35C-1 Alkynylated THIQ Compounds(University of Belgrade)

A series of 35C-1-alkynylated THIQ compounds (25 new and 10 known) was synthesized, and their inhibitory potential against monoamine oxidase-B (MAO-B) and cholinesterase enzymes was assessed by evaluating the effects of introducing substituents at R¹, R², and on the phenylacetylene motif. Drug-likeness, including stability, lipophilicity and membrane permeability, was assessed theoretically and using ultra-high-performance liquid chromatography and parallel artificial membrane assays. The cytotoxic effects were evaluated on three human cell lines. The inhibition mechanism was examined by analysing the reversibility of inhibition combined with kinetic and fluorescence measurements and docking studies. Structure-activity relationship studies revealed that introducing of an alkynyl group at the C-1 position of the N-aryl-THIQs significantly influenced their inhibitory potential towards MAO-B and cholinesterase enzymes, with the effects being primarily determined by the nature of the substituents on the phenylacetylene motif and at the R² position. Only fluoro substitution at R¹ led to a significant reduction in inhibition potency for cholinesterase enzyme while in the case of MAO-B any R¹ substituent was found to notably diminish the inhibitory potential. With low cytotoxic effects, satisfactory stability, and the ability to cross a blood-brain barrier, the synthesized compounds are promising candidates for further optimization in AD drug discovery.