Synthesis, in vitro and in silico enzyme (COX-1/2 & LOX-5), free radical scavenging and cytotoxicity profiling of the 2,4-dicarbo substituted quinazoline 3-oxides

Series of the 3-methylquinazoline 3-oxide derivatives were evaluated through enzymatic assays in vitro and in silico for potential inhibitory effect against cyclooxygenase-1/2 (COX-1/2) and lipoxygenase-5 activities as well as for free radical scavenging potential and cytotoxicity. The 6-bromo (3k) and 6-iodo substituted 2-(4-chlorophenyl)-4-methylquinazoline 3-oxide (3q) exhibited significant inhibitory effect against both COX-1 (IC50 = 13.9 ± 3.21 µM and 9.7 ± 0.09 µM, respectively) and COX-2 (IC50 = 6.4 ± 0.74 µM and 4.6 ± 1.45 µM, respectively) compared to quercetin (IC50 = 13.84 ± 1.57 µM and 5.06 ± 2.60 µM, respectively). Their activity was, however, modest compared to the selective COX-2 inhibitor, celecoxib, with IC50 values of 7.35 ± 0.88 µM and 0.62 ± 0.74 µM against COX-1 and COX-2, respectively. The two compounds exhibited comparable effect on LOX-5 (IC50 = 15.0 µM), which is moderate compared to quercetin (IC50 = 8.04 ± 1.12 µM) and modest against zileuton (IC50 = 0.42 ± 0.51 µM). Structure–activity relationship analysis suggested that the presence of a halogen atom at the C-6 position and a 2-aryl group enhance inhibitory effect against COX-2. This observation is well supported by molecular docking studies.