Synergistic fusion of carbazole, quinoline, and chalcone scaffolds: A computational and experimental exploration of hybrid compounds as selective anticancer agents
Küçük Resim Yok
Tarih
2025
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Elsevier
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
Novel carbazole-quinoline-chalcone hybrids (nQCC1-4) were synthesized via Claisen-Schmidt condensation and evaluated against AGS gastric adenocarcinoma cells. The most potent compound, 1QCC-1, exhibited significant antiproliferative activity (IC50 values of 19.11 mu g/mL and 7.91 mu g/mL at 24 h and 48 h). Compounds 1QCC-4, 1QCC-3, and 2QCC-2 demonstrated comparable cytotoxic efficacy against AGS cells. Density functional theory (DFT) calculations revealed substituent-dependent electronic properties, with chloro-quinoline derivatives displaying enhanced electrophilicity (omega = 13.745-14.157 eV) and reduced HOMO-LUMO gaps (Delta E = 3.304-3.347 eV), correlating with improved bioactivity profiles. Molecular docking studies identified robust binding interactions with oncogenic targets, MAPK1 p38 kinase, HER2, and RhoA, with 1QCC-4 exhibiting superior binding affinity for HER2 (Delta G = -12.05 kcal/mol, IC50 = 1.48 nM) through hydrogen bonding with Lys114 and it-alkyl interactions with Leu156. ADMET profiling highlighted favorable drug-likeness parameters despite solubility challenges (LogS = -7.846 to -6.291) and potential CYP450 inhibition. Non-covalent interaction (NCI-RDG) and molecular electrostatic potential (MEP) analyses elucidated key stabilizing interactions and nucleophilic/electrophilic hotspots. These hybrids represent a strategic integration of natural product pharmacophores, leveraging synergistic electronic and steric effects for selective kinase inhibition, positioning them as promising leads for targeted gastric cancer therapy.
Açıklama
Anahtar Kelimeler
Carbazole, Chalcone, Quinoline, AGS Cancer, In silico
Kaynak
Journal of Molecular Structure
WoS Q Değeri
Q2
Scopus Q Değeri
Q1
Cilt
1348
