Biological evaluation of guanidines, bisguanidines, and their derivatives as anti-Trypanosoma cruzi agents.

Chagas disease remains a major public health concern, and the limited efficacy and safety of current therapies underscore the need for new antitrypanosomal agents. In this study, a series of guanidine and bisguanidine derivatives were evaluated for their trypanocidal activity against Trypanosoma cruzi NINOA and INC-5 strains, as well as for their cytotoxicity on J774 murine macrophages. An initial screening at 12.5 μg/mL identified several compounds with activity comparable to the reference drugs nifurtimox and benznidazole, prompting the determination of LC50 values. Among the tested derivatives, compounds 2d, 2e, and 2f exhibited superior potency against both T. cruzi strains, with compound 2e emerging as the most active. Structure-activity analysis revealed that the incorporation of two iodine atoms into the bisguanidine scaffold significantly enhanced trypanocidal activity, in agreement with previous reports on biologically active bisguanidines. Despite their promising antiparasitic potency, the most active compounds also displayed notable cytotoxicity and limited selectivity profile, highlighting the need for further optimization. Overall, these findings support guanidine- and bisguanidine-based scaffolds as promising leads for antitrypanosomal drug development, while emphasizing the importance of continued structure-activity relationship studies to improve selectivity and safety.