Structure–activity relationships of fenarimol analogues with potent <i>in vitro</i> and <i>in vivo</i> activity against <i>Madurella mycetomatis</i> , the main causative agent of mycetoma

The fenarimol analogue EPL-BS1246 was previously discovered to be potent against <i>Madurella mycetomatis</i>, the causative agent of the neglected tropical disease mycetoma. Further evaluation of a small set of fenarimol analogues <i>in vivo</i> revealed a correlation between efficacy and the lipophilicity (log <i>D</i>) 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) <i>in vitro</i> activity was found for 22 analogues, five of which gave promising results in an <i>in vivo</i> larval survival assay. Again, a trend towards prolonged larval survival (better <i>in vivo</i> activity) was noted in analogues with log <i>D</i> values <2.5. Insights into the SAR could be gleaned that suggested optimal substituents for the rings forming the fenarimol core.