Design, synthesis, and evaluation of new benzimidazole‏ ‏left-to-right markthiourea left-to-right markderivatives as antitumor agents

Novel benzimidazole thiourea derivatives were designed and synthesized based on sorafenib as a lead compound. The benzimidazole moiety was traded by the pyridine ring to enhance the hydrophobic interaction and retain hydrogen bonding in the hinge region, while lipophilic moieties with different bulkiness were employed in the deep hydrophobic pocket for better hydrophobic interactions. Thiourea as a urea bioisostere was also utilized. Substantial activity was demonstrated against a leukemia subpanel in an in vitro antitumor screening at the NCI. In the single-dose assay, compounds 7i, 7j, and 7l had a GI%) higher than sorafenib against most leukemia cell lines (GI% = 86.2%-137.1%), while in the five-dose assay, compound 7l outperformed sorafenib against the HL-60(TB) and SR leukemia cell lines in terms of GI(50), TGI, and LC50. Compound 7l also caused cycle arrest at the G0-G1 and S phases in the HL-60(TB) leukemia cell line and induced apoptosis via elevating the Bax/Bcl-2 ratio and increasing caspases 3, 7, and 9 by 5.1-, 3.2-, and 5.2-fold, respectively. Compounds 7i, 7j, and 7l also inhibited the vascular left-to-right markendothelial growth factor receptor-2 (VEGFR-2), B-Raf((V600E)), and platelet-derived growth factor receptor left-to-right markbeta (PDGFR-& beta;) enzymes with an IC50 range of 0.063-0.44 & mu;M. COMPARE analysis and a molecular docking study were also performed to predict the possible mechanism of action and binding mode, respectively.