Design, synthesis, antitumor estimation, and molecular docking of new imidazothiazolediones as potential dual EGFR and IDO1 inhibitors and apoptosis stimulators.

Design, synthesis, molecular docking, ADMET and anticancer evaluation of novel pyridine/thiazole hybrids as dual VEGFR-2 and EGFR kinase inhibitors.

Here, we highlight the synthesis of a number of novel pyridine/thiazole hybrids 1 to 6a,b and their screening as possible anticancer drugs through dual targeting of VEGFR-2 and EGFR. The novel compounds were created in accordance with the structural specifications of the target receptors. The MTT assay was used to assess the compounds' cytotoxicity against the cancer cell lines HepG2, MCF-7, HCT116, and A549. With IC50 values of 6.50, 7.00, 5.55, and 6.85 μM against HepG2, MCF-7, A549, and HCT116 cell lines, respectively, compound 5b demonstrated the strongest anticancer activity. Although it was less effective than sorafenib against the studied cell lines, it was more effective than erlotinib against HepG2, MCF-7, and HCT116, while it was less effective against A549. The six potent compounds 4a, 4b, 4c, 5a, 5b, 6a, and 6b were assessed for their toxic effects on VERO normal cell lines to determine cytotoxicity levels. Results across all studies indicated that every synthesized compound demonstrated minimal toxicity toward VERO normal cells, with IC50 values ranging between 47.60 and 52.22 μM. Additionally, molecular modeling studies were used to investigate how well the novel derivatives could interact with EGFR and VEGFR-2 receptors. Furthermore, the compounds underwent additional testing to measure their capacity to inhibit both EGFRT790M and VEGFR-2. Compounds 5b, 4b, 4c, and 6b demonstrated excellent inhibitory potency against VEGFR-2, exhibiting IC50 values of 0.95, 1.00, 1.15, and 1.35 μM, respectively. Also, compounds 5b, 4c, 4b, and 6b inhibited EGFRWT activity with IC50 = 0.24, 0.30, 0.37 and 0.40 μM respectively. Similarly, these same compounds displayed superior inhibitory effects on EGFRT790M, with corresponding IC50 values of 0.26, 0.36, 0.44, and 0.50 μM, respectively. Notably, derivatives 5b, 4b, and 4c exhibited good in silico ADMET predictions.

Synthesis of Novel Benzoxazole–Piperazine Hybrids as Anticancer Leads: Biological, Molecular Docking, and ADMET Evaluations

Design, Synthesis and Anti-Breast Cancer Activity of New Benzimidazole-1,2,4-thiadiazoles-benzamide Hybrids

A new series of benzimidazole-1,2,4-thiadiazole-benzamide hybrids (7a-l) was synthesized and characterized. The synthesized hybrids were evaluated for anticancer activity against two breast cancer cell lines, MCF-7 and MDA-MB-231, using the MTT assay, with Erlotinib as the reference drug. The results revealed that hybrid 7i exhibited more potent activity against both tested cancer cell lines than the standard drug Erlotinib. The other three hybrids, 7j, 7k and 7l, displayed activity values close to that of the standard drug. Based on these findings, hybrids 7i, 7j, 7k and 7l were further evaluated for tyrosine kinase EGFR inhibitory activity using Erlotinib as the reference drug. Hybrids 7i and 7j exhibited higher EGFR inhibitory activity than erlotinib. Molecular docking studies of the potent hybrids with the EGFR receptor supported the biological results, with hybrids 7i and 7l exhibiting strong interactions with the EGFR protein and superior binding affinities compared with erlotinib. The combined anticancer, EGFR inhibitory and docking results identify hybrid 7i as the most promising hybrid, while hybrids 7j and 7l represent potential EGFR-targeting anticancer candidates.

Design, synthesis, anticancer evaluation, and molecular dynamics-based computational investigation of novel pyrimidine-benzothiazole/phenyl hybrid-based VEGFR-2-targeted derivatives with antioxidant, DNA nicking, DNA interaction, and cytotoxicity studies.

Overall, K12 emerged as the most promising lead compound, combining potent antiproliferative activity, high selectivity, efficient DNA-binding characteristics, and robust computational performance, highlighting its potential for further development as a novel anticancer agent.

Design, Synthesis, In Vitro Biological Evaluation, and In Silico Studies of Novel Imidazo[4,5-b]Pyridine-Acrylonitrile-Based Derivatives as VEGFR-2 Inhibitors Against Breast Cancer and Hepatocellular Carcinoma.

Vascular endothelial growth factor receptor-2 (VEGFR-2) is a vital mediator of angiogenesis. Therefore, VEGFR-2 inhibition is considered a promising therapeutic target to combat cancer. In the present study, a series of 22 imidazo[4,5-b]pyridine-acrylonitrile-based derivatives was designed and synthesized. All compounds were evaluated for their VEGFR-2 inhibitory activity. Seven of the tested compounds showed high inhibitory activity against VEGFR-2 with IC50 (0.029-0.087 µM) compared to reference drug sorafenib IC50 = 0.091 µM. Four of these derivatives were selected for in vitro cytotoxic activity against breast cancer (MCF-7) and hepatocellular (HepG2) carcinoma cell lines, showing IC50 (0.073-0.196 µM) and (0.20-0.21 µM), respectively, relative to sorafenib IC50 0.16 and 0.19 µM, respectively. Compound 2f exhibiting a superior VEGFR-2 inhibition (IC50 = 0.029 µM compared to sorafenib IC50 = 0.091 µM) and cytotoxicity against MCF-7 and HepG2 (IC50 = 0.073 µM and IC50 = 0.09 µM, respectively), was subjected to cell cycle analysis, apoptosis assay, and molecular modeling studies, which strongly supported the results. It caused cell cycle arrest at G2/M phase by 13.67% and a promising apoptosis induction. 2f exhibited a promising binding score and pose inside the VEGFR-2 active sites. It also showed a good safety profile with a moderate selectivity index. Based on the prediction of physicochemical and pharmacokinetic properties for 2f, it showed excellent prediction results to be orally bioavailable.

Novel benzofuran-1,3,4-thiadiazole aryl urea hybrids as dual VEGFR-2/BRAF inhibitors: anticancer activity, apoptosis induction, and molecular modeling studies.

A novel series of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker were designed as dual VEGFR-2/BRAFWT inhibitors using sorafenib as a pharmacophoric template, with compound 7j emerging as the most active analogue.