Synthesis, biosimulation and pharmacological evaluation of benzimidazole derivatives with antihypertensive multitarget effect

  • Bioorg Med Chem Lett. 2024 Jul 6:110:129879. doi: 10.1016/j.bmcl.2024.129879.
Abraham Gutiérrez-Hernández  1 ,  Samuel Estrada-Soto  1 ,  Carlos Martínez-Conde  1 ,  Emmanuel Gaona-Tovar  1 ,  José L Medina-Franco  2 ,  Emanuel Hernández-Núñez  3 ,  Sergio Hidalgo-Figueroa  4 ,  Patricia Castro-Moreno  5 ,  Maximiliano Ibarra-Barajas  5 ,  Gabriel Navarrete-Vazquez  6
Affiliations
  • 1. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico.
  • 2. Grupo de investigación DIFACQUIM, Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, 04510 México City, Mexico.
  • 3. Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados, IPN, Unidad Mérida, Yucatán 97310, Mexico.
  • 4. CONAHCyT-División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica A. C., S. L. P, San Luis Potosí 78216, Mexico.
  • 5. Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090 Estado de México, Mexico.
  • 6. Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico. Electronic address: [email protected].
PMID: 38977106 DOI: 10.1016/j.bmcl.2024.129879
Abstract

In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of Calcium Channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier.

Keywords
Benzimidazole; Bioisosteres; Hypertension; Multitarget effect.
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