Synthesis, biological evaluation, molecular modeling, and DFT calculations of novel quinoline-conjugated sulfonyl...

Despite early diagnosis and advanced treatment options, cancer remains a serious public health threat, especially breast cancer, which presents a high risk of death and significant challenges for women. In this study, we report the design and synthesis of new quinoline-containing sulfonyl hydrazones (QSH1-QSH15) as potential cytotoxic agents. The compounds were obtained through the reaction of various benzaldehydes with quinoline-8-sulfonohydrazide, which was in-house prepared from quinoline-8-sulfonyl chloride and an excess amount of hydrazine hydrate. Following structural analysis, QSH1-QSH15 were examined for their potential to inhibit the growth of human breast cancer cell lines MCF-7 and MDA-MB-231. The results from the MTT assay revealed that lipophilic chlorine and fluorine atoms positioned particularly at the ortho or meta-position of the terminal phenyl ring were favored substituents on the quinoline-sulfonyl hydrazone scaffold for cytotoxic activity. Three compounds with the lowest IC₅₀ values against MDA-MB-231 cell line (QSH6, QSH8, and QSH14) were examined for their impact on the apoptotic pathway. Additionally, evaluating significant parameters for drug-likeness and pharmacokinetic profile demonstrated the suitability of selected compounds for drug development against breast cancer. Molecular docking and molecular dynamics simulations indicated that this class of molecules may function by inhibiting cyclin-dependent kinase 2 (CDK2) as their potential mechanism of action. Finally, DFT studies for these three compounds (QSH6, QSH8, and QSH14) were carried out by density functional theory using B3LYP level with the 6-31+G(d,p) basis set.