International Journal of Molecular Sciences | |
Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes | |
Juan A. Hermoso1  Siseth Martínez-Caballero1  Rafael Castillo2  Alicia Hernández-Campos2  Erick Sierra-Campos3  Mónica Valdez-Solana3  Claudia Avitia-Domínguez4  Alfredo Téllez-Valencia4  Irene Betancourt-Conde4  Jesús Oria-Hernández5  Sara T. Méndez5  Antonio Romo-Mancillas6  Lilián Yépez-Mulia7  | |
[1] Departamento de Cristalografía y Biología Estructural, Instituto Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, 28006 Madrid, Spain;Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Av. Artículo 123 S/N Fracc. Filadelfia, Gómez Palacio 35010, Mexico;Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitúa S/N, Durango 34000, Mexico;Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico;Laboratorio de Diseño Asistido por Computadora y Síntesis de Fármacos, Facultad de Química, Universidad Autónoma de Querétaro, Querétaro 76010, Mexico;Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, Unidad Médica de Alta Especialidad-Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; | |
关键词: leishmaniasis; arginase; virtual screening; enzyme inhibition; molecular dynamics; benzimidazole derivatives; | |
DOI : 10.3390/ijms222413613 | |
来源: DOAJ |
【 摘 要 】
Leishmaniasis is a disease caused by parasites of the Leishmania genus that affects 98 countries worldwide, 2 million of new cases occur each year and more than 350 million people are at risk. The use of the actual treatments is limited due to toxicity concerns and the apparition of resistance strains. Therefore, there is an urgent necessity to find new drugs for the treatment of this disease. In this context, enzymes from the polyamine biosynthesis pathway, such as arginase, have been considered a good target. In the present work, a chemical library of benzimidazole derivatives was studied performing computational, enzyme kinetics, biological activity, and cytotoxic effect characterization, as well as in silico ADME-Tox predictions, to find new inhibitors for arginase from Leishmania mexicana (LmARG). The results show that the two most potent inhibitors (compounds 1 and 2) have an I50 values of 52 μM and 82 μM, respectively. Moreover, assays with human arginase 1 (HsARG) show that both compounds are selective for LmARG. According to molecular dynamics simulation studies these inhibitors interact with important residues for enzyme catalysis. Biological activity assays demonstrate that both compounds have activity against promastigote and amastigote, and low cytotoxic effect in murine macrophages. Finally, in silico prediction of their ADME-Tox properties suggest that these inhibitors support the characteristics to be considered drug candidates. Altogether, the results reported in our study suggest that the benzimidazole derivatives are an excellent starting point for design new drugs against leishmanisis.
【 授权许可】
Unknown