Cytotoxicity and Antimicrobial Activity of GaMF1 Analogs.

Recent studies have identified the mycobacterial adenosine triphosphate synthase inhibitor GaMF1 and its structural analogs as compounds with noteworthy antituberculosis activity. Despite these promising results, a significant limitation remains their cytotoxicity against human cells, which, in its current state, overshadows the therapeutic potential. Therefore, addressing this off-target toxicity is essential for the further development of these compounds as viable drug candidates. In this study, we systematically explored structural modifications of the original GaMF1 scaffold with the primary aim of reducing its inherent cytotoxicity. Individual regions of the parent structure were progressively replaced, enabling the identification of substituents that effectively attenuate cytotoxic effects. Importantly, these structural refinements also led to the emergence of pronounced antiparasitic activity, particularly against trypanosomal species such as Trypanosoma cruzi, Trypanosoma brucei brucei, and Trypanosoma brucei rhodesiense. These findings suggest that the biological potential of this compound class extends beyond what has previously been described. Furthermore, we evaluated the cytotoxicity of selected derivatives against a panel of tumor cell lines, where some compounds showed encouraging antiproliferative effects.