bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Indole and Pyridazinoindole Analogs — Synthesis and Study as Inhibitors of Phosphodiesterases and as Inhibitors of Blood Platelet Aggregation
Authors: Monge Antonio , Navarro María‐Eugenia , Font María , Santiago Esteban , Alberdi Elena , Martínez‐Irujo Juan‐José 
Published: October 2006

AbstractThis paper presents the synthesis of new indole, pyridazino[4,5‐b]indole, and pyridazino[4,5‐a]indole analogs as well as a study of their “in vitro” activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro‐aggregants, is also included. The selected compounds 8‐benzyloxy‐3,4‐dihydro‐1‐(3,4,5‐trimethoxy)benzylideneaminopyridazino[4,5‐b]indole 14g, and 8‐benzyloxy‐4‐[(3,5‐dimethyl)pyrazolyl]pyridazino[4,5‐b]indole 20 present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8‐benzyloxy‐3,4‐dihydro‐1‐[4‐(methyl)piperazino]acetamidopyridazino[4,5‐b]indol‐4‐one 16c and 8‐benzyloxy‐3,4‐dihydro‐1‐[4‐(2‐methoxyphenyl)piperazino]acetamidopyridazino[4,5‐b]indol‐4‐one 16f stood out as inhibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade.
4‐(4‐Guanidinobenzoyl)‐2‐imidazolones and Related Compounds: Phosphodiesterase Inhibitors and Novel Cardiotonics with Combined Histamine H2 Receptor Agonist and PDE III Inhibitor Activity
Authors: Glaß D. , Buschauer A. , Tenor H. , Bartel S. , Will‐Shahab L. , Krause E.‐G. 
Published: October 2006

AbstractA series of new positive inotropic agents was synthesized with the aim of combining the pharmacophores of the imidazolone‐type phosphodiesterase (PDE) inhibitor enoximone and guanidine‐type histamine H2 receptor agonists such as arpromidine. All compounds are para‐substituted 4‐benzoyl‐5‐alkyl‐2‐imidazolones. H2 agonism was incorporated by p‐(hetero)arylalkyl substituents, in particular by an imidazolylpropyl guanidine group. In addition analogous ureas, cyanoguanidines, alkyl guanidine carboxylates, and amides were prepared. These functional groups were either directly attached to the phenyl ring or linked by an appropriate spacer. The compounds were screened for positive inotropic activity in the isolated electrically stimulated guinea pig papillary muscle and for inhibition of PDE III (cGMP‐inhibited cAMP PDE, isolated from guinea pig heart). The cardiotonics obtained proved to be either PDE III inhibitors, some of them surmounting up to 3‐fold the potency of enoximone, or pharmacological hybrids combining both PDE III inhibitor and histamine H2 receptor agonist activities. These hybrids were the most potent positive inotropic substances at the papillary muscle, probably due to their synergistic mechanism of action. The participation of histamine H2 receptors could be demonstrated in the papillary muscle preparation by pretreatment with the H2 antagonist famotidine (10 μM) as well as by further pharmacological experiments using isolated perfused hearts of guinea pigs and rats, isolated guinea pig right atria, adenylyl cyclase and H2 receptor binding assays. At equieffective concentrations the moderate PDE III inhibitor and histamine H2 agonist N1‐{4‐[(1,3‐dihydro‐5‐methyl‐2‐oxo‐3H‐imidazol‐4‐yl)‐carbonyl]phenyl}‐N2‐[3‐(1H‐imidazol‐4‐yl)propyl]guanidine 65 and the 5‐ethyl homologue 66 were about 2 and 10 times more potent than enoximone at the papillary muscle. Moreover, both compounds produced a 2.5‐fold higher maximal response than the reference compound.
Asymmetric Synthesis and Enantiospecificity of Binding of 2‐(1,2,3,4‐Tetrahydro‐1‐isoquinolyl)‐ethanol Derivatives to μ and κ Receptors
Authors: Wanner Klaus Th. , Praschak Ilona , Höfner Georg , Beer Herbert 
Published: October 2006

AbstractA number of 2‐(1,2,3,4‐tetrahydro‐1‐isoquinolyl)‐ethanol derivatives 7a—e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at μ and κ opioid receptors. The amido ketones 5a—c and ent‐5a—c, which were accessible by employing 3b and ent‐3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a—c and ent‐5a—c the amido alcohols l‐6a—c, u‐6a—c, ent‐l‐6a—c and ent‐u‐6a—c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l‐7a—c, u‐7a—c, ent‐l‐7a—c and ent‐u‐7a—c and upon reductive methylation of l‐7b—c, u‐7b—c, ent‐l‐7b—c and ent‐u‐7b—c with CH2O and NaCNBH3 the tertiary amino alcohols l‐7d—e, u‐7d—e, ent‐l‐7d—e and ent‐u‐7d—e were obtained.The binding affinities of the final compounds l‐7a—e, u‐7a—e, ent‐l‐7a—e and ent‐u‐7a—e at both the μ and the κ receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the μ than at the κ receptor. For the secondary amino alcohols 7a—c the affinity at the μ receptor followed the stereochemical order l‐7 > ent‐l‐7 > ent‐u‐7 > u‐7 whereas for the tertiary amino alcohols the order l‐7 > u‐7 > ent‐l‐7 > ent‐u‐7 was found. The stereoisomers l‐7d and l‐7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a Ki value of 7.17 which is close to that of Morphine (Ki = 1.64). In an in vivo model, the Writhing Test, both compounds l‐7d and l‐7e displayed high analgetic activity.
Synthesis of Vitamin E Analogues: Possible Active Forms of Vitamin E
Authors: Fujishima Toshie , Kagechika Hiroyuki , Shudo Koichi 
Published: October 2006

AbstractWe synthesized several vitamin E analogues containing oxygenated functional groups in place of the 8‐methyl group which is common to all the natural vitamin E congeners, based on the hypothesis that the methyl group might be metabolically oxidized to produce active forms which might have specific functions other than the antioxidant function. All the vitamin E analogues examined had antioxidant activity. 8‐[6‐Hydroxy‐2,5,7‐trimethyl]‐2‐(4,8,12‐trimethyltridecanyl)chroman'methanol (1d) and 2,5,7‐trimethyl‐2‐(4,8,12‐trimethyltridecanyl)chroman‐6‐ol (4d) showed similar activity to α‐tocopherol. 6‐Hydroxy‐2,5,7‐trimethyl‐2‐(4,8,12‐trimethyltridecanyl) chroman‐8‐carbaldehyde (2d) and 6‐hydroxy‐2,5,7‐trimethyl‐2‐(4,8,12‐trimethyltridecanyl)chroman‐8‐carboxylic acid (3d) showed weaker activity than α‐tocopherol, but their duration of action, especially that of 3d was considerably longer.
Pyroglutamic Acid in Drug Synthesis, Part 1 A Method for the Synthesis of Enantiomerically Pure 4‐Alkyl‐4‐arylpyroglutamic Acids
Authors: Fleischhacker Wilhelm , Riedl Thomas , Völlenkle Horst , Noe Christian R. 
Published: October 2006

AbstractSynthesis of the title compounds is described, starting from alkylation of the pyroglutaminol‐acetal 4a[1] at the α‐lactam position C‐6 with methyl iodide. Subsequent addition of 2‐cyclohexen‐1‐one led to diastereoselective formation of the 1,2‐aldol addition product 7b/7c, which after dehydratization was aromatized with DDQ to yield the 6‐methyl‐6‐phenyl derivative 7h. Acetal cleavage and Jones oxidation yielded 4,4‐disubstituted, enantiomerically pure pyroglutamic acid 3b. X‐ray analysis confirmed the assignment of the configuration of the newly created chiral centre.
Preparation of Novel Analogues of the Nonredox‐Type Non‐Competitive Leukotriene Biosynthesis Inhibitor AKBA
Authors: Sailer Eckart‐Roderich , Hoernlein Rainer F. , Subramanian Lakshminarayanapuram R. , Ammon Hermann P. T. 
Published: October 2006

AbstractAKBA (acetyl‐11‐keto‐β‐boswellic acid, 1) and KBA (11‐keto‐β‐BA, 2) from Boswellia serrata Roxb. and Boswellia carterii Birdw. are direct, nonredox‐type inhibitors of 5‐lipoxygenase, the key enzyme for leukotriene biosynthesis (IC50 = 1.5 and 3μM in intact neutrophils, respectively). In order to study the impact of the carboxyl function for enzyme inhibition, we synthesized novel analogues of boswellic acids. The C‐4 alcohol derivative of KBA (4) still exerted 5‐lipoxygenase inhibitory activity (IC50 = 4.5 μM), whereas (8), the C‐4 alcohol analogue of β‐boswellic acid (7), the methyl ester analogue of KBA (5), and acetyl‐11‐keto‐amyrin (9) possessed no inhibitory potential in concentrations up to 50 μM. These findings reveal that a hydrophilic group at C4 in combination with an 11‐keto‐function is essential for 5‐lipoxygenase inhibition by boswellic acids.
New NO‐Donors with Antithrombotic and Vasodilating Activities, Part 15 Nitrolic Acids
Authors: Rehse Klaus , Herpel Martin , Piechocki Daniela 
Published: October 2006

AbstractFive 1‐oximino‐1‐nitro compounds (nitrolic acids) were prepared and tested for antithrombotic and blood pressure lowering activities. 1‐Nitro‐ethanone 1‐oxime (1, ethylnitrolic acid) 2 h after oral administration to rats inhibited thrombus formation by a laser beam in mesenteric arterioles of rats by 69% and by 46% in venules (60 mg/kg). The blood pressure of SHR rats even at this high dose only was decreased by 10% suggesting that antithrombotic and blood pressure effects can be dissociated. The in vitro decomposition of 1 at 37 °C nearly exclusively gave N2O and acetic acid indicating that HNO primarily had been formed.
Synthesis and Pharmacology of Combined Histamine H1‐/H2‐Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives
Authors: Wolf Cornelia , Schunack Walter 
Published: October 2006

AbstractThe classical histamine H1‐receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b—d, 10) were connected with a 2‐guanidinothiazole containing structure (28) derived from the H2‐receptor antagonist tiotidine in order to obtain combined H1‐/H2‐receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H1‐ and H2‐receptor antagonist activity at the isolated guinea‐pig ileum (H1) and the isolated guinea‐pig right atrium (H2), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H1‐receptors. The tricyclic cyproheptadine and its 10,11‐dihydro derivative (30–32, 34), however, cause a decrease of H2‐receptor antagonist potency compared to the diphenhydramines (29a—d, 33a—d). Using nitroethenediamine as the polar group is apparently more favourable to H1‐ and H2‐receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4‐fluoro‐ or 4‐methyl‐substituted diphenhydramine as H1‐receptor antagonist moiety (29c, d) display the most potent H1‐ and H2‐receptor antagonist effects. The presented concept is a very promising way to combine H1‐ and H2‐receptor antagonist properties in one molecule.
Synthesis and Biochemical Studies of Spirocyclic Amino Acid Esters, Part 3 Activity of 2‐Azaspiro[4.5]decane‐6‐carboxylates as GABA‐Uptake Inhibitors
Authors: Fleischhacker Wilhelm , Lauritz Silvia , Urban Ernst , Baumann Peter , Bittiger Helmut 
Published: October 2006

AbstractNovel GABA analogous spirocyclic amino acid esters 7a—d and 8a—d were prepared and investigated for interaction with GABA‐A and GABA‐B receptors as well as the GABA uptake system. Starting from known bromoethyl lactones 1 or 2 and arylalkylamines spirocyclic hydroxyalkyl lactams 3a—d and 4a—d were obtained and reduced by LiAlH4 to yield spirocyclic hydroxymethyl pyrrolidines 5a—d and 6a—d. Oxidation by Jones reagent followed by subsequent esterification gave the title compounds 7a—d and 8a—d which represent conformationally restricted analogues of GABA. Whereas the new spirocyclic amino acid esters 7a—d and 8a—d showed no activity at GABA receptors they proved to be active as GABA uptake inhibitors. An examination of the relationship between structure and GABA uptake inhibition revealed a strong dependence of activity upon the length of the alkyl chain in N‐arylalkyl substituents and upon the ring size of underlying spirocyclic system.
Chitosan‐Indomethacin Conjugates. Effect of Different Substituents on the Polysaccharide Molecule on Drug Release
Authors: Orienti Isabella , Aiedeh Khaled , Gianasi Elisabetta , Ponti Cristina , Zecchi Vittorio 
Published: October 2006

AbstractThe conjugation of indomethacin with chitosan partially substituted with the hydrophilic residues triethylene glycol glutarate and triethylene glycol choline ether glutarate is described. Mucoadhesive conjugates were obtained showing gelling properties both in acid and basic environment. Among the substituents, triethylene glycol choline ether glutarate better enhances the gelling properties of the macromolecules. In all cases the kinetics of drug release from the macromolecules approached zero order.
Synthesis of Potent and Orally Active HIV‐Protease Inhibitors
Authors: Capraro Hans‐Georg , Bold Guido , Fässler Alexander , Cozens Robert , Klimkait Thomas , Lazdins Janis , Mestan Jürgen , Poncioni Bernard , Rösel Johannes L. , Stover David , Lang Marc 
Published: October 2006

AbstractA series of potent HIV‐protease inhibitors has been prepared. Several of the newly synthesized compounds showed high plasma levels after oral administration to animals. Based on the overall biological profile, CGP 61755 was chosen for further preclinical evaluation. For this compound, a 10 step synthesis potentially suitable for large scale production was developed.
3‐(ω‐Aminoalkyl)‐5,5‐dialkyl(or spirocycloalkyl‐1′,5‐)hydantoins as New 5‐HT1A and 5‐HT2A Receptor Ligands
Authors: Byrtus Hanna , Pawlowski Maciej , Charakchieva‐Minol Sijka , Duszyńska Beata , Mokrosz Maria J. , Mokrosz Jerzy L. , Zejc Alfred 
Published: October 2006

AbstractA series of new 3‐(ω‐aminoalkyl)‐5,5‐disubstituted hydantoins, containing 1‐phenylpiperazine, 1‐(o‐methoxyphenyl)piperazine or 1,2,3,4‐tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5‐HT1A and 5‐HT2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5‐HT1A and 5‐HT2A receptors due to the presence of a 1‐arylpiperazine fragment; however, the terminal hydantoin moiety plays an important role in stabilization of the receptor‐ligand complex. It has also been found that the two 1‐phenylpiperazine derivatives 32 and 36 are new, selective 5‐HT2A receptor ligands (Ki = 34 and 37 nM, respectively), whereas the derivative of 1‐(o‐methoxyphenyl)piperazine (38) is a new, highly potent 5‐HT1A receptor ligand (Ki = 0.51 nM) with a moderate affinity for 5‐HT2A receptors (Ki = 213 nM).
Asymmetric Synthesis and Structure‐Activity Relationship of the Four Stereoisomers of the Antibiotic Amidinomycin Part 1: The Synthesis
Authors: Sung Sun‐Young , Frahm August Wilhelm 
Published: October 2006

AbstractThe natural amidinomycin ((1R, 3S)‐14) and its three stereoisomers are synthesized from homochiral 3‐oxocyclopentanecarboxylic acids (1a) by asymmetric methods, which are based on an asymmetric reductive amination to produce methyl cis‐N‐(1‐phenylethyl)‐3‐aminocyclo‐pentanecarboxylates (3b) via optically active methyl N‐(1‐phenylethyl)‐3‐iminocyclopentane‐carboxylates (2b) for the cis‐isomers of 14. Optically pure trans‐3‐aminocyclopentane‐carboxylic acids (4a) are obtained from the homochiral keto acids 1a via asymmetric reductive amination of 3‐hydroxy‐iminocyclopentanecarboxylic acids (5a) and lead to the trans‐isomers of 14.
Synthesis and Antidepressant Evaluation of New Hetero[2,1]benzothiazepine Derivatives
Authors: Díaz Juan A. , Vega Salvador , Expósito María A. , Mateo Candelaria C. Sánchez , Darias Victoriano 
Published: October 2006

AbstractAs a part of a research program directed to the discovery of novel antidepressant agents, a series of new hetero[2,1]benzothiazepine derivatives was synthesized. Some of these compounds antagonized the ptosis and motor depression induced by tetrabenazine and were also active in the Porsolt forced swimming test.
Pyridazines 79[1] Novel Oxazolo[3′,2′:1,2]pyrrolo[3,4‐d]pyridazines and Imidazolo[1′,2′:1,2]pyrrolo[3,4‐d]pyridazines: Synthesis and Biological Evaluation
Authors: Barth Birgit , Dierich Manfred , Heinisch Gottfried , Matuszczak Barbara , Mereiter Kurt , Soder Josef , Stoiber Heribert 
Published: October 2006

AbstractStarting from conveniently accessible ethyl 5‐aroyl‐4‐pyridazine‐carboxylates 6 representatives of the novel tricyclic systems 2 (with X = O and X = NH) were synthesised and screened as potential non‐nucleoside HIV‐1 reverse transcriptase inhibitors.
Binding of Clozapine Metabolites and Analogues to the Histamine H3 Receptor in Rat Brain Cortex
Authors: Alves‐Rodrigues Alexandra , Leurs Rob , Willems Edwin , Timmerman Henk 
Published: October 2006

AbstractFollowing up the finding that the non‐imidazole drug clozapine shows a considerable histamine H3 receptor antagonistic activity[1,2], a series of analogues and metabolites (clozapine‐N‐oxide, and N‐desmethylclozapine) were tested for their affinity towards the H3 receptor using the radiolabelled H3 antagonist [125I]‐iodophenpropit.Qualitative structure affinity relationships are derived for the tested compounds. In the clozapine molecule four structurally different moieties may be considered. In comparison with the affinity for the H3 receptor shown by clozapine, the following main conclusions can be drawn: The 4‐piperazinyl region does not allow substituents longer than a CH3 or electronegative atoms such as an O (as in clozapine‐N‐oxide); the lack of the CH3 group (as in N‐desmethylclozapine) also reduces the affinity for H3 receptors. Substitutions at the 5‐diazepine position do not drastically alter the affinity for the H3 receptor, although a basic nitrogen is favoured over CH2, O, or S. The 8 position in ring I is an important modulatory site for H3 affinity; electronegative substituents such as chloro and fluoro in this aromatic ring increase the affinity. When these substituents are, however, present at position X2 in the ring, they disable binding to the H3 receptor.The two major clozapine metabolites (clozapine‐N‐oxide, and N‐desmethylclozapine) will not be responsible for a possible contribution of the H3 receptor antagonism to the clinical profile of clozapine.
In Vitro Anti‐Mycobacterium avium Activity of N‐(2‐Hydroxyethyl)‐1,2‐benzisothiazol‐3(2H)‐one and ‐thione Carbamic Esters
Authors: Pagani Giuseppe , Borgna Pietro , Piersimoni Claudio , Nista Domenico , Terreni Marco , Pregnolato Massimo 
Published: October 2006

AbstractA series of N‐(2‐hydroxyethyl)‐1,2‐benzisothiazol‐3(2H)‐one and ‐thione carbamic esters have been synthesised and tested against Mycobacterium avium strains. The MIC values determined by the radiometric broth dilution method were between 2 and 8 μg/mL for the benzisothiazolthione derivatives and between 16 and 32 μg/mL or higher for the corresponding benzisothiazolone derivatives.
Synthesis and Antimicrobial Properties of New 4‐(Alkylidene/arylidene)‐amino‐5‐(2‐furanyl)‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones and 6‐Aryl‐3‐(2‐furanyl)‐7H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazines
Authors: Ergenç Nedime , Ulusoy Nuray , Çapan Gültaze , Sanis Gülten Ötük , Kiraz Muammer 
Published: October 2006

AbstractA series of 4‐(alkylidene/arylidene)amino‐5‐(2‐furanyl)‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones (2) and 6‐aryl‐3‐(2‐furanyl)‐7H‐1,2,4‐triazolo[3,4‐b][1,3,4] thiadiazines (3) were synthesized. The configuration of 2g was assigned on the basis of 1H‐NMR data. Of the new derivatives tested, only 2b, 2g, and 4f were found to be active against Staphylococcus aureus and/or Staphylococcus epidermidis (MIC 125–1.95 μg/ml), whereas all exhibited varying degrees of antifungal activity (MIC 25–0.8 μg/ml).
Synthesis and Antibacterial Activity of 1‐β‐Methylcarbapenem Having a 1,3‐Diazabicyclo[3.3.0]octan‐4‐one Moiety
Authors: Nam Ki Hong , Oh Chang‐Hyun , Cho Jin Koo , Kim Hyo Jung , Lee Ki‐Soo , Cho Jung‐Hyuck 
Published: October 2006

AbstractThe synthesis of new series of 1‐β‐methylcarbapenems having a 1,3‐diazabicyclo[3.3.0]octan‐4‐one moiety is described. Their in vitro antibacterial activities against both Gram‐positive and Gram negative bacteria are reported and the effect of the substituent on the bicyclic ring was investigated and was in agreement with findings from our previous studies.
Three Lupane Derivatives from Leptospermum scoparium
Authors: Mayer Ralf 
Published: October 2006

AbstractThe ether extract of the aerial parts of Leptospermum scoparium cultivars yielded a lactone with a 20,29,30‐ trinorlupane skeleton (1). Furthermore, 2α‐hydroxyursolic acid (2), platanic acid (3) and 3β,30‐dihydroxy‐lup‐20(29)‐en‐28‐oic acid (4) were isolated.
Antimalarial Activity of 1,4‐Epidioxy‐bisabola‐2,12‐diene Derivatives
Authors: Rücker Gerhard , Breitmaier Eberhard , Manns Detlef , Maier Walter , Marek Anne , Heinzmann Berta , Heiden Klemens , Seggewies Stephan 
Published: October 2006

Abstract1,4‐Epidioxy‐bisabola‐2,12‐diene (3) and aromatic hydroperoxides (4, 5) were prepared by photoxidation of γ‐curcumene (1). Reduction and esterification of 6 and 7 afforded compounds 9 to 10. All compounds were tested in vitro for antimalarial activity. The activity could not be increased significantly, compared with 3. The most active compounds, 3 and 9, did not show in vivo antimalarial activity in mice.
Pyridazines 82[1]. Synthesis of Pyridazino[3,4‐b][1,5]benzodiazepin‐5‐ones and their Biological Evaluation as Non‐nucleoside HIV Reverse Transcriptase Inhibitors
Authors: Heinisch Gottfried , Huber Elisabeth , Matuszczak Barbara , Maurer Astrid , Prillinger Ulrike 
Published: October 2006

AbstractStarting from 3,6‐dichloro‐N‐(2−chloro‐5‐nitrophenyl)‐pyrid‐azine‐4‐carboxamide (7) a series of 6,11‐dialkylated pyridazino‐[3,4‐b][1,5]benzodiazepin‐5‐ones with a 3−chloro‐8‐nitro, 8‐amino, 8‐acetylamino, or 8−chloro substitution pattern was prepared via N‐alkyl‐3‐alkylamino‐6−chloro‐N‐(2−chloro‐5‐nitro‐phenyl)‐pyridazine‐4‐carboxamides. The new compounds were screened as non‐nucleoside reverse transcriptase inhibitors. The influence of the substitution pattern in compounds 10–13 on inhibitory potency is discussed.
Synthesis and In Vitro Evaluation of 3‐(1‐Azolylmethyl)‐1H‐indoles and 3‐(1‐Azolyl‐1‐phenylmethyl)‐1H‐indoles as Inhibitors of P450 arom
Authors: Borgne Marc Le , Marchand Pascal , Duflos Muriel , Delevoye‐Seiller Bénédicte , Piessard‐Robert Sylvie , Baut Guillaume Le , Hartmann Rolf W. , Palzer M. 
Published: October 2006

AbstractIn the challenge to develop potent inhibitors of aromatase for reducing the levels of estrogens, we found that azolyl‐substituted indoles inhibit aromatase activity. 3‐(1‐Azolylmethyl)‐1H‐indoles 9–15 and 3‐(1‐azolyl‐1‐phenylmethyl)‐1H‐indoles 22–25 were prepared, and tested on their ability to inhibit P450 arom. Analysis of the inhibitory effect exerted by several derivatives (11, 12, 22, and 23) on microsomal aromatase in vitro activity indicates that azolyl‐substituted indoles containing an imidazole moiety are more potent inhibitors than triazole derivatives. In the first series, the introduction of the N‐benzyl moiety has been found to enhance the inhibitory profile of these 3‐(1‐azolylmethyl)‐1H‐indole derivatives. The corresponding 4‐fluoro derivative 12 displays the highest inhibitory activity (IC50 = 0.0718 μM) of all investigated compounds; thus, 12 is 258 times as potent as aminoglutethimide (AG). The presence of a chloro grouping in para position of the phenyl ring in compounds 22 and 24 exerts a positive effect only in the triazol‐1‐yl sub‐series: compound 25 is 4‐fold more potent than 24.