New quinazolinone-thiazolidinedione hybrids as selective anti-lung cancer agents and promising EGFR inhibitors
Future Medicinal Chemistry, cilt.18, sa.4, ss.415-428, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 18 Sayı: 4
- Basım Tarihi: 2026
- Doi Numarası: 10.1080/17568919.2026.2620368
- Dergi Adı: Future Medicinal Chemistry
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, EMBASE, MEDLINE, Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Health Research Premium Collection (ProQuest)
- Sayfa Sayıları: ss.415-428
- Anahtar Kelimeler: Quinazolin-4(3H)-one, thiazolidine-2, 4-dione, lung cancer, EGFR, cytotoxicity
- Sağlık Bilimleri Üniversitesi Adresli: Evet
Özet
Aim: Lung cancer remains a leading cause of cancer-related deaths, largely due to therapy resistance and toxicity. This study develops novel quinazolinone-thiazolidinedione (TZD) hybrids by combining two anticancer pharmacophores to achieve more selective and potent EGFR inhibitors. Materials and methods: A total of 14 quinazolinone-TZD hybrids were synthesized and characterized. Their cytotoxicity was evaluated in A549 lung adenocarcinoma and BEAS-2B normal bronchial cells. EGFR binding was analyzed via molecular docking and MM-GBSA, with 500 ns molecular dynamics simulations supporting the stability of selected complexes. ADME predictions assessed drug-likeness and oral bioavailability. Results: Several compounds showed selective cytotoxicity against A549 cells, with compound 9 (thiophen-2-ylmethyl substituent) emerging as the most active (IC50 = 3.85 μM, SI = 36.0), outperforming gefitinib (IC50 = 9.59 μM, SI = 1.9) and exhibiting higher selectivity than sorafenib (IC50 = 3.24 μM, SI = 5.4). Computational analyses revealed key interactions with EGFR residues (Cys-797, Arg-841, Asn-842, and Phe-997), supported by stable molecular dynamics behavior and favorable ADME predictions. Conclusion: These findings indicate that the synthesized hybrids, particularly compound 9, represent promising leads for selective EGFR-targeted lung cancer therapy and support further optimization.