Evaluation of the In Vitro Antifungal Activity of New Sampangine Analogs and Studies on the Mode of Action of Sampangine.



The discovery of 3-methozysampangine as the major antifungal constituent of the West African tree, Cleistopholis patens, has led us to initiate an investigation of the structure-anti(ungal activity relationships of the sampangine (SAM) class of antifungal antibiotics. Thus, the in vitro antifungal activities of a series of A, B, C, and D-ring modified sampangine analogs have been determined by agar welldiffusion assays followed by determination of MIC values in at least two culture media (yeast nitrogen base broth, Sabouraud dextrose broth) using a two-fold broth macrodilution assay. More than six new analogs were evaluated for in vitro antifungal activity against Cryptococcus neoformans, Candida albicans, Aspergillus flavus, and Aspergillus fumigatus. In general, the SAMs exhibit exceptional in vitro activity against Cryptococcus. However, it was found that the nature and site of substituents dramatically affects both the potency and spectrum of antifungal activity. For example, 4-methylsampangine exhibits a MIC of 0.2 ug/ml for C. neoformans, but 12.5 ug/ml for C. albicans, whereas 3-methylsampangine exhibits MIC of 0.39 ug/ml for both organisms. Generally, substitution of the 4-position appears to diminish antiCandidal activity, while some 4-substituted analogs retain excellent activity against Cryptococcus. In general any modification to the carbonyl functionality of SAM significantly diminishes activity, with MIC values for C-ring modified analogs typically in the range of 3.12 - 6.25 ug/ml. Sampangine, at a concentration 2 5 ug/ml is fungicidal for C. neoformans and C. albicans, based on subculturing from MIC dilution tubes and time-to-kill studies. The presence of excess ergosterol has no effect on the in vitro activity of sampangine, suggesting a mechanism of action different from that of amphotericin B.

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ICAAC 33rd, 1993
    • ICAAC 33rd