Pharmacokinetics, MDS, and ADME of Spirooxindole-Pyrrolidines Embedded with Pyrazole Heterocycleas α-Amylase Inhibitor and Potential Cytotoxic Compounds

Abstract

Background: Cancer is the second leading cause of death world-wide, surpassed only by heart diseases. Diabetes Mellitus is the most globally recorded disease, and a significant number of patients receive diagnoses for both cancer and diabetes. Diabetic patients are prone to developing liver and pancreatic cancer. The objective of this study to identify spirooxindoles scaffold with a broad spectrum of biological targets, particularly those associated with cancer and diabetes. Methods: New spirooxindole-pyrrolidines analogs were designed, synthesized and isolated through a [3 + 2] cycloaddition reaction (32CA) protocol. Following separation and purification via column chromatography, the target spirooxindole-pyrrolidines analogs underwent screening for anticancer activity against breast cancer cells (MDA-MB-231) and liver carcinoma (HepG2) cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Additionally, molecular docking and investigation of Absorption, Distribution, Metabolism, and Excretion (ADME) pharmacokinetics were conducted for the studied compounds. Results: The compound 8e demonstrated the highest activity against triple-negative breast cancer and liver cancer, with Half maximal inhibitory concentration (IC₅₀) values of 4.1 and 8 μM, respectively. The inhibition potential of α-Amylase ranged from 25.25% to 62.96%. Notably, within this series, compound 8c exhibited the highest activity, showing an inhibition rate of 62.96%. To gain insights into the binding mode of these compounds within the enzymes active site, a molecular docking study was conducted. The results of the docking study identified compound 8c as the most potent within the series, with docking scores of –8.91. Furthermore, a molecular dynamic simulation (MDS) was carried out for the most active compound. The analysis revealed that compound 8c remained highly stable throughout the 50 ns simulation. Conclusions: A new class of spirooxindole analogs has been identified as small molecule inhibitors with potential applications in diabetes and cancer. These compounds exhibit promising characteristics, warranting further in-depth investigations.