Synthesis, Molecular Docking, Biological Potentials and Structure Activity Relationship of New Quinazoline and Quinazoline-4-one Derivatives

Abstract

In this work, a new derivative of ethyl 5-chloro-2-(3-(4-hydroxyphenyl)propanamido)benzoate (1) was synthesized by reacting the amino group of 3-(4-hydroxyphenyl)propanoic acid (0.01 mol) and methyl 2-amino-5-chlorobenzoate in presence of PCl3. Cyclcondensation of 1 with hydrazine hydrate afforded the corresponding 2-(4-hydroxyphenethyl)-3-amino-6-chloroquinazolin-4(3H)-one (2). Also, new Schiff base 3 was prepared via reaction of 2-(4-hydroxyphenethyl)-3-amino-6-chloroquinazolin- 4(3H)-one (2) with 4-hydroxy-3-methoxybenzaldehyde. The synthesized compounds were characterized by elemental analysis, IR, 1H NMR and mass spectral data. Also, the median lethal doses (LD50s) of compounds 1-3 in rats were 1125, 835 and 1785 mg/kg b.w., respectively. IC50 values of compounds (1, 3) as measured by DPPH• method was 136.47 and 73.54 μg/mL, respectively. IC50 values of compounds (1-3) as measured by ABTS•+ radical method was 0.8, 0.92 and 0.08 mg/mL, respectively. Antiulcerogenic activity at dose 1/20 LD50 in albino rats was 47.94, 24.60 and 56.45%, respectively. However, the anti-inflammatory effect at dose 1/20 LD50 of compounds (1-3) induced edema model after 120 min were 74.19, 69.93 and 59.03%, respectively. The synthesized compounds also possess hepatocytes and gastric mucosa protective activity against ibuprofen induced ulceration and LPS-induced liver toxicity, respectively in rats via normalization of oxidative stress biomarkers and inflammatory mediators (Na+/K+-ATPase, ALT, AST, LDH, TNF-α, NO, TBARS, GPx, CAT and SOD). Also, TNF-α, NO, PGE2 and COX-2 were inhibited in peritoneal macrophage cells at a concentration of 100 μg/L. Molecular docking suggested that the most active compounds 1 and 2 can be positioned within the active sites of COX-2 at Arg121 & Tyr356 similarly to ibuprofen (Arg-120, Glu-524 and Tyr-355). The compound 3–COX-2 complex generated by docking, revealed intricate interactions with a COX-2 channel, including hydrogen bonds with key residues Arg121 and phe519. These findings suggest that compounds 1-3 exhibited good antioxidant, antiulcer, anti-inflammatory activity and safe on liver enzymes in rats.