Aug 2026· Bioorganic chemistry (Print)· Vol 181, pp.
110394
· 0 citations· 72 references
Medicine
TL;DR
G glycine conjugation of a coumarin-quinazoline hybrid has not been reported previously, and the results identify it as a substituent- and cell-line-dependent strategy for improving anticancer potency and selectivity.
Abstract
A novel series of twelve coumarin-quinazoline hybrids, comprising six glycine-conjugated (9a-f) and six directly linked analogues (8a-f), was synthesized and characterized by FT-IR, 1H/13C NMR, elemental analysis and LC-MS. Cytotoxicity was assessed against PC-3 prostate, PANC-1 pancreatic, A549 lung and MCF-7 breast cancer cell lines by the MTT assay, with HEK-293 cells used to estimate selectivity and with doxorubicin, cisplatin and gemcitabine as reference drugs. Most hybrids were active in the low micromolar range (3.56-6.96 μM) and gave selectivity indices of up to 3.17, compared with 1.14-1.65 for doxorubicin. Compound 9d was the most active against A549 (IC50 = 3.57 ± 0.05 μM), whereas 9c and 9f were the most active against PANC-1 (IC50 = 3.56 ± 0.05 μM), several derivatives exceeding the reference drugs in individual cell lines. Cell-cycle, Annexin V/PI and LDH-release experiments showed a uniform G0/G1 accumulation with depletion of the S-phase population, indicating apoptotic cell death rather than non-specific membrane damage. Molecular docking against PI3Kα, PI3Kγ and ribonucleotide reductase indicated that the glycine linker provides the conformational flexibility required to reproduce key interactions of the co-crystallized ligands, and the G0/G1 arrest was consistent with PI3K rather than RNR inhibition. To the best of our knowledge, glycine conjugation of a coumarin-quinazoline hybrid has not been reported previously, and the results identify it as a substituent- and cell-line-dependent strategy for improving anticancer potency and selectivity.
Findings identify compound 9 as a promising multi-target quinoxaline-based agent with dual antiproliferative and anti-inflammatory activities, mediated through induction of mitochondrial apoptosis and modulation of oxidative stress and cytokine signaling pathways.
S. Alshawwa, Ghazi A. Bamagous, Hatem A. Sembawa et al.· RSC Advances· 0 citations
A novel series of pyrazole-pyridine-1,3,4-oxadiazole hybrid derivatives (10a-m) was designed, synthesized, and characterized by IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The multi-step route proceeded via nucleophilic aromatic substitution, cyclocondensation, oxidative aromatization, and S-alkylation, affording target compounds in good to excellent yields (88-93%). Derivatives were screened for anticancer activity against A549 (lung) and MCF-7 (breast) cell lines using Foretinib as reference. Compound 10d (2,4-di-OCH3) was most potent, with IC50 values of 0.29 ± 0.15 μM (A549) and 3.1 ± 0.5 μM (MCF-7), comparable to, or numerically better than, Foretinib (IC50 = 0.49 ± 0.026 μM, A549); no formal statistical comparison was performed. SAR analysis showed electron-donating substituents, especially methoxy groups, enhanced potency. Compounds 10c, 10d, and 10h were markedly less cytotoxic toward non-cancerous NIH/3T3 fibroblasts (IC50 = 138.41, 66.36, and 95.03 μM) than toward the cancer lines, indicating a favorable selectivity margin. Docking against c-Met (PDB: 3LQ8) showed 10d had the highest binding affinity (-5.54 kcal mol-1), forming hydrogen-bond and π-cation interactions with ASP 1222 and ARG 1203, consistent with c-Met as a plausible target, though direct biochemical confirmation is needed. DFT calculations (B3LYP/6-311++G(d,p)) for 10c, 10d, and 10h confirmed that 10d has the smallest HOMO-LUMO gap (3.74 eV) and highest chemical softness, consistent with its superior activity. Collectively, these findings identify 10d as a promising scaffold for further optimization and biological evaluation.
Prince A. Dave, Jay B. Maheta, Darshna K. Lakhnotra et al.· Organic and biomolecular che...· 0 citations
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
The present work reports the synthesis of novel pyrrolo[2,3-d]pyrimidine and 1,3,4–oxadiazole hybrids bearing 1,2,3–triazole substituents, efficiently obtained via CuAAC click reactions. The results indicated that 1,2,3–triazole hybrids 5b and 5g demonstrated the highest cytotoxicity against A-549 and HCT-116 cells with IC50 values of 6.12±1.15 µM and 8.01±1.72 µM and 5.20±0.99 µM and 6.60±1.90 µM, respectively, compared with the reference drug doxorubicin (5.40±1.75 µM for A-549 and 6.60±1.23 µM for HCT-116). Molecular docking revealed the structural basis for this activity, showing compounds 5b, 5e and 5g strong binding to key target like EGFR mutant in lung cancer pocket of (PDB code: 8d76) via binding affinities ranging from −7.49 to −7.79 kcal/mol. The in-silico ADME/Tox analysis confirmed the drug-likeness of all the prepared compounds, indicating their potential for oral bioavailability and overall therapeutic efficacy. Collectively, these properties distinguish 5b, 5e and 5g, positioning it as the most potent and selective anticancer lead.
Structural–activity relationship analysis revealed the importance of the TZD core, electron-rich aromatic moieties, and balanced lipophilicity for enhanced anticancer activity, identifying TZD hybrids as promising EGFR-targeted anticancer leads.
Rajyalaxmi Injamuri, D. Makula· International journal of res...· 0 citations
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.
Karan Kamle, Shreyansh R. Mevada, Reena Hirani et al.· Bioorganic chemistry (Print)· 0 citations
