Exploring Novel Nitrofuryl-1,3,4-Thiadiazole-Based Derivatives: Design, Synthesis, and Evaluation of In Vitro Leishmanicidal and Trypanocidal Activity.

Neglected tropical diseases remain a major global health challenge, highlighting the need for new antiparasitic agents. In this study, a series of substituted 1-[5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-yl]piperidine-4-carboxamides was designed, synthesized, and evaluated for in vitro antileishmanial and antitrypanosomal activity. Compound 18 emerged as the most promising derivative, showing submicromolar activity against all tested parasites with acceptable selectivity toward THP-1 cells. Mechanistic studies in T. b. brucei bloodstream cells revealed a reversible cytostatic effect rather than apoptosis, and assessment of cellular and mitochondrial ROS levels indicated that oxidative stress was not a primary contributor to activity. In silico ADME analysis supported the drug-likeness of the synthesized compounds. Taken together, these findings identify 18 as a valuable lead for further antiparasitic drug development.