TY - JOUR
KW - benzimidazole
KW - Antiparasitic drug
KW - Drug Resistance
AU - Kondža M
AU - Rezić V
AU - Drmač D
AB - <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>
BT - ChemMedChem
DA - 08/2026
DO - 10.1002/cmdc.70426
IS - 15
LA - ENG
M3 - Article 
N2 - <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>
PB - Wiley
PY - 2026
T2 - ChemMedChem
TI - Twenty Years of Benzimidazole Scaffold Optimization in Antiparasitic Drug Discovery
VL - 21
SN - 1860-7179, 1860-7187
ER -