02316nas a2200181   4500000000100000008004100001260001900042653001800061653002300079653002000102100001400122700001300136700001300149245008800162490000700250520185200257022002502109       2026                            d  c08/2026bWiley10abenzimidazole10aAntiparasitic drug10aDrug Resistance1 aKondža M1 aRezić V1 aDrmač D00aTwenty Years of Benzimidazole Scaffold Optimization in Antiparasitic Drug Discovery0 v213 a<jats:p>
                    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
                    <jats:italic>ChemMedChem</jats:italic>
                    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
                    <jats:italic>Plasmodium</jats:italic>
                    ,
                    <jats:italic>Leishmania</jats:italic>
                    , and
                    <jats:italic>Trypanosoma</jats:italic>
                    . 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
                    <jats:italic>Leishmania mexicana</jats:italic>
                    arginase, pteridine reductase,
                    <jats:italic>Trypanosoma cruzi</jats:italic>
                    cruzain, and
                    <jats:italic>Plasmodium falciparum</jats:italic>
                    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.
                  </jats:p>  a1860-7179, 1860-7187