Structure–activity relationships of fenarimol analogues with potent in vitro and in vivo activity against Madurella mycetomatis, the main causative agent of eumycetoma

05 May 2025, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

The fenarimol analogue EPL-BS1246 was previously discovered to be potent against Madurella mycetomatis, the causative agent of the neglected tropical disease eumycetoma. Further evaluation of a small set of fenarimol analogues in vivo revealed a correlation between efficacy and the lipophilicity (logD) of the analogues. To explore both this correlation and the series structure-activity relationship (SAR), we have evaluated a total of 185 fenarimol analogues derived from five different daughter chemotypes. Potent (MIC50 < 9 μM) in vitro activity was found for 22 analogues, five of which gave promising results in an in vivo larval survival assay. Again, a trend towards prolonged larval survival (better in vivo activity) was noted in analogues with logD values < 2.5. Insights into the SAR could be gleaned that suggested optimal substituents for the rings forming the fenarimol core.

Keywords

Drug Discovery
Antifungal
Neglected Tropical Disease
Mycetoma
Open Science

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