One-Pot Multicomponent Synthesis of Novel Pyrazole-Linked Thiazolyl-Pyrazolines: Molecular Docking and Cytotoxicity Assessment on Breast and Lung Cancer Cell-lines

Abstract

Cancer remains a foremost cause of mortality globally, with approximately 20 million new cases and nearly 10 million deaths reported in 2022. Lung and breast cancers are particularly prevalent and deadly, underscoring the critical need for novel therapeutic strategies. This study utilized a one-pot, multicomponent reaction (MCR) approach to synthesize a novel series of pyrazole-linked thiazolyl-pyrazolines. The optimal reaction conditions were determined by systematically varying bases, temperatures, reaction times, and solvents. The best yield was achieved using NaOH as the base at 50°C with 2 hours of stirring in ethanol. The synthesized compounds underwent thorough characterization through IR, mass spectrometry, and NMR spectroscopy. Molecular docking studies indicated strong binding affinities to the ErbB4 kinase, suggesting potential utility as kinase inhibitors. Compounds 5E, 5F, and 5G exhibited significant cytotoxicity against breast cancer cell lines, with IC50 values ranging from 15.79±1.272 to 28.38±1.520 µM. Meanwhile, compounds 5A, 5B, 5D, and 5G demonstrated potent effects against lung cancer cell lines, with IC50 values between 7.945±0.99 and 9.295±1.074 µM. Remarkably, compound 5G showed potent efficacy against both breast and lung cancers, with IC50 values of 28.38±1.520 µM and 9.02±1.07 µM, respectively. This study illuminates the critical role of pyrazole-linked thiazolyl-pyrazoline scaffolds in crafting powerful cancer therapeutics targeting ErbB4 (HER4) kinase. Unique in its dual functionality, ErbB4 can act as either an oncogene or a tumor suppressor in lung and breast cancers, contingent on specific cellular contexts and isoform variations. The dynamic expression of ErbB4 intricately modulates tumor growth and patient outcomes, marking it as a compelling therapeutic target for innovative treatments in both breast and lung cancer.