Synthesis, characterization, in-silico, and pharmacological evaluation of new 2-amino-6‑trifluoromethoxy benzothiazole derivatives

Abstract

Alzheimer's disease (AD), a relentless neurodegenerative disorder, is still waiting for safer profile drugs, risk factors affecting AD's pathogenesis include aβ accumulation, tau protein hyperphosphorylation, and neuroinflammation. This research aimed to synthesize 2-amino-6‑trifluoromethoxy benzothiazole schiff bases. Synthesis was straightforward, combining the riluzole skeleton with compounds containing the azomethine group. Schiff bases synthesized were characterized spectroscopically using proton NMR (¹H NMR), and FTIR. In-vivo biological evaluation against scopolamine-induced neuronal damage revealed that these newly synthesized schiff bases were effective in protecting neurons against neuroinflammatory mediators. In-vitro results revealed that these compounds had remarkable potential in improving the anti-oxidant levels. It downregulated glutathione (GSH), glutathione S-transferase (GST), catalase levels, and upregulated lipid peroxidation (LPO) levels. Immunohistochemical studies revealed that groups treated with the newly synthesized schiff bases had reduced expression of inflammatory mediators such as cyclooxygenase 2 (COX-2), JNK, tumor necrosis factor (TNF-α), nuclear factor kappa B (NF-kB) in contrast to the disease group. Moreover, molecular docking studies on these compounds also showed that they possessed a better binding affinity for above mentioned inflammatory mediators. The results of these studies showed that 2-amino-6-trifluoromethoxy benzothiazole schiff bases are remarkably effective against oxidative stress-mediated neuroinflammation.

Keywords: Alzheimer’s disease (AD); Anti- neuroinflammation; Benzothiazole derivatives; Oxidative stress; Riluzole; Schiff bases.