Carbazole-based semicarbazones and hydrazones as multifunctional anti-Alzheimer agents.

With the aim to combat a multi-faceted neurodegenerative Alzheimer's disease (AD), a series of carbazole-based semicarbazide and hydrazide derivatives were designed, synthesized and assessed for their cholinesterase (ChE) inhibitory, antioxidant and biometal chelating activity. Among them, ( E )-2-((9-ethyl-9 H -carbazol-3-yl)methylene)- N -(pyridin-2-yl)hydrazinecarbothioamide ( 62 ) and ( E )-2-((9-ethyl-9 H -carbazol-3-yl)methylene)- N -(5-chloropyridin-2-yl)hydrazinecarbothioamide ( 63 ) emerged as the premier candidates with good ChE inhibitory activities (IC ₅₀ values of 1.37 µM and 1.18 µM for h AChE, IC ₅₀ values of 2.69 µM and 3.31 µM for Eq BuChE, respectively). All the test compounds displayed excellent antioxidant activity (reduction percentage of DPPH values for compounds ( 62 ) and ( 63 ) were 85.67% and 84.49%, respectively at 100 µM concentration). Compounds ( 62 ) and ( 63 ) conferred specific copper ion chelating property in metal chelation study. Molecular docking studies of compounds ( 62 ) and ( 63 ) indicate strong interactions within the active sites of both the ChE enzymes. Besides that, these compounds also exhibited significant in silico drug-like pharmacokinetic properties. Thus, taken together, they can serve as a starting point in the designing of multifunctional ligands in pursuit of potential anti-AD agents that might further prevent the progression of ADs.Communicated by Ramaswamy H. Sarma.