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

Autor: Francisco A. Rojo-Vázquez, Esther del Olmo, María Álvarez Bardón, Nerea Escala, Elora Valderas-García, Arturo San Feliciano, Verónica Castilla Gómez de Agüero, Ricardo Escarcena, José Luis López-Pérez, María Martínez-Valladares, Rafael Balaña-Fouce
Přispěvatelé: Red de Investigación Cooperativa en Enfermedades Tropicales (España), Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Castilla y León, European Commission, Rojo Vázquez, Francisco A. [0000-0001-5913-0131], Martínez Valladares, María [0000-0002-3723-1895], Rojo Vázquez, Francisco A., Martínez Valladares, María
Rok vydání: 2020
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
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ISSN: 0223-5234
Popis: 12 páginas, 2 tablas, 4 figuras.
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 EC 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 EC = 6.30 μM, for the susceptible strain, while BZ 2 showed the lowest EC 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.
We would like to express our gratitude to Dr. Dave Bartley at Moredun Research Institute for providing the triple-resistant strainof T. circumcincta. Authors thank Bioinformatic & Molecular Design Research Centre (BMDRC, Yonsey University, Seoul, Korea) and Idorsia Pharmaceuticals Ltd. (Allschwil, Switzerland) for compli-mentary access to preADMET and Osiris Data Warrior databases, respectively. RE thanks financiation from RICET-USAL ProgramRD16/0027/0018. Financial support came from MINECO: RETOS(AGL2016-79813-C2-1R/2R) and Junta de Castilla y León co-financed by FEDER, UE (LE020P17). EVG was funded by FPU16/03536, VCGA by Junta de Castilla y León and FSE (LE082-18), MAVby Junta de Castilla y León (LE051-18) and MMV by the Spanish “Ramon y Cajal” Programme (Ministerio de Economía y Competitividad; MMV, RYC-2015-18368), respectively.
Databáze: OpenAIRE
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