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

التفاصيل البيبلوغرافية
العنوان: Synthesis, biosimulation and pharmacological evaluation of benzimidazole derivatives with antihypertensive multitarget effect.
المؤلفون: Gutiérrez-Hernández A; Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico., Estrada-Soto S; Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico., Martínez-Conde C; Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico., Gaona-Tovar E; Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico., Medina-Franco JL; Grupo de investigación DIFACQUIM, Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, 04510 México City, Mexico., Hernández-Núñez E; Departamento de Recursos del Mar, Centro de Investigación y de Estudios Avanzados, IPN, Unidad Mérida, Yucatán 97310, Mexico., Hidalgo-Figueroa S; CONAHCyT-División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica A. C., S. L. P, San Luis Potosí 78216, Mexico., Castro-Moreno P; Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090 Estado de México, Mexico., Ibarra-Barajas M; Unidad de Investigación en Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090 Estado de México, Mexico., Navarrete-Vazquez G; Facultad de Farmacia, Universidad Autónoma del Estado de Morelos, Cuernavaca 62209, Morelos, Mexico. Electronic address: gabriel_navarrete@uaem.mx.
المصدر: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Sep 15; Vol. 110, pp. 129879. Date of Electronic Publication: 2024 Jul 06.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, c1991-
مواضيع طبية MeSH: Benzimidazoles*/chemistry , Benzimidazoles*/pharmacology , Benzimidazoles*/chemical synthesis , Antihypertensive Agents*/pharmacology , Antihypertensive Agents*/chemical synthesis , Antihypertensive Agents*/chemistry , Rats, Inbred SHR* , Molecular Docking Simulation*, Animals ; Rats ; Structure-Activity Relationship ; Blood Pressure/drug effects ; Hypertension/drug therapy ; Receptor, Angiotensin, Type 1/metabolism ; Molecular Structure ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Angiotensin II Type 1 Receptor Blockers/chemical synthesis ; Angiotensin II Type 1 Receptor Blockers/chemistry ; Calcium Channel Blockers/pharmacology ; Calcium Channel Blockers/chemical synthesis ; Calcium Channel Blockers/chemistry ; Calcium Channels, L-Type/metabolism
مستخلص: In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT 1 R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1 H NMR, 13 C 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 AT 1 R 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Keywords: Benzimidazole; Bioisosteres; Hypertension; Multitarget effect
المشرفين على المادة: 0 (Benzimidazoles)
0 (Antihypertensive Agents)
0 (Receptor, Angiotensin, Type 1)
0 (Angiotensin II Type 1 Receptor Blockers)
0 (Calcium Channel Blockers)
0 (Calcium Channels, L-Type)
تواريخ الأحداث: Date Created: 20240708 Date Completed: 20240728 Latest Revision: 20240806
رمز التحديث: 20240806
DOI: 10.1016/j.bmcl.2024.129879
PMID: 38977106
قاعدة البيانات: MEDLINE
الوصف
تدمد:1464-3405
DOI:10.1016/j.bmcl.2024.129879