Novel quinoxaline derivatives as dual EGFR and COX-2 inhibitors: synthesis, molecular docking and biological evaluation as potential anticancer and anti-inflammatory agents

Novel quinoxaline derivatives (2a–d, 3, 4a, 4b and 5–15) have been synthesized via the reaction of 4-methyl-3-oxo-3,4-dihydroquinoxaline-2-carbohydrazide (1) with different aldehydes, ketones, diketones, ketoesters, as well as hydrazine, phenyl isothiocyanate, carbon disulphide. The synthesized products have been screened for their in vitro anticancer and COX inhibitory activities. Most of the synthesized compounds exhibited good anticancer and COX-2 inhibitory activities. MTT assay revealed that compounds 11 and 13 were the most potent and exhibited very strong anticancer activity against the three cancer cell lines with IC(50) values ranging from 0.81 μM to 2.91 μM. Compounds 4a and 5 come next and displayed strong anticancer activity against the three cancer cell lines with IC(50) values ranging from 3.21 μM to 4.54 μM. Mechanistically, compounds 4a and 13 were the most active and potently inhibited EGFR with IC(50) = 0.3 and 0.4 μM, respectively. Compounds 11 and 5 come next with IC(50) = 0.6 and 0.9 μM, respectively. Moreover, compounds 11 and 13 were the most potent as COX-2 inhibitors and displayed higher potency against COX-2 (IC(50) = 0.62 and 0.46 μM, respectively) more than COX-1 (IC(50) = 37.96 and 30.41 μM, respectively) with selectivity indexes (SI) of 61.23 and 66.11, respectively. Compounds 4a and 5 comes next with IC(50) = 1.17 and 0.83 μM and SI of 24.61 and 48.58, respectively. Molecular docking studies into the catalytic binding pocket of both protein receptors, EGFR and COX-2, showed good correlation with the obtained biological results. Parameters of Lipinski's rule of five and Veber's standard were calculated and revealed that compounds 4a, 5, 11 and 13 had a reasonable drug-likeness with acceptable physicochemical properties. Therefore, based on the obtained biological results accompanied with the docking study and physicochemical parameters, it could be concluded that compounds 4a, 5, 11 and 13 could be used as promising orally absorbed dual anti-inflammatory agents via inhibition of COX-2 enzyme and anticancer candidates via inhibition of EGFR enzyme and could be used as a future template for further investigations.