Synthesis and antifungal activity of new 1-halogenobenzyl-3-imidazolylmethylindole derivatives.
A series of 1-benzyl-3-(imidazol-1-ylmethyl)indole derivatives 35-46 were prepared under mild reaction conditions and tested for their antifungal activity. Pharmacomodulation at N(1), C(2) and C(5) of the indole ring and at the level of the alkyl chain (R(1)) was carried out starting from the corresponding 3-acylindoles 6, 7 or 3-formylindoles 11-22. Target imidazolyl compounds 35-46 were obtained in satisfactory yields by CO(2) elimination from the intermediate carbamates. All of the compounds were evaluated in vitro against two human fungal pathogens, Candida albicans (CA980001) and Aspergillus fumigatus (AF980003); amphotericin B, fluconazole and itraconazole were used as references. Seven out of 27 compounds (35b, 35e, 35g, 35h, 36a, 38a and especially 40a) exerted significant antifungal activity against C. albicans, with MIC in the range of 1-6 microg mL(-1). As regards inhibitory activity against A. fumigatus, the MIC figures of most of our compounds were in excess of 20 microg mL(-1) in contrast to the reference drugs, amphotericin B and itraconazole, whose MIC(90) and MIC(80) values were 0.14 and 0.50 microg mL(-1), respectively. The most potent compound, 45a, exhibited MIC value (8 +/- 1 microg mL(-1)) 16-fold higher than that of itraconazole.
Na
Young-Min
YM
Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, 1, rue Gaston Veil, 44035 Nantes cedex, France. youngminna@hotmail.com
Le Borgne
Marc
M
Pagniez
Fabrice
F
Le Baut
Guillaume
G
Le Pape
Patrice
P
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects; D001393:Azoles / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D005650:Fumarates / Q000138:chemical synthesis; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D015394:Molecular Structure; D009566:Nitrates / Q000138:chemical synthesis
D000935:Antifungal Agents; D001393:Azoles; D001555:Benzene Derivatives; D005650:Fumarates; D007093:Imidazoles; D007211:Indoles; D009566:Nitrates