Neuroprotective thiazole sulfonamides against 6-OHDA-induced Parkinsonian model: in vitro biological and in silico pharmacokinetic assessments

Abstract

The limitations of currently existing medications in delaying or halting the development of Parkinson's disease (PD) remain dramatically problematic, making it the second most prevalent neurodegenerative disorder. Moreover, it is expected that the number of PD cases will double within the next 30 years. Herein, to discover a novel neuroprotective therapeutic strategy, a series of multifunctional thiazole sulfonamides underwent preliminary assessment owing to their neuroprotective capabilities against 6-hydroxydopamine (6-OHDA)-induced damage in human neuronal SH-SY5Y cells. Pretreatment with novel synthetic hybrids, including 1, 2, and 8, significantly improved cell viability, reduced lactate dehydrogenase (LDH) leakage, prevented mitochondrial dysfunction, and mitigated intracellular oxidative stress. Insight molecular mechanisms and potential targets of these compounds were elucidated through their activation and binding interaction with sirtuin 1 (SIRT1), suggesting their influencing roles on relevant downstream cascades of PD. Furthermore, in silico pharmacokinetic analysis revealed the drug-likeness of these three hybrids, which are capable of being distributed into the central nervous system (CNS) with slight toxicity. Therefore, these novel neuroprotective thiazole sulfonamides are promising candidates for further development (i.e., in vivo and clinical trials) of effective PD therapy.