Cardioprotective effect of 2-methoxy phenol derivatives against oxidative stress-induced vascular complications: An integrated in vitro, in silico, and in vivo investigation

• Published in: Biomedicine & pharmacotherapy Vol. 165; p. 115240
• Main Authors: Aqeel, Muhammad Tahir, Rahman, Nisar-ur, Khan, Arif-ullah, Khan, Muhammad Tariq, Ashraf, Zaman, Hassan, Syed Shams ul, Bungau, Simona Gabriela, Majid, Muhammad
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2023; Elsevier
• Subjects: ADMET; Antioxidant; Cardiovascular; COX; Molecular docking; Phenolic; Vasorelaxant; Cardiovascular; Phenolic; Vasorelaxant; Antioxidant; ADMET; COX; Molecular docking
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.115240

Oxidative stress and inflammation play crucial roles in macro/microvascular complications. Phenolic compounds and their derivatives show promise as therapeutic agents for diseases like cancer, metabolic disorders, and cardiovascular diseases. With their antioxidant and anti-inflammatory properties, these compounds hold potential for mitigating vascular complications and improving overall health. This study aimed to assess the therapeutic potential of five 2-methoxy phenol derivatives (T2, T5, T6, T7, and T8) as antioxidants, anti-inflammatory agents, and vasorelaxants using in vitro, in silico, and in vivo approaches. Among all, T2 exhibited substantial antioxidant potential against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radicals with IC50 (27.97 µg/mL), nitric oxide (NO) radicals (IC50 = 34.36 µg/mL), hydroxyl (OH) radicals (IC50 = 34.83 µg/mL) and Iron chelation (IC50 = 24.32 µg/mL). Molecular docking analysis confirms that all derivatives, particularly T2, exhibit favorable binding energies with the target proteins, ACE (−7.7 Kcal/mol), ECE-1 (−7.9 Kcal/mol), and COX-1 (−7.8 Kcal/mol). All of the compounds demonstrated satisfactory physicochemical and pharmacokinetic characteristics, and showed minimal to no toxicity during in silico, in vitro, and in vivo assessments. In isolated aortic rings from Sprague Dawley rats, pre-contracted with high K+ (80 mM), T2 induced vasorelaxation in dose dependent manner and shifted calcium response curves to the right as compared to verapamil. T2 also showed substantial platelet aggregation inhibition in a dose dependent manner with IC50 21.29 µM. All derivatives except T7 exhibited significant conservation of endogenous antioxidants i.e. catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) and significantly suppressed serum levels of inflammatory markers i.e. nitric oxide (NO), peroxides (TBARS), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). The study concludes that T2 has significant antioxidant potential and vasorelaxant effects with adequate pharmacokinetics, making it a promising lead compound for further molecular investigation in cardiovascular disorders. [Display omitted] •The study encompasses the synthesis of derivatives of methoxy phenol and contain a 2-methoxyphenoxy ring.•The study evaluated five 2-methoxy phenol derivatives as antioxidants, anti-inflammatory agents, and cardioprotective using in-vitro, in-silico, and in-vivo approaches.•T2 exhibited substantial antioxidant potential and favorable binding energies with target proteins ACE, ECE-1, and COX-1.•T2 induced vasorelaxation in dose-dependent manner and showed substantial platelet aggregation inhibition.