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

Novel benzofuran-furan-pyrano[2,3-c]pyrazole hybrids as potential anticancer agents: design, synthesis, in silico profiling, and multi-mechanistic biological evaluation

It is demonstrated that benzofuran-furan-pyrano[2,3-c]pyrazole hybrids possess promising multifaceted in vitro anticancer activity by inhibiting cancer cell proliferation, migration, invasion, and clonogenicity while inducing ROS-mediated mitochondrial apoptosis, highlighting these hybrid scaffolds as attractive candidates for further anticancer drug development.

Rational design of thiazolidine-2,4-dione-integrated combretastatin A-4 analogues as potent and selective tubulin-targeting agents for triple-negative breast cancer.

Microtubule-targeting agents remain among the most effective chemotherapeutics for the treatment of cancer. Inspired by the natural tubulin polymerization inhibitor combretastatin A-4 (CA-4), a series of novel thiazolidine-2,4-dione derivatives was designed, synthesized, and evaluated as potential tubulin-targeting anticancer agents. The cytotoxic activities of the compounds were assessed against the MDA-MB-231, while human umbilical vein endothelial cells (HUVEC) were employed to evaluate selectivity. Compounds 2 and 3 emerged as the most active members of the series (IC50 = 3.60 and 3.71 μM, respectively), accompanied by remarkably high selectivity indices of 49.7 and 51.3. To elucidate their mechanism of action, compounds 2 and 3 were further evaluated in an in vitro tubulin polymerization assay. Compound 3 displayed the strongest inhibitory activity (IC50 = 1.07 μM), surpassing the reference inhibitor CA-4 (IC50 = 2.73 μM). Flow cytometric analysis showed that compound 3 induced G2/M cell-cycle arrest, increasing the G2/M population from 21.8% to 30.8%, and markedly promoted apoptosis, with total apoptotic cells increasing from 0.13% to 43.9% in MDA-MB-231 cells. Molecular docking and MM-GBSA calculations revealed favorable binding within the colchicine-binding site of tubulin, with compounds 2 and 3 exhibiting substantially stronger predicted binding affinities (ΔG = -89.53 and -92.86 kcal/mol, respectively) than CA-4 (ΔG = -70.08 kcal/mol). Molecular dynamics simulations confirmed the stability of the ligand-protein complexes throughout the simulation period, supporting the proposed binding mode. Furthermore, in silico ADME analysis suggested favorable drug-likeness, high predicted oral absorption, and improved pharmacokinetic characteristics compared with paclitaxel. The present study identifies compounds 2 and 3 as promising lead candidate that combines potent and selective antiproliferative activity, strong tubulin polymerization inhibition, and favorable binding characteristics.

1-Butylindoline-2,3-dione derivatives as potent VEGFR-2 inhibitors: synthesis, mechanistic anticancer studies, and molecular dynamics simulations

A novel series of N-butyl isatin (indolin-2-one) derivatives was designed and synthesized as potential VEGFR-2-targeted anticancer agents, drawing inspiration from the oxindole-based inhibitor sunitinib. The synthesized compounds were assessed for antiproliferative activity against colorectal cancer cell lines (HT29 and HCT116) and for their inhibitory potential on VEGFR-2. Compound 6b exhibited the highest potency, demonstrating strong VEGFR-2 inhibition comparable to that of sunitinib. Mechanistic investigations in HCT116 cells demonstrated that 6b induced G0/G1 cell cycle arrest and promoted apoptosis, which was associated with the upregulation of p53 and Bax, downregulation of Bcl-2, and suppression of Cyclin D1 and Cyclin E expression. Furthermore, 6b markedly decreased VEGF-A expression, supporting modulation of VEGF/VEGFR-2-associated signaling. Molecular docking studies involving VEGFR-2 (PDB ID: 4AGD) demonstrated favorable binding of compound 6b in the ATP-binding pocket, establishing essential interactions with essential residues. Docking validation was established through the successful redocking of sunitinib, yielding an RMSD of 0.44 Å. Additionally, 500 ns molecular dynamics simulations indicated stable backbone behavior, regulated ligand fluctuations, preserved structural compactness, and sustained hydrogen bonding within the 6b-VEGFR-2 complex. The findings collectively identify compound 6b as a promising lead candidate for further development as a VEGFR-2-targeted anticancer agent.

Striking two targets with one scaffold via benzo[d]imidazole-isatin conjugates as potent dual VEGFR-2/c-MET antagonists.

A series of benzo[d]imidazole-isatin hybrids (4a-d, 6a-d, and 8a-d) was developed and synthesized as prospective dual inhibitors of VEGFR-2 and c-MET to address tumor growth and resistance-related signaling pathways. The biological assessment demonstrated encouraging dual kinase inhibitory action, with compound 8b identified as the most balanced inhibitor, displaying IC50 values of 92 nM and 63 nM against VEGFR-2 and c-MET, respectively. In-vitro antiproliferative evaluation against MDA-MB-231 and A549 cancer cell lines revealed notable cytotoxicity for compound 8b, yielding IC50 values of 2.37 μM and 1.79 μM, respectively, exceeding the efficacy of the reference medication sunitinib. Additionally, 8b exhibited a favorable selectivity profile for normal MCF-10A cells. Mechanistic studies demonstrated that 8b caused substantial G2/M cell cycle arrest and facilitated apoptosis in MDA-MB-231 cells. Biomarker studies revealed a reduction in VEGF-A, MMP-9, and Bcl-2 levels, alongside an increase in Bax and Caspase-3, suggesting potential anti-angiogenic and pro-apoptotic characteristics in-vitro. Molecular docking analyses provided supporting models for the identified biological activities and exhibited advantageous binding interactions within both kinase active sites. These data collectively suggest that chemical 8b may serve as a promising candidate for further anticancer research.

Urea and carbamate-functionalized quinazolin-2,4-dione derivatives as EGFR tyrosine kinase inhibitors: synthesis, anticancer evaluation, molecular docking and molecular dynamics studies

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

A novel set of imidazo[2,1-b]thiazolediones 4a,b and 5a-d, with anticipated EGFR and IDO1 inhibition activities, was designed and prepared. These novel derivatives were evaluated in the NCI 60 cell line panel in which the superior compounds 5b and 5d were chosen for further evaluation of their five dose cytotoxicity toward the most sensitive cancer cells namely non-small cell lung cancer EKVX and HOP-92, breast HS 578 T, and normal WI-38 cells. The presence of a substituted benzylidene moiety at position-2 of the imidazothiazole scaffold in compounds 5a-d positively influences anticancer activity, with the phenylallylidene moiety at position-6 exhibiting superior cytotoxic effects compared to the 2-thienylidene moiety. Among the examined hybrids, 5d showed significant antiproliferative effect against HS 578 T tumor cell. To explore the underlying cell-death mechanisms, secondary biological evaluations were conducted, including cell-free EGFR and IDO1 enzymatic inhibition, apoptosis assay, and cell cycle analysis. In cell-free biochemical assays, the most active derivatives demonstrated a promising potential dual inhibitory profile against EGFR and IDO1, with compound 5d exhibiting sub-micromolar activity against both target enzymes, providing a plausible biochemical rationale for its potent cell killing. Furthermore, compound 5d induced cell cycle arrest at the G2/M phase and triggered apoptosis in HS 578 T cells, as supported by the up-regulation of Caspase-3 and Bax accompanied by the down-regulation of Bcl-2. In-silico ADMET profiling and molecular docking simulations further supported the favorable drug-like properties and binding modes of the key compounds within the target active sites. Overall, these findings highlight compound 5d as a promising lead candidate for further optimization and cellular mechanistic validation in anti-cancer drug discovery.