Design, Synthesis, and Evaluation of Novel Analogues as Multifunctional Cardiovascular Agents

Abstract

Cardiovascular diseases (CVDs) remain a leading cause of global mortality, driving the urgent need for novel therapeutic agents with improved efficacy and multi-factorial mechanisms of action. Heterocyclic compounds represent privileged scaffolds in cardiovascular drug discovery due to their versatile pharmacological profiles. This study describes the design, synthesis, and comprehensive evaluation of a new series of quinoline-pyrazole hybrid analogues as potential multi-target cardiovascular agents. The target compounds were efficiently synthesized through a multi-step reaction sequence and characterized by spectral analysis (IR, 11H NMR, 13C NMR, and Mass spectrometry). The synthesized library was screened for in vitro angiotensin-converting enzyme (ACE) inhibition and antioxidant activity using DPPH radical scavenging assay. Several compounds demonstrated significant dual activity, with compound 8c emerging as the most potent candidate, exhibiting exceptional ACE inhibition (IC5050​ = 0.85 µM) comparable to Captopril and substantial antioxidant activity (85.2% radical scavenging at 100 µM). In an in vivo L-NAME-induced hypertensive rat model, compound 8c (25 mg/kg, p.o.) produced a remarkable reduction in systolic blood pressure (34.5 ± 1.8 mmHg) and demonstrated favorable hemodynamic parameters. Molecular docking studies revealed a strong binding interaction of 8c with the ACE active site, coordinating with the zinc ion and key amino acid residues. Structure-activity relationship analysis established that electron-withdrawing groups at the para-position and a free carboxylic acid moiety are crucial for optimal activity. These findings position compound 8c as a promising lead candidate for the development of novel multi-target cardiovascular therapeutics, warranting further investigation into its detailed mechanism of action and preclinical development.