ABSTRACT
An efficient microwave-assisted synthesis of new (Z)-5-arylidenerhodanines under solvent-free conditions is described and their in vitro antifungal activity was evaluated following the CLSI (formerly NCCLS) guidelines against a panel of both standardized and clinical opportunistic pathogenic fungi. An analysis of the structure-activity relationship (SAR) along with computational studies showed that the most active compounds (F- and CF(3)-substituted rhodanines) possess high logP values and low polarizability. Mechanism-based assays suggest that active compounds neither would bind to ergosterol nor would produce a damage to the fungal membrane.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Mitosporic Fungi/drug effects , Rhodanine , Yeasts/drug effects , Antifungal Agents/radiation effects , Computer Simulation , Drug Design , Microbial Sensitivity Tests , Microwaves , Molecular Structure , Rhodanine/analogs & derivatives , Rhodanine/chemical synthesis , Rhodanine/pharmacology , Sensitivity and Specificity , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We have studied the crude methanolic extract (CME), some fractions (hexane, dichloromethane and ethyl acetate) and four pure compounds: eupomatenoid-3 (1), eupomatenoid-5 (2), conocarpan (3) and orientin (4), from Piper solmsianum, for possible antifungal activity against 12 pathogenic fungi. The minimal inhibitory concentration (MIC) was determined and the experiments showed that the CME exhibited antifungal action against all the dermatophytes tested, with MIC values of between 20 microg/ml to 60 microg/ml. Similar activity also was verified for the hexane, dichloromethane and ethyl acetate fractions. However, the starting material (CME), and all the fractions, did not exert inhibitory effect against hyaline hyphomycetes and were only discretely active against the zigomycetes and yeasts. Compounds 2, 3 and 4 also exhibited pronounced activity against all the dermatophytes tested (MIC< or =1 to 9 microg/ml) with potency as high as the standard antifungal drug (ketoconazole). Compound 3 also exhibited activity against all the yeasts tested. In conclusion, the antifungal activity of P. solmsianum seems to be related mainly to the presence of compounds 2, 3 (neolignans) and 4 (flavonoid), however it was verified that another active compound, as yet unidentified, exists in the plant.
