Novel Benzofuranyl Chalcones With Antileishmanial Activity: Synthesis, Structure-Activity Relationships, and...

Leishmaniasis remains a major unmet medical need, and the development of new selective antileishmanial chemotypes is still urgently required. Herein, we report the design, synthesis, and biological evaluation of two series of benzofuranyl chalcones as antileishmanial agents against L. mexicana. Primary screening at 5 µg/mL identified 25 compounds that inhibited parasite metabolism by more than 50%, supporting the benzofuranyl chalcone framework as a productive antileishmanial scaffold. Dose-response studies revealed several low-micromolar leads, with compound 14l as the most potent analog (IC₅₀ = 2.1 µM), followed by 13e (IC₅₀ = 3.3 µM), 14p (IC₅₀ = 4.2 µM), 13h (IC₅₀ = 4.3 µM), and 14c (IC₅₀ = 4.4 µM). All prioritized compounds displayed low cytotoxicity toward J774A.1 murine macrophages, resulting in high selectivity indices, with 14l showing SI > 666.7. Structure-activity relationship analysis indicated that activity is strongly influenced by both substituent identity and scaffold orientation; ortho-chloro and ortho-nitro substitution were favored in one series, whereas meta-CF₃ and 3,4,5-trimethoxy substitution were particularly beneficial in the complementary framework. Computational studies suggest a plausible interaction with the FAD-associated region of L. mexicana fumarate reductase, although direct biochemical validation remains necessary.