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.
Aug 2026· Bioorganic chemistry (Print)· Vol 181, pp.
110422
· 0 citations· 43 references
Medicine
TL;DR
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.
Abstract
A series of novel pyrimidine-based benzothiazole/phenyl hybrids was rationally designed and synthesized via molecular hybridization to develop promising anticancer agents. The compounds were evaluated against human lung carcinoma (A549) and breast adenocarcinoma (MCF-7) cell lines, while HEK-293 cells were used to assess selectivity toward normal cells. Among the derivatives, K12, K5, and K4 showed potent activity against A549 cells, with IC50 values of 6.18, 7.01, and 7.54 μM, respectively. K5 and K12 also showed significant activity against MCF-7 cells, with IC50 values of 8.33 and 9.30 μM, respectively. All compounds displayed minimal cytotoxicity toward HEK-293 cells, indicating favorable selectivity for cancer cells. UV-Vis DNA-binding studies suggested a probable intercalative binding mode, while DNA nicking assays demonstrated protection against oxidative DNA damage. K12 showed the strongest DNA-binding affinity and DNA-protective activity. Molecular docking against the VEGFR-2 kinase domain (PDB ID: 4ASD), followed by 501 ns MD simulations, revealed stable protein-ligand complexes, supported by RMSD, RMSF, DCCM, PCA, and free energy landscape analyses. MM/GBSA calculations indicated favorable binding free energies, dominated by van der Waals interactions. 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.
Novel 1,3,4-oxadiazole-2-thiol derivatives (8a-j) were synthesized via multistep reactions and characterized using IR, 1H NMR, and 13C NMR spectroscopy. The compounds were evaluated for dual anticancer and antibacterial activities through computational and experimental approaches. Molecular docking against EGFR (1M17) and DNA gyrase B (2XCT) revealed compound 8h as the most potent EGFR inhibitor (-7.528 kcal/mol), surpassing methotrexate (-7.448 kcal/mol), while compound 8c demonstrated superior DNA gyrase B binding (-7.263 kcal/mol), exceeding ciprofloxacin (-6.11 kcal/mol) by 19%. In vitro cytotoxicity against A549 human lung carcinoma cells identified compound 8c as the most active anticancer agent (IC50 = 14.59 ± 0.19 µg/mL), comparable to methotrexate (IC50 = 11.82 ± 1.22 µg/mL). Antibacterial screening against S. aureus, E. coli, and K. pneumoniae revealed compound 8d as the most effective broad-spectrum agent (MIC = 25 µg/mL across all strains), demonstrating 2-fold superior activity against S. aureus versus ciprofloxacin. Comprehensive DFT calculations on compound 8c elucidated frontier orbital energies (HOMO-LUMO gap: 4.7528 eV), global reactivity descriptors, optimized geometry, Mulliken charge distribution, and topological properties (MEP, RDG, ELF, LOL). ADMET profiling revealed favorable drug-likeness with 0-1 Lipinski violations, optimal lipophilicity (cLogP: 2.7-3.97), and good predicted oral absorption (57-64%). These findings establish 1,3,4-oxadiazole-2-thiol derivatives as promising dual-action therapeutic scaffolds.
Ila M. Ram, Jay B. Maheta, Darshna K. Lakhnotra et al.· Future Medicinal Chemistry· 0 citations
It is suggested that 4c exerts anticancer activity through ROS-mediated mitochondrial apoptosis and cell-cycle disruption, highlighting its promise as an oncotherapeutic candidate for TNBC and Dalton lymphoma.
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.
M. Sarg, Fatma G. Abdulrahman, Yasmin S. Sheta et al.· Bioorganic & Medicinal Chemi...· 0 citations
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.
E. Hutanu, Bassam A. Najri, A. Abdelsalam et al.· RSC Advances· 0 citations
Among the synthesized compounds, PBc1 exhibited the greatest in vitro antiproliferative activity against both MDA-MB-231 and SK-OV-3 cell lines, suggesting that PBc1 is a promising compound for further biological and mechanistic investigation.
Prachita Gauns Dessai, Parixit J. Bhandurge, C. Nazareth et al.· Journal of the Iranian Chemi...· 0 citations
In this study, three novel triphenylphosphonium-containing 1,2,3-triazole derivatives (7–9) were synthesized and structurally characterized by FT-IR, 1H NMR, and elemental analysis. DNA binding properties were investigated by UV-Vis titration and fluorescence competitive displacement experiments. Spectral changes, including hypochromic and hyperchromic effects, showed a strong affinity towards FSds–DNA, with binding constants on the order of 105 M−1. Fluorescence quenching studies using ethidium bromide and Hoechst 33258 revealed effective probe displacement with higher Stern–Volmer constants for the Hoechst system, suggesting a preferential minor groove binding mode. Lipophilicity assessment (Log P = 1.60–2.05) showed that para-substitution significantly altered hydrophobicity while preserving drug-like properties. Biological evaluation demonstrated potent antiproliferative activity against lung (A549, Calu-1, H1650) and bone (Saos-2) cancer cell lines and exhibited lower GI50 values (∼1 µg mL−1) compared to 5-fluorouracil (5FU). Compounds containing electron-attracting substituents (7 and 9) exhibited enhanced cytotoxicity, moderate TGI and LC50 values, and improved tumor selectivity indices (TSI = 1.97 and 2.78, respectively) while maintaining low toxicity against normal cells. LDH assays confirmed limited membrane damage (<20%) at TGI concentrations, and fluorescence microscopy (DAPI, Rhodamine-123, Hoechst/PI) demonstrated mitochondrial membrane depolarization and apoptosis induction, particularly for compounds 7 and 9. Overall, the results highlight that modulation of para-substituents critically influences DNA interaction, lipophilicity, mitochondrial targeting, and anticancer activity. These triphenylphosphonium–triazole derivatives represent promising mitochondria-targeted anticancer candidates for further optimization. The binding affinity and interaction modes of compound 9, which showed the highest inhibitory activity in both DNA-binding and anticancer assays, were elucidated via molecular docking studies.
Özge Güngör, B. A. Mısır, Ali Aydın et al.· RSC Advances· 0 citations
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