Twenty Years of Benzimidazole Scaffold Optimization in Antiparasitic Drug Discovery

Abstract

The benzimidazole scaffold occupies a unique position in antiparasitic medicinal chemistry: simple in structure yet extraordinarily versatile in biological action. Over the 20 years since ChemMedChem was established, substituted benzimidazoles have been among the most intensively optimized heterocyclic platforms for treating helminthiasis, malaria, leishmaniasis, and trypanosomiasis. This review surveys structure–activity relationship (SAR) studies published between 2005 and 2025, covering anthelmintic derivatives targeting β‐tubulin in nematodes, cestodes, and trematodes, as well as antiprotozoal scaffolds directed against Plasmodium, Leishmania, and Trypanosoma. We examine how substitutions at N‐1, C‐2, C‐5, and C‐6 modulate target affinity, selectivity, and pharmacokinetic properties, and discuss how growing benzimidazole drug resistance has driven structural innovation. Newly uncovered mechanisms of action, including inhibition of Leishmania mexicana arginase, pteridine reductase, Trypanosoma cruzi cruzain, and Plasmodium falciparum dihydroorotate dehydrogenase, are highlighted alongside classical tubulin‐directed SAR. The review also covers formulation advances and future directions including hybrid molecule design, in silico methods, and repurposing strategies.