Efficient Access to New Thienobenzo-1,2,3-Triazolium Salts as Preferred Dual Cholinesterase Inhibitors.

Abstract

In previous research, 1,2,3-triazolium salts showed significant biological activity as potential inhibitors of cholinesterase enzymes (ChEs), which are crucial for neurotransmission. In this research, pairs of uncharged thienobenzo-triazoles and their charged salts were prepared in order to further examine the role of the positive charge on the nitrogen of the triazole ring in interactions within the active site of the enzymes, and to compare the selectivity of 1,2,3-triazolium salts in relation to their uncharged analogs obtained by photochemical cyclization. Neutral thienobenzo-triazoles showed very good selective activity toward butyrylcholinesterase (BChE), while their salts showed excellent non-selective inhibition toward both BChE (the most active 23: IC₅₀ 0.47 μM) and acetylcholinesterase (AChE) enzymes (the most active 23: IC₅₀ 4.4 μM). These new structures with incorporated 1,2,3-triazolium salts present the new scaffold for drug development as it is known that the current therapy in Alzheimer's disease (AD) comprises selective AChE inhibitors, while in Parkinson's and all stages of AD, non-selective inhibitors of ChEs are preferred. Molecular docking of the selected compounds and their corresponding salts into the active sites of ChEs was conducted to identify the interactions responsible for the stability of the non-covalent cholinesterase-ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the synthesized compounds have shown that compound 18 is the most promising candidate for genotoxic safety.