Tert-Butyl 4-(2-((3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)-1H-1,2,3-triazol-1-yl)ethyl)piperazine-1-carboxylate** (β18). With 58, eluent (EtOAc/MeOH, 9/1, v/v, UV), orange oil, 71.3% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.11-8.02 (m, 2H), 7.71-7.67 (m, 2H), 7.50 (s, 1H), 4.38 (t, J=6.4 Hz, 2H), 4.08 (s, 2H), 3.37 (t, J=5.1 Hz, 4H), 2.78 (t, J=6.4 Hz, 2H), 2.40 (t, J=4.9 Hz, 4H), 2.37 (s, 3H), 1.45 (s, 9H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 185.3, 184.7, 154.8, 145.1, 144.3, 143.8, 133.7, 133.6, 132.3, 132.1, 126.6, 126.3, 122.9, 79.9, 57.6, 53.0, 47.8, 28.5, 23.8, 13.3. HRMS (ESI) calcd. for C₂₅H₃₂O₄N₅: 466.2440. Found: 466.2449 (M + H⁺).

### Procedure [b]

Azide 9 (1 equiv.) or alkyne 10 (1 equiv.) was mixed with the corresponding alkyne or azide (1.5 equiv.) in DCM (0.1 M) under argon. Cu(MeCN)₄BF₄ (0.4 equiv.) was then added. The mixture was stirred at 40 °C under argon for 16 h. The organic solvent was removed under reduced pressure, extracted three times with DCM, washed with water, dried over magnesium sulphate, and the solvent was removed under vacuum. The crude was purified by silica gel chromatography using the appropriate eluent (see below).

**2-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)-3-methylnaphthalene-1,4-dione** (β13). With (azidomethyl)benzene 59, eluent (CHX/EtOAc, 6/4, v/v, UV), yellow solid, 91% yield. M.p. 115-117 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.09-7.95 (m, 2H), 7.70-7.65 (m, 2H), 7.35-7.31 (m, 3H), 7.24-7.21 (m, 2H), 5.43 (s, 2H), 4.04 (s, 2H), 2.33 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 185.2, 184.5, 145.1, 144.8, 143.5, 134.7, 133.6, 133.5, 132.2, 131.9, 129.1, 128.7, 128.1, 126.5, 126.3, 122.0, 54.1, 23.7, 13.2. HRMS (ESI) calcd. for C₂₁H₁₇O₂N₃Na: 366.1213. Found: 366.1191 (M + Na⁺).

**2-((4-(2-Hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione** (α27). With 3-methyl-butyrolnol, eluent (CHX/EtOAc, 8/2 to 0/10, v/v, UV), yellow solid, 91% yield. M.p. 113-115 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.20-8.00 (m, 2H), 7.77-7.69 (m, 2H), 7.62 (s, 1H), 5.53 (s, 2H), 2.45 (s, 3H), 1.59 (s, 6H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 184.8, 184.0, 148.7, 138.2, 134.3, 134.1, 132.2, 131.5, 126.9, 126.7, 44.9, 30.5, 13.3. HRMS (ESI) calcd. for C₁₇H₁₈N₃O₃: 312.1343. Found: 312.1334 (M + H⁺).

**2-((4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione** (α29). With 2-propyn-1-ol, eluent (EtOAc, UV), yellow solid, 42% yield. M.p. 109-111 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.21-8.01 (m, 2H), 7.82-7.62 (m, 3H), 5.56 (s, 2H), 4.75 (s, 2H), 2.46 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃) δ 184.6, 183.9, 148.5, 147.6, 138.1, 134.2, 134.1, 132.1, 131.4, 126.8, 126.6, 122.8, 56.6, 44.9, 13.2. HRMS (ESI) calcd. for C₁₅H₁₄N₃O₃: 284.1029. Found: 284.1031 (M + H⁺).
<figure><img src="image_26.png" /></figure>

### Procedure [c]

Azide 9 (1 equiv.) or alkyne 10 (1 equiv.) was mixed with the corresponding alkyne (2 equiv.) or azide respectively (1.5 equiv.) in DCM (0.1 M) under argon. Cu(MeCN)₄BF₄ (0.4 equiv.) and bathoproine (0.4 equiv.) were then added. The mixture was stirred at 40 °C under argon for 72 h. The organic solvent was removed under reduced pressure, extracted three times with DCM, washed with water, dried over magnesium sulphate, and the solvent was removed under vacuum. The crude was purified by silica gel chromatography using the appropriate eluent (see below).

2-((1-(2-Hydroxyethyl)-1H-1,2,3-triazol-4-yl)methyl)-3-methylnaphthalene-1,4-dione (β36). With 11, eluent (CHX/EtOAc, 8/2 to 0/10, v/v, UV), yellow solid, 45.5% yield. M.p. 102–104 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.12–8.03 (m, 2H), 7.72–7.67 (m, 2H), 7.50 (s, 1H), 4.46–4.36 (m, 2H), 4.10 (s, 2H), 4.05 (q, *J* = 5.2 Hz, 2H), 2.38 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃) δ 185.3, 184.7, 145.2, 143.6, 133.8, 133.6, 132.3, 132.1, 126.6, 126.4, 61.4, 52.6, 23.8, 13.3. HRMS (ESI) calcd. for C₁₆H₁₆N₃O₃: 298.1186. Found: 298.1183 (M + H⁺).

2-Methyl-3-((4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (α14). With trimethylsilylacetylene, eluent (CHX/EtOAc, 8/2 to 6/4, v/v, UV), yellow solid, 56.5% yield. M.p. 117–119 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.11–8.05 (m, 2H), 7.75–7.70 (m, 2H), 7.67 (s, 1H), 5.57 (s, 2H), 2.47 (s, 3H), 0.28 (s, 9H). ¹³C {¹H} NMR (126 MHz, CDCl₃) δ 184.8, 184.1, 148.6, 146.8, 138.5, 134.2, 134.1, 132.2, 131.5, 129.9, 126.8, 126.6, 44.3, 13.4, -1.0. HRMS (ESI) calcd. for C₁₇H₂₀N₃O₂Si: 326.1319. Found: 326.1335 (M + H⁺).

### Procedure [d]

Azide 9 (1 equiv.) was mixed with the corresponding alkyne (2 equiv.) in MeCN (0.01 M) under argon. Cu(MeCN)₄BF₄ (0.1 equiv.) and bathoproine (0.1 equiv.) were then added. The mixture was stirred under reflux at 80 °C under argon for 72 h. The organic solvent was removed under reduced pressure, extracted three times with DCM, washed with water, dried over magnesium sulphate, and the solvent was removed under vacuum. The crude was purified by silica gel chromatography using the appropriate eluent (see below).

2-((4-(Bromomethyl)-1H-1,2,3-triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione (α23). With 3-bromopropyne, eluent (CHX/EtOAc, 8/2 to 3/7, v/v, UV), yellow solid, 6% yield, contains a small impurity. M.p. 93–95 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.14–8.08 (m, 2H), 7.79 (s, 1H), 7.75 (dd, *J* = 5.8, 3.3 Hz, 2H), 5.55 (s, 2H), 4.53 (s, 2H), 2.47 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃) δ 184.7, 184.1, 148.8, 138.0, 134.4, 134.2, 132.2, 131.5, 126.9, 126.7, 45.2, 21.6, 13.4. HRMS (ESI) calcd. for C₁₅H₁₃BrN₃O₂: 346.0186. Found: 346.0168 (M + H⁺).

### General Procedure for TFA Deprotection

The Boc-protected 1,2,3-[TRZ-methyl]-menadione (1 equiv.) was solubilized in DCM (0.03 M) and then TFA was added (32 equiv.). The mixture was stirred at r.t. for 1 h. The organic solvent was removed and the crude was dissolved in MeOH and dried under vacuum. This procedure was repeated three times. The same procedure was then carried out with CDCl₃.

2-Methyl-3-((4-(piperazin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)methyl)naphthalene-1,4-dione (α19). From α17, the pure product was obtained quantitatively as a TFA salt, orange solid. M.p. 125–127 °C. ¹H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 8.08–7.94 (m, 2H), 7.81–7.67 (m, 2H), 5.64 (s, 2H), 4.36 (s, 2H), 3.51–3.45 (m, 4H), 3.41 (dd, *J* = 6.9, 3.8 Hz, 4H), 2.36 (s, 3H). ¹³C {¹H} NMR (101 MHz, MeOD) δ 185.8, 184.9, 149.5, 139.3, 135.2, 135.1, 133.5, 132.9, 127.5, 127.3, 58.3, 46.5, 43.6, 41.7, 18.4, 13.1. HRMS (ESI) calcd. for C₁₉H₂₂N₅O₂: 352.1770. Found: 352.1768 (M + H⁺).

2-((4-(Aminomethyl)-1H-1,2,3-triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione (α15). From α16, the pure product was obtained quantitatively as a TFA salt, brown solid. M.p. 127–129 °C. ¹H NMR (500 MHz, MeOD) δ 8.17 (s, 1H), 7.95 (dq, *J* = 7.1, 4.1 Hz, 2H), 7.72 (dt, *J* = 6.3, 3.0 Hz, 2H), 5.62 (s, 2H), 4.27 (s, 2H), 2.33 (s, 3H). ¹³C {¹H} NMR (126 MHz, MeOD) δ 185.7, 184.7, 149.3, 141.2, 139.2, 135.2, 135.1, 133.2, 132.6, 127.4, 127.2, 126.4, 46.3, 35.4, 13.1. HRMS (ESI) calcd. for C₁₅H₁₅N₄O₂: 283.1189. Found: 283.1196 (M + H⁺).

2-Methyl-3-((1-(2-(piperazin-1-yl)ethyl)-1H-1,2,3-triazol-4-yl)methyl)naphthalene-1,4-dione (β20). From β18, the pure product was obtained quantitatively as a TFA salt, brown solid. M.p. 85–87 °C. ¹H NMR (400 MHz, MeOD) δ 8.07–8.01 (m, 2H), 7.85 (s, 1H), 7.78–7.72 (m, 2H), 4.55 (t, *J* = 6.1 Hz, 2H), 4.07 (s, 2H), 3.25–3.21 (m, 4H), 3.05 (t, *J* = 6.1 Hz, 2H), 2.90–2.82 (m, 4H), 2.24 (s, 3H). ¹³C {¹H} NMR (101 MHz, MeOD) δ 186.2, 185.4, 146.1, 145.6, 144.4, 134.8, 134.8, 133.5, 133.3, 127.2, 127.1, 124.8, 57.6, 50.4, 48.1, 44.4, 24.1, 13.1. HRMS (ESI) calcd. for C₂₀H₂₄O₂N₅: 366.1924. Found: 366.1921 (M + H⁺).

### Synthesis of 1,2,4-TRZ-, 3-Nitro-1,2,4-TRZ- and 2-Nitroimidazole-Menadiones

#### General Procedure for SN₂ with 2-(Chloromethyl)-1,4-Dimethoxy-3-Methylnaphthalene

2-(chloromethyl)-1,4-dimethoxy-3-methylnaphthalene (1 equiv.) was dissolved in MeCN (0.05 M). Then the nucleophile (2.5 equiv.) with TEA (3 equiv.) was slowly added. The reaction mixture was stirred under reflux at 80 °C for 16 h. The organic solvent was removed under reduced pressure, extracted three times with DCM, washed with water, dried over magnesium sulphate, and solvent was removed under vacuum. The crude was purified by silica gel chromatography using the appropriate eluent (see below).

1-((1,4-Dimethoxy-3-methylnaphthalen-2-yl)methyl)-1H-1,2,4-triazole (42). With 4H-1,2,4-triazole, eluent (CHX/EtOAc, 3/7, v/v, UV), white solid, 39.8% yield. M.p. 115–117 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.19–8.04 (m, 2H), 7.97 (s, 1H), 7.93 (s, 1H), 7.64–7.45 (m, 2H), 5.58 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.38 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 152.1, 151.8, 150.9, 129.6, 127.3, 127.1, 126.2, 126.2, 122.9, 122.9, 122.6, 63.2, 61.7, 46.0, 12.4. HRMS (ESI) calcd. for C₁₆H₁₈O₂N₃: 284.1393. Found: 284.1402 (M + H⁺).

1-((1,4-Dimethoxy-3-methylnaphthalen-2-yl)methyl)-3-nitro-1H-1,2,4-triazole (45). With 3-nitro-1,2,4-triazole, eluent (CHX/EtOAc, 8/2 to 4/6, v/v, UV), yellow oil, 50.4% yield. ¹H NMR (400 MHz, MeOD) δ 8.58 (s, 1H), 8.06–7.97 (m, 2H), 7.57–7.40 (m, 2H), 5.68 (s, 2H), 3.93 (s, 3H), 3.80 (s, 3H), 2.41 (s, 3H). ¹³C {¹H} NMR (101 MHz, MeOD) δ 153.6, 151.9, 147.2, 130.8, 128.3, 128.1, 127.3, 127.1, 123.8, 123.5, 123.4, 63.5, 61.9, 48.3, 12.6. HRMS (ESI) calcd. for C₁₆H₁₆O₄N₄Na: 351.1064. Found: 351.1071 (M + Na⁺).

1-((1,4-Dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-nitro-1H-imidazole (46). With 2-nitroimidazole, eluent (CHX/EtOAc, 8/2 to 4/6, v/v, UV), yellow oil, 78.9% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.18–8.01 (m, 2H), 7.60–7.45 (m, 2H), 6.95 (d, *J* = 1.2 Hz, 1H), 6.61 (d, *J* = 1.2 Hz, 1H), 5.79 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.24 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 152.3, 150.9, 145.2, 129.6, 128.2, 127.4, 126.9, 126.3, 125.6, 124.2, 122.8, 122.5, 122.0, 63.1, 61.5, 45.9, 11.9. HRMS (ESI) calcd. for C₁₇H₁₇O₄N₃Na: 350.1111. Found: 350.1115 (M + Na⁺).
<figure><img src="image_27.png" /></figure>

General Procedure for the Oxidative Demethylation

Boron trichloride (6 equiv.) was added dropwise at –78°C to a stirred solution of the protected substituted menadione and tetrabutylammonium iodide (2 equiv.) in dry DCM (0.007 M). The reaction mixture was then allowed to heat to r.t. and stirred for 16 h. The yellow reaction mixture was quenched with water and the crude was extracted three times with DCM, dried over magnesium sulphate, and the solvent was removed under vacuum. The crude was purified by silica gel chromatography using the appropriate eluent.

2-((1H-1,2,4-Triazol-1-yl)methyl)-3-methylnaphthalene-1,4-dione (41). From 42, eluent (CHX/EtOAc, 8/2 to 0/10, v/v, UV), orange solid, 20.9% yield. M.p. 129–131 °C. ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H), 8.55 (s, 1H), 8.19–8.08 (m, 3H), 7.81–7.76 (m, 2H), 5.52 (s, 2H), 2.51 (s, 3H). ¹³C NMR {¹H} (101 MHz, CDCl₃) δ 184.0, 183.8, 149.8, 145.9, 142.9, 135.5, 134.8, 134.6, 132.1, 131.1, 127.2, 127.1, 47.5, 13.7. HRMS (ESI) calcd. for C₁₄H₁₂O₃N₃: 254.0924. Found: 254.0928 (M + H⁺).

2-Methyl-3-((3-nitro-1H-1,2,4-triazol-1-yl)methyl)naphthalene-1,4-dione (43). From 45, eluent (CHX/EtOAc, 8/2 to 5/5, v/v, UV), yellow solid, 25.7% yield, very low solubility in deuterated solvent no ¹³C NMR spectra was obtained. M.p. 132–134 °C. ¹H NMR (400 MHz, acetone-d₆) δ 8.79 (s, 1H), 8.13–7.99 (m, 2H), 7.92–7.81 (m, 2H), 5.68 (s, 2H), 2.44 (s, 3H). HRMS (ESI) calcd. for C₁₄H₁₀O₄N₄Na: 321.0594. Found: 321.0591 (M + Na⁺).

2-Methyl-3-((2-nitro-1H-imidazol-1-yl)methyl)naphthalene-1,4-dione (44). From 46, eluent (CHX/EtOAc, 8/2 to 0/10, v/v, UV), orange solid, 14.6% yield. M.p. 132–134 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.16–8.04 (m, 2H), 7.79–7.74 (m, 2H), 7.17 (d, *J* = 1.2 Hz, 1H), 7.12 (d, *J* = 1.2 Hz, 1H), 5.68 (s, 2H), 2.33 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 184.4, 183.8, 148.4, 138.1, 134.4, 134.4, 132.0, 131.6, 128.6, 126.9, 126.8, 126.1, 45.3, 13.4. HRMS (ESI) calcd. for C₁₅H₁₂O₄N₃: 298.0822. Found: 298.0845 (M + H⁺).

Oxidation of 1,2,3-[TRZ-Methyl]-Menadione by UV-Irradiation

Reactions were irradiated with a 350 nm light generated by eight RPR-3500 A lamps of 200 W with a photochemical reactor for 72 h at a distance of 3 cm from the light source.

2-(1-Benzyl-1H-1,2,3-triazole-4-carbonyl)-3-methylnaphthalene-1,4-dione (β51). In a tube was dissolved in a mixture of propan-2-ol (0.74 mL) and DCM (0.92 mL), followed by β13 (55 mg, 0.16 mmol, 1 equiv.). The mixture was bubbled in O₂ for 5 min, then stirred under O₂ pressure at 16 °C for 72 h under UV irradiation. The solvent was removed under vacuum and purified by silica gel chromatography (CHX/EtOAc, 8/2, v/v, UV) to afford 2-(1-benzyl-1H-1,2,3-triazole-4-carbonyl)-3-methylnaphthalene-1,4-dione (15.6 mg, 27.2%) as orange solid. M.p. 115–117 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.17–8.11 (m, 2H), 8.08–8.03 (m, 1H), 7.78–7.73 (m, 2H), 7.43 (dd, *J* = 5.1, 2.0 Hz, 2H), 7.35–7.32 (m, 2H), 5.58 (s, 2H), 2.10 (s, 3H). ¹³C {¹H} NMR (101 MHz, CDCl₃) δ 187.2, 185.1, 183.4, 147.5, 144.2, 143.8, 134.2, 134.1, 133.2, 132.1, 131.8, 129.6, 129.6, 128.8, 126.8, 126.5, 126.4, 54.8, 13.7. HRMS (ESI) calcd. for C₂₁H₁₆N₃O₃: 358.1186. Found: 358.1183 (M + H⁺).

Supporting Information Summary

Supporting Information (SI) content: pages S2–S8 (Figures S1–S10) – electrochemistry CV, SWV curves and UV-visible absorption curves; pages S9–S11: synthesis of precursors; page S12 (Table S1) – CuAAC reaction with 1 using different conditions; pages S13–S15 – By-product and reduction after CuAAC from 1; pages S16–S17 – synthesis of azido-substrates engaged in the CuAAC reaction

to form b-[TRZ-methyl]-menadione; pages S18–S19 – synthesis of alkyne-substrates engaged in the CuAAC reaction to form a-[TRZ-methyl]-menadione; pages S20–S65 – ¹H, ¹⁹F {¹H} and ¹³C {¹H} NMR spectra of compounds 1–β51.

The authors have cited additional references within the Supporting Information.[60–78]

Acknowledgements

E.D.-C. wish to thank the Laboratoire d'Excellence (LabEx) ParaFrap [ANR-11-LABX-0024], for funding, providing B.D.'s PhD salary, and for initiating and fostering this scientific research and collaboration. This work was furthermore supported by the Agence Nationale de la Recherche, France (Program ANR-PRCI with the Swiss National Science Foundation (SNF), Project "ROSaction", grant ANR-22-CE93-0005-01 and SNF 315230L_212983 to E.D.-C., M.R., P.M, and J.K. The laboratory (E.D.-C.) also received support from CNRS and from the University of Strasbourg.

Conflict of Interests

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

Keywords: Click chemistry (or CuAAC) • Plasmodione • 1,2,3-triazole • Plasmodium falciparum • Schistosoma mansoni

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Manuscript received: September 14, 2024

Revised manuscript received: December 11, 2024

Accepted manuscript online: December 16, 2024

Version of record online: January 8, 2025
RESEARCH ARTICLE

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The present study describes the synthesis and thorough investigation of 1,2,3-triazole-methyl-menadione derivatives with particular emphasis on their electrochemical and physico-chemical properties and their antiparasitic activities against *Plasmodium*

*falciparum* and *Schistosoma mansoni*. Although less effective against *P. falciparum*, several compounds showed potent antischistosomal activity, highlighting their potential to develop more effective candidates for the treatment of schistosomiasis.

B. Dupouy, T. Karpstein, C. Häberli, M. Cal, Dr. M. Rottmann, Prof. Dr. P. Mäser, Prof. Dr. J. Keiser, Dr. B. Cichocki, Dr. M. Elhabiri, Dr. E. Davioud-Charvet*

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Synthesis of 1,2,3-Triazole-Methyl-Menadione Derivatives: Evaluation of Electrochemical and Antiparasitic Properties against two Blood-Dwelling Parasites

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