Five and six membered heterocyclic rings endowed with azobenzene as dual EGFRT790M and VEGFR-2 inhibitors: design, synthesis, in silico ADMET profile, molecular docking, dynamic simulation and anticancer evaluations

Novel azobenzene scaffold-joined heterocyclic isoxazole, pyrazole, triazole, and/or triazine moieties have been developed and synthesized utilizing microwave and traditional methods. Our compounds were tested for growth inhibition of A549, MCF-7, HCT-116, and HepG2 tumors by dual targeting the VEGFR-2 and EGFR(T790M) enzymes. The suggested compound's manner of binding with EGFR(T790M) and VEGFR-2 active sites was explored through molecular design and MD modeling. The information from the results of the biological screening and the docking studies was highly correlated. The A549 cell line was the one that responded to the novel compound's effects most effectively. Having IC50 values of 5.15, 6.37, 8.44 and 6.23 mu M, respectively, 14 was the most effective derivative on the four A549, MCF-7, HCT116 and HepG2 cancer cells. It had greater activity than erlotinib and slightly inferior activities on the tested cell lines than sorafenib, respectively. The cytotoxicity of the most effective derivatives, 5, 6, 10 and 14, was evaluated against typical VERO cell lines. Having IC50 values ranging from 42.32 to 55.20 mu M, the results showed that the investigated drugs have modest toxicity against VERO normal cells. Additionally all derivatives were assessed for their dual VEGFR-2 and EGFR(T790M) inhibitory effects. Among them, derivatives 14, 5 and 10 were established as the greatest inhibitors of VEGFR-2 at IC50 values of 0.95, 1.25 and 1.50 mu M correspondingly. As well, derivatives 14, 6, 5 and 10 could inhibit EGFR(T790M) activity demonstrating strongest effects with IC50 = 0.25, 0.35, 0.40 and 0.50 mu M respectively. Furthermore, the ADMET profile was evaluated for compounds 5, 6, 10 and 14 in contrast to reference drugs sorafenib and erlotinib.

Automated summary

Novel azobenzene scaffold-joined heterocyclic isoxazole, pyrazole, triazole, and/or triazine derivatives were synthesized and tested for their growth inhibition effects on A549, MCF-7, HCT-116, and HepG2 cancer cells. The compounds showed dual targeting effects on VEGFR-2 and EGFR(T790M) enzymes. Molecular design and MD modeling revealed the binding mode of the compounds with the active sites. The compounds demonstrated significant inhibitory effects, particularly compound 14, which showed the highest activity on A549 cells.