Vicinal diaryl pyrazole with tetrazole/urea scaffolds as selective angiotensin converting enzyme-1/cyclooxygenase-2 inhibitors: Design, synthesis, anti-hypertensive, anti-fibrotic, and anti-inflammatory.

Autor: Fadaly WAA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt., Elshaier YAMM; Organic & Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt., Ali FEM; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt., El-Bahrawy AH; Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt., Abdellatif KRA; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.; Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah, Kingdom of Saudi Arabia., Nemr MTM; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Drug development research [Drug Dev Res] 2024 Jun; Vol. 85 (4), pp. e22217.
DOI: 10.1002/ddr.22217
Abstrakt: As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC 50 1.87 and 2.03 μM, respectively). 17b (IC 50 0.078 μM) and 17 f (IC 50 0.094 μM) inhibited ACE-1 comparable to perindopril (PER) (IC 50 0.048 μM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to  l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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