Exploration of a library of triazolothiadiazole and triazolothiadiazine compounds as a highly potent and selective family of cholinesterase and monoamine oxidase inhibitors: design, synthesis, X-ray diffraction analysis and molecular docking studies

There is a high demand for the collection of small organic molecules (especially N-heterocycles) with diversity and complexity in the process of drug discovery. This need for privileged scaffolds in medicinal research gives an impetus for the development of nitrogen-containing compounds which are widely encountered in natural products, drugs and pharmaceutically active compounds. In this context, a diverse library of new triazolothiadiazole (4a-l) and triazolothiadiazine (5a-p) compounds was designed, synthesized and evaluated as potent and selective inhibitors of electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE) by Ellman's method using neostigmine and donepezil as standard inhibitors. Among the screened triazolothiadiazoles, 4j emerged as a lead candidate showing the highest inhibition with an outstanding IC50 value of 0.117 +/- 0.007 mu M against AChE, which is similar to 139-fold greater inhibitory efficacy as compared to neostigmine, whereas 4k displayed similar to 506-fold strong inhibition with IC50 of 0.056 +/- 0.001 mu M against BChE. In the triazolothiadiazine series, 5j and 5e depicted a clear selectivity towards EeAChE with IC50 values of 0.065 +/- 0.005 and 0.075 +/- 0.001 mu M, respectively, which are similar to 250- and similar to 218-fold stronger inhibition as compared to neostigmine (IC50 = 16.3 +/- 1.12 mu M). In addition, the synthesized compounds were also tested for their monoamine oxidase (MAO-A and MAO-B) inhibition, where 4a from the triazolothiadiazole series delivered the highest potency against MAO-A with an IC50 value of 0.11 +/- 0.005 mu M which is similar to 33-fold higher inhibition as compared to the standard inhibitor, clorgyline (IC50 = 3.64 +/- 0.012 mu M), whereas compound 5c from the triazolothiadiazine series turned out to be a lead inhibitor with an IC50 value of 0.011 +/- 0.001 mu M which is similar to 330-fold stronger inhibition. Moreover, compounds 4b (triazolothiadiazole series) and 5o (triazolothiadiazine series) were identified as lead inhibitors against MAO-B. Molecular modelling studies were performed against human AChE and BChE to observe the binding site interactions of these compounds.