Design, synthesis and evaluation of benzothiazole-derived phenyl thioacetamides as dual inhibitors of monoamine oxidases and cholinesterases.

A series of rationally designed benzothiazole-derived thioacetamides was synthesized and investigated for monoamine oxidases (MAO-A and MAO-B) and cholinesterases (AChE and BChE) inhibition properties. The tested compounds 18-31 inhibited MAO-A and MAO-B in the micromolar to nanomolar range and AChE in the submicromolar range. Compound 28 was identified as the most potent MAO-A inhibitor with an IC₅₀ = 0.030 ± 0.008 µM, whereas compound 30 showed the highest potency towards MAO-B and AChE with IC₅₀ values of 0.015 ± 0.007 µM and 0.114 ± 0.003 µM, respectively. Further, compound 30 inhibited BChE at an IC₅₀ value of 4.125 ± 0.143 µM. Among all screened molecules, compound 30 emerged as the lead dual MAO-B and AChE inhibitor that blocked these enzymes in a competitive-reversible and mixed-reversible mode, respectively. Selected compounds have displayed iron-chelation and antioxidant properties. Further, computational assessment of ligand binding affinity and pharmacokinetic parameters of all new compounds and molecular dynamic simulation of compound 30 with MAO-B and AChE were carried out to understand ligand efficiency, pharmacokinetic, and virtual molecular interaction profile, respectively. The in silico ADMET prediction studies revealed a few undesired pharmacokinetic attributes of our compounds. The attempted virtual lead-based library synthesis and subsequent biological investigation produced a new benzothiazole-bearing dual MAO-B and AChE inhibitor as a prospective MTDL candidate for treating neurological disorders.