Novel 4‐chlorophenyl and 3/4‐chlorophenoxy Based Triazole/Thiazole Derivatives: Synthesis and Investigation of Their Effects on Neurodegenerative Disorders‐Related Enzymes via In Vitro and In Silico

In this study, nine new synthesized compounds were investigated for their enzyme inhibition activity and evaluated for their ADME parameters and DFT-based properties. The compounds were classified into two main structures: derivatives of 2-(3/4-chlorophenoxy)-N-(3-(4-chlorophenyl)-4-(4-substituted phenyl)thiazol-2(3H)-ylidene)propanehydrazide (4a-4f) and N-(6-substituted benzothiazol-2-yl)-2-((5-(1-(3-chlorophenoxy)ethyl)-4-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl)thio)acetamide (6a-6c). The inhibitory effects of these compounds on cholinesterase and MAO enzymes were studied, and their percentages of inhibition were determined. It was found that the compounds exhibited higher inhibition of AChE than BChE, with compounds 4e, 6a, and 6b showing the highest percentage inhibition against AChE. In terms of MAO inhibition, compounds 6a and 6b demonstrated significant potency against MAO-A, while compounds 4a, 4 d, 4 f, and 6c exhibited inhibition against MAO-A above 55.372%. The compounds also showed notable inhibition against MAO-B, with compounds 4a, 4 f, 6a, and 6b displaying the highest inhibitory activity. DFT studies revealed the optimized molecular structures and the energy difference between the HOMO and LUMO orbitals. Compound 4a exhibited greater activity and compound 4 f showed nucleophilic character, while compound 6a displayed higher electronegativity and nucleophilic character. In silico analyses indicated that the benzothiazole moiety was localized at the outer region of the MAOs, whereas the phenoxy and 4-chlorophenyl moieties were positioned near the FAD cofactor within the inner pocket. It was also suggested that the acyl moiety is pivotal in forming H-bonds with the key residues. These findings contribute to the understanding of the enzyme inhibition activity and molecular properties of the azole-based ether derivatives in modulation of neuroprotective enzymes.