Remarkable utilization of quinazoline-based homosulfonamide for in vitro cytotoxic effects with triple kinase inhibition activities: cell cycle analysis and molecular docking profile

• Published in: RSC advances 2025-01, Vol.15 (1), p.541-558
• Main Authors: El-Azab, Adel S., Abdel-Aziz, Alaa A.-M., Bakheit, Ahmed H., Alkahtani, Hamad M., Obaidullah, Ahmad J., Hefnawy, Mohamed M., Al-Suwaidan, Ibrahim A.
• Format: Article
• Language: English
• Subjects: Chemistry
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/D4RA07174C

We tested newly synthesized compounds 1–13 on 59 cancer cell lines and found that acylhydrazones 5, 6, 7, 9, and 12 showed the best in vitro cytotoxic activity. They stopped the mean growth percentage (MG%) by an average of 23.5, 55.2, 89.4, 88.5, and 88.4%, respectively. Compound 5 was subjected to NCI tests at five-dose dilutions on 59 tumor cells. It is more effective in killing tumor cells than gefitinib (mean GI 50 : 7.7 μM) and erlotinib (mean GI 50 : 2.1 μM). Its mean GI 50 value was 1.0 μM, and its LC 50 value was over 100 μM, whereas gefitinib's was 95.6 μM and erlotinib's was 14.3 μM. Its TGI was 89.2 μM, while those drugs were 66.3 and 14.3 μM, respectively. We evaluated acylhydrazones 5, 6, 7, 9, and 12 for dose-dependent enzymatic inhibition of EGFR, HER2, and CDK9 kinases to study the mechanism of the in vitro cytotoxicity. With IC 50 values of 84.4 and 51.5 nM, compounds 5 and 6 are the most potent EGFR inhibitor analogs, similar to Gefitinib (IC 50 of 53.1 nM). Compounds 5, 6, and 12 blocked HER2 like Gefitinib did (IC 50 = 38.8 nM); their IC 50 values were 53.9, 44.1, and 110.6, respectively. Compounds 5, 6, and 7 had IC 50 values of 146.9, 96.1, and 155.4 nM, which means they blocked CDK9 activity almost as well as Dinaciclib (IC 50 53.1 nM). Flow cytometers count the amount of DNA in T-47D and MOLT4 cells treated with compounds 5 and 6. The IC 50 value of compound 5 increases from 6.6% for the DMSO/T-47D control to 26.3% in the G2-M phase, while compound 6 goes from 61.4 for the DMSO/MOLT4 control to 89.0% in the G1 phase. The tested compounds cause early death, ranging from 0.4% and 0.6% (a DMSO control sample) to 9.3% and 19.2%, respectively. Derivatives 5 and 6 also increased late death from 0.1 to 14.8% and 12.6 to 0.3%, respectively, favoring the apoptotic route over the necrotic one for cell death to 50.5 μM. When tested for cell death against the standard WI-38 fibroblast cell line, imines 5 and 6 were less toxic than doxorubicin.