Synthesis, bioevaluation and docking studies of some 2-phenyl-1H-benzimidazole derivatives as anthelminthic agents against the nematode Teladorsagia circumcincta

• Published in: European journal of medicinal chemistry Vol. 208; p. 112554
• Main Authors: Escala, Nerea, Valderas-García, Elora, Bardón, María Álvarez, Gómez de Agüero, Verónica Castilla, Escarcena, Ricardo, López-Pérez, José Luis, Rojo-Vázquez, Francisco A., San Feliciano, Arturo, Balaña-Fouce, Rafael, Martínez-Valladares, María, Olmo, Esther del
• Format: Journal Article
• Language: English
• Published: Elsevier Masson SAS 15-12-2020
• Subjects: 2-Phenyl-1H-benzimidazoles; Cytotoxicity; in vitro assays; Teladorsagia circumcincta; Tubulin docking studies; Cytotoxicity; 2-Phenyl-1H-benzimidazoles; in vitro assays; Tubulin docking studies; Teladorsagia circumcincta
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112554

Gastrointestinal nematode infections are the main diseases in herds of small ruminants. Resistance to the main established drugs has become a worldwide problem. The purpose of this study is to obtain and evaluate the in vitro ovicidal and larvicidal activity of some 2-phenylbenzimidazole derivatives on susceptible and resistant strains of Teladorsagia circumcincta. Compounds were prepared by known procedures from substituted o-phenylenediamines and arylaldehydes or intermediate sodium 1-hydroxyphenylmethanesulfonate derivatives. Egg Hatch Test (EHT), Larval Mortality Test (LMT) and Larval Migration Inhibition Test (LMIT) were used in the initial screening of compounds at 50 μM concentration, and EC50 values were determined for the most potent compounds. Cytotoxicity evaluation of compounds was conducted on human Caco-2 and HepG2 cell lines to calculate their Selectivity Indexes (SI). At 50 μM concentration, nine out of twenty-four compounds displayed more than 98% ovicidal activity on a susceptible strain, and four of them showed more than 86% on one resistant strain. The most potent ovicidal benzimidazole (BZ) 3 showed EC50 = 6.30 μM, for the susceptible strain, while BZ 2 showed the lowest EC50 value of 14.5 μM for the resistant strain. Docking studies of most potent compounds in a modelled Teladorsagia tubulin indicated an inverted orientation for BZ 1 in the colchicine binding site, probably due to its fair interaction with glutamic acid at codon 198, which could justify its inactivity against the resistant strain of T. circumcincta.
[Display omitted]
•9 BZs inhibited hatching of T. circumcincta eggs.•5 BZs showed effect on the MDR strain.•2 BZs caused 100% death of L1 larvae.•BZs active on a MDR strain dock differently in tubulin.