Structural Requirements for the Antifungal Activities of Natural Drimane Sesquiterpenes and Analogues, Supported by Conformational and Electronic Studies

Seventeen drimanes including polygodial ( 1), isopolygodial ( 2), drimenol ( 3) and confertifolin ( 4) obtained from natural sources and the semi-synthetic derivatives 5–17 obtained from 1–3, were evaluated in vitro for antifungal properties against a unique panel of fungi with standardized procedures by using two end-points, MIC 100 and MIC 50. A SAR analysis of the whole series, supported by conformational and electronic studies, allowed us to show that the Δ 7,8 -double bond would be one of the key structural features related to the antifungal activity. The MEPs obtained for active compounds exhibit a clear negative minimum value (deep red zone) in the vicinity of the Δ 7,8 -double bond, which is not present in the inactive ones. Apart of this negative zone, a positive region (deep blue) appears in 1, which is not observed either in its epimer 2 nor in the rest of the active compounds. The Log P of active compounds varies between 2.33 and 3.84, but differences in MICs are not correlated with concomitant variations in Log P values.