Design, synthesis, molecular docking, in silico ADMET profile and anticancer evaluations of sulfonamide endowed with hydrazone-coupled derivatives as VEGFR-2 inhibitors

A new series of sulfonamide endowed with hydrazone coupled to dimethyl and/or diethyl malonates were prepared. Various sulfa drugs were diazotized and followed by coupling with active methylene of dimethyl and/ or diethyl malonate to afford the new intermediates hydrazones 3a-c and 4a-c. The reactivity of hydrazone derivatives towards hydrazines was investigated. Thus, a novel series of 3,5-dioxopyrazolidine7a-cwere obtained by treatment with hydrazine hydrate. When hydrazones were allowed to react with phenyl hydrazine, the alkyl 2((4-(N-(substituted)sulfamoyl)phenyl)diazenyl)-3-oxo-3-(2-phenylhydrazinyl)propanoateswere obtained 8(a-c) and/or 10(a-c). Their anticancer activities were evaluated against HepG2, HCT-116 and MCF-7. HepG2 was the most sensitive one. In particular, compounds 7(c), 7(b) and 10(c) were found to be the most potent derivatives with IC50 = 6.43 +/- 0.5, 9.66 +/- 0.8, 10.57 +/- 0.9 mu M, 8.65 +/- 0.7, 7.49 +/- 0.6, 14.29 +/- 1.3 mu M and 8.97 +/- 0.7, 10.13 +/- 0.9, 13.82 +/- 1.1 mu M respectively. Sorafenib and doxorubicin were used as reference drugs. The most potent derivatives 7(a), 7(b), 7(c), 8(c) and 10(c) were tested for their cytotoxicity against normal VERO cell lines. Compounds 7(a), 7(b), 7(c), 8(c) and 10(c) are respectively, 2.41, 4.85, 4.08, 3.23 and 5.89 fold times more toxic in HCT116 than in VERO normal cells. Moreover, the most active anti-proliferative derivatives 7(a), 7(b), 7(c), 8(c) and 10c were subjected to further biological study to evaluate their inhibitory potentials against VEGFR-2. The tested compounds dis played high to good inhibitory activity with IC50 values ranging from 0.14 +/- 0.02 to 0.23 +/- 0.03 mu M. Among them, compounds 7c, 7b and 10c were found to be the most potent derivative that inhibited VEGFR-2 at IC50 values of 0.14 +/- 0.02, 0.15 +/- 0.02 and 0.15 +/- 0.02 mu M respectively. sorafenib was used as reference drug. Furthermore, ADMET profile was evaluated for the four most active compounds in comparison to doxorubicin as a reference drug. The data obtained from docking studies were highly correlated with that obtained from the biological screening.

Automated summary

A novel series of sulfonamide derivatives containing hydrazone were synthesized and evaluated for their anticancer activities. Some compounds showed high sensitivity in HepG2 cells and good inhibitory activity against VEGFR-2.