Design, synthesis, anti-proliferative evaluation, docking, and MD simulations studies of new thiazolidine-2,4-diones targeting VEGFR-2 and apoptosis pathway

Abstract

We report herein, the design and synthesis of thiazolidine-2,4-diones derivatives as new inhibitors for VEGFR-2. The designed members were assessed for their in vitro anticancer activity against four cancer cell lines; A549, Caco-2, HepG-2 and MDA-MB-231. Compound 14a showed the most potent effects against Caco-2, and HepG-2 cell lines (IC50 = of 1.5 and 31.5 μM, respectively). Next, the in vitro VEGFR-2 inhibitory activity, safety profiles and selectivity indices were examined for all the synthesized members against the normal Vero cell line. Compound 14a (the safest member against Caco-2 cell line) was further investigated for its ability to inhibit Caco-2 cells migration and healing. Moreover, the apoptotic induction of compound 14a against Caco-2 cell line was investigated by assessing against four apoptotic genes (Bcl2, Bcl-xl, TGF, and Survivin). The results revealed that compound 14a can exert apoptosis through significant reduction of Bcl2, Survivin, and TGF gene expression levels. Finally, deep computational studies including molecular docking, ADMET, toxicity studies, and MD simulation were carried out. Also, the DFT calculations were performed and discussed, and the results confirmed the inhibitory reactivity of 14a against VEGFR-2. Compound 14a is expected to be used as a potential lead in the development of new VEGFR-2 inhibitors with increased potency.

Recent updates in click and computational chemistry for drug discovery and development

“…Frontiers in Chemistry frontiersin.org polymerization inhibitor (Dwivedi et al, 2022), PARP-1 inhibitor 2 (Syam et al, 2022), CDK2 inhibitor 3 (Qayed et al, 2022), HDAC-1-3 inhibitor 4 (Cheshmazar et al, 2022), VEGFR-2 inhibitor 5 (Taghour et al, 2022) were identified for cancer therapies. Furthermore, AChE inhibitor 6 (Macedo Vaz et al, 2022) for treatment of Alzheimer's disease and Mtb RNAP inhibitor 7 (Mekonnen Sanka et al, 2022) for antitubercular and antimicrobial treatment were deserve further study.…”

“…To effectively and efficiently design and develop new drugs, computational methods had been applied for drug design including target identification, seeking out and optimizing lead compounds prediction of pharmacokinetic and toxicological properties as well as compound synthesis by molecular docking and molecular dynamics, virtual screening, pharmacophore and ADMET prediction. Novel quinazoline derivative 1 as tubulin polymerization inhibitor ( Dwivedi et al, 2022 ), PARP-1 inhibitor 2 ( Syam et al, 2022 ), CDK2 inhibitor 3 ( Qayed et al, 2022 ), HDAC-1-3 inhibitor 4 ( Cheshmazar et al, 2022 ), VEGFR-2 inhibitor 5 ( Taghour et al, 2022 ) were identified for cancer therapies. Furthermore, AChE inhibitor 6 ( Macedo Vaz et al, 2022 ) for treatment of Alzheimer’s disease and Mtb RNAP inhibitor 7 ( Mekonnen Sanka et al, 2022 ) for antitubercular and antimicrobial treatment were deserve further study.…”

Design, synthesis, anticancer evaluation, and in silico ADMET analysis of novel thalidomide analogs as promising immunomodulatory agents

“…In silico studies are preferred for a variety of reasons, including the restrictions on cost, time, and effort as well as the strict laws regarding animal testing. 25,26 Although there are many in vitro studies that can be carried out to investigate the properties of ADMET, they are not always the most effective method. 27,28 Therefore, the ADMET characteristics of the examined compounds were assessed computationally using Discovery Studio 4.0.…”

Identification of Flavone Derivative Displaying a 4′-Aminophenoxy Moiety as Potential Selective Anticancer Agent in NSCLC Tumor Cells

“…Various chemotherapeutic agents have been commonly and successfully used for the treatment of cancer [ 1 , 2 , 3 ]; however, the development of inducible drug resistance and the difficulty to limit the associated side effects are often the main cause of chemotherapy failure. Therefore, the identification of novel anticancer drugs with great cancer-selective toxicity remains the main challenge for medicinal chemistry researchers [ 4 , 5 , 6 , 7 ]. The flavone scaffold has emerged as a versatile source in the field of drug discovery ( Figure 1 A).…”