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

Hung Phat Duong; Dmitrij Melechov; Wilson Lim; Jingyi Ma; Kymberley R Scroggie; Luxsika Rajendra; Benjamin Perry; Luiza R Cruz; Rahman Shah Zaib Saleem; Peter J Rutledge; Alice Motion; Wendy W J van de Sande; Matthew H Todd

doi:10.1039/d5md00427f

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

RSC Med Chem. 2025 Sep 18;16(12):6094-6108. doi: 10.1039/d5md00427f. eCollection 2025 Dec 10.

Authors

Hung Phat Duong¹, Dmitrij Melechov^{2

3}, Wilson Lim⁴, Jingyi Ma⁴, Kymberley R Scroggie¹, Luxsika Rajendra², Benjamin Perry⁵, Luiza R Cruz⁵, Rahman Shah Zaib Saleem^{2

3

6}, Peter J Rutledge¹, Alice Motion¹, Wendy W J van de Sande⁴, Matthew H Todd^{2

3}

Affiliations

¹ School of Chemistry, Faculty of Science, The University of Sydney NSW 2006 Australia alice.motion@sydney.edu.au.
² UCL School of Pharmacy, University College London 29-39 Brunswick Square London WC1N 1AX UK matthew.todd@ucl.ac.uk.
³ Structural Genomics Consortium, University College London 29-39 Brunswick Square London WC1N 1AX UK.
⁴ Department of Medical Microbiology & Infectious Diseases, Erasmus MC, University Medical Center Rotterdam Dr. Molewaterplein 40 3015 GD Rotterdam The Netherlands w.vandesande@erasmusmc.nl.
⁵ The Drugs for Neglected Diseases Initiative 15 Chemin Camille-Vidart 1202 Geneva Switzerland.
⁶ Department of Chemistry and Chemical Engineering, Syed Babar Ali School of Science and Engineering, Lahore University of Management Sciences Lahore 54792 Pakistan.

Abstract

The fenarimol analogue EPL-BS1246 was previously discovered to be potent against Madurella mycetomatis, the causative agent of the neglected tropical disease mycetoma. Further evaluation of a small set of fenarimol analogues in vivo revealed a correlation between efficacy and the lipophilicity (log D) 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 log D values <2.5. Insights into the SAR could be gleaned that suggested optimal substituents for the rings forming the fenarimol core.