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

by Duong HP, Melechov D, Lim W, Jingyi M, Scroggie KR, Rajendra L, Perry B, Cruz LR, Saleem RSZ, Rutledge P, Motion A, van de Sande WWJ, Todd MH. RSC Medicinal Chemistry 2025. doi: 10.1039/D5MD00427F

Summary: The fenarimol analogue EPL-BS1246 is potent against Madurella mycetomatis, the causative agent of eumycetoma. Further evaluation of a small set of fenarimol analogues in vivo has revealed a correlation between the efficacy and lipophilicity (logD) of the analogues. To explore both this correlation and the structure-activity relationship, the authors of this manuscript evaluated 185 fenarimol analogues derived from five different daughter chemotypes. Potent in vitro activity was found for 22 analogues, five of which gave promising results in an in vivo larval survival assay. A trend towards prolonged larval survival (better in vivo activity) was noted in analogues with logD values <2.5. Insights into the structure-activity relationship can be used to suggest optimal substituents for the rings forming the fenarimol core.y endpoint is sustained elimination of parasitaemia from the end of treatment through 12 months of follow-up.

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