Discovery of New VEGFR-2 Inhibitors: Design, Synthesis, Anti-Proliferative Evaluation, Docking, and MD Simulation Studies

Abstract

Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners were synthesized possessing the pharmacophoric essential features to bind correctly with the VEGFR-2 active pocket. All members were evaluated for their cytotoxic and VEGFR-2 inhibitory potentialities. Compound 6 was the most potent showingIC50 values of 9.3 ± 0.02 and 7.8 ± 0.025 µM against HCT-116 and HepG-2 cells, respectively, and IC50 of 60.83 nM regarding VEGFR-2 enzyme inhibition. Compound 6 arrested the growth of HCT-116 cells at the pre-G1 and G2-M phases. Further, it induced both early and late apoptosis. Additionally, compound 6 caused a significant decrease in TNF-α and IL6 by 66.42% and 57.34%, respectively. The considered compounds had similar docking performances to that of sorafenib against the VEGFR-2 (PDB ID: 2OH4). The correct binding of compound 6 with VEGFR-2 was validated using MD simulations, and MM-GPSA calculations.

Novel promising benzoxazole/benzothiazole‐derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis

“…In another modification, we thought that if we change the methylene group between the NH 2 and the carbonyl group, we might get better binding results by adding a new hydrogen bonding site (Figure 4). In continuation of our efforts to obtain new immunomodulatory [35][36][37][38][39][40][41][42][43][44] and/or anticancer agents, [45][46][47][48][49][50][51] we designed and synthesized novel thalidomide analogs that were tested in vitro against the HepG-2, HCT-116, PC3, and MCF-7 cancer cell lines. By measuring the immunomodulatory effects of the synthesized compounds in HCT-116 cells against CASP8, TNF-α, VEGF, and NF-κB P65, we conducted additional research to better understand their immunomodulatory effect.…”

Design, synthesis, anti-proliferative evaluation, docking, and MD simulation studies of new thieno[2,3-d]pyrimidines targeting VEGFR-2

“…Elaboration on the details of this experimental methodology can be found in the ESI Data section † of the research. 75 4.3.10. Toxicity studies.…”

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

“…Unfortunately, treatment with the currently FDA approved VEGFR-2 inhibitors faced several drawbacks represented in their serious adverse reactions and development of a secondary resistance. 10 There drawbacks motivated the medicinal chemists to continue searching for new small molecules aiming to overcome the adverse effects and minimize resistance. 11–14…”

“…Unfortunately, treatment with the currently FDA approved VEGFR-2 inhibitors faced several drawbacks represented in their serious adverse reactions and development of a secondary resistance. 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.…”