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Over the 20 years since\n                    <jats:italic>ChemMedChem<\/jats:italic>\n                    was established, substituted benzimidazoles have been among the most intensively optimized heterocyclic platforms for treating helminthiasis, malaria, leishmaniasis, and trypanosomiasis. This review surveys structure\u2013activity relationship (SAR) studies published between 2005 and 2025, covering anthelmintic derivatives targeting \u03b2\u2010tubulin in nematodes, cestodes, and trematodes, as well as antiprotozoal scaffolds directed against\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    ,\n                    <jats:italic>Leishmania<\/jats:italic>\n                    , and\n                    <jats:italic>Trypanosoma<\/jats:italic>\n                    . We examine how substitutions at N\u20101, C\u20102, C\u20105, and C\u20106 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\n                    <jats:italic>Leishmania mexicana<\/jats:italic>\n                    arginase, pteridine reductase,\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    cruzain, and\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    dihydroorotate dehydrogenase, are highlighted alongside classical tubulin\u2010directed SAR. The review also covers formulation advances and future directions including hybrid molecule design, in silico methods, and repurposing strategies.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70426","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T06:23:53Z","timestamp":1786083833000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Twenty Years of Benzimidazole Scaffold Optimization in Antiparasitic Drug Discovery"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3904-4994","authenticated-orcid":false,"given":"Martin","family":"Kond\u017ea","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy University of Mostar  Mostar Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7251-237X","authenticated-orcid":false,"given":"Valentina","family":"Rezi\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Mostar  Mostar Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doris","family":"Drma\u010d","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy University of Mostar  Mostar Bosnia and Herzegovina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"e_1_2_12_2_1","volume-title":"Ending the Neglect to Attain the Sustainable Development Goals: A Road Map for Neglected Tropical Diseases 2021\u20102030","author":"World Health Organization","year":"2020"},{"key":"e_1_2_12_3_1","first-page":"467","volume-title":"In Disease Control Priorities in Developing Countries","author":"Hotez P. 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