Design, synthesis, molecular modeling and biological evaluation of novel Benzoxazole-Benzamide conjugates via a 2-Thioacetamido linker as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

Abstract

A novel series of 2-thioacetamide linked benzoxazole-benzamide conjugates 1 – 15 was designed as potential inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR-2). The prepared compounds were evaluated for their potential antitumor activity and their corresponding selective cytotoxicity was estimated using normal human fibroblast (WI-38) cells. Compounds 1 , 9 – 12 and 15 showed good selectivity and displayed excellent cytotoxic activity against both HCT-116 and MCF-7 cancer cell lines compared to sorafenib, used as a reference compound. Furthermore, compounds 1 and 11 showed potent VEGFR-2 inhibitory activity. The cell cycle progression assay showed that 1 and 11 induced cell cycle arrest at G2/M phase, with a concomitant increase in the pre-G1 cell population. Further pharmacological studies showed that 1 and 11 induced apoptosis and inhibited the expression of the anti-apoptotic Bcl-2 and Bcl-xL proteins in both cell lines. Therefore, compounds 1 and 11 might serve as promising candidates for future anticancer therapy development.

Novel hydrazone‐isatin derivatives as potential EGFR inhibitors: Synthesis and in vitro pharmacological profiling

“…The experimental procedures of in vitro biological evaluation assays including antiproliferative activities, [50,51,55] EGFR inhibition assay, [56] cell cycle analysis, [57] annexin V-FITC apoptosis assay, [57] Bax, Bcl2, Caspase-3-level expressions were conducted as reported previously. [58,59] All assay procedures were provided in detail in the Supporting Information data.…”

“…[ 5–9 ] Protein kinases are involved in signal transduction pathways that regulate many physiological activities, including cell proliferation, differentiation, and death. [ 10–12 ] Growth factor receptor tyrosine kinases (TKs) are seen in a number of tumor forms, resulting in improper mitogenic signaling. Protein TKs are thus appealing targets in the quest for therapeutic drugs not just against cancer, but also against a wide range of other diseases.…”

Synthesis, biological evaluation and computer-aided discovery of new thiazolidine-2,4-dione derivatives as potential antitumor VEGFR-2 inhibitors

“…Compounds 3, 5a-c, 6a-c, and 11a-e were synthesized as previously reported. 21,[36][37][38][39][40] 2.1.1. General procedure for the synthesis of target compounds 12-17.…”

Design, synthesis, in silico studies, and biological evaluation of novel pyrimidine-5-carbonitrile derivatives as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

“…Condensation of the keton derivatives 5 and 6 with the appropriate acid hydrazides 10a-g (obtained according to the reported procedures) 16,23,24 at heating and reuxing temperature in absolute ethanol containing catalytic amount of glacial acetic acid afforded the respective hydrazono compounds 11a-e and 12a-g, respectively (Scheme 3).…”

“…10 There drawbacks motivated the medicinal chemists to continue searching for new small molecules aiming to overcome the adverse effects and minimize resistance. [11][12][13][14] Observing the structure-activity relationship of the FDA approved VEGFR-2 inhibitors revealed that they almost shared four common features namely, (a) a heterocyclic head with minimum one nitrogen atom to occupy the hinge region of the active site, (b) a spacer to occupy gatekeeper region, (c) a hydrogen bonding moiety or a pharmacophore that makes essential H-bonds with the DFG amino acids, and (d) a hydrophobic tail that lls the receptor's allosteric site [15][16][17][18][19][20] (Fig. 1A).…”