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

Abstract

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-9H-carbazol-3-yl)methylene)-N-(pyridin-2-yl)hydrazinecarbothioamide (62) and (E)-2-((9-ethyl-9H-carbazol-3-yl)methylene)-N-(5-chloropyridin-2-yl)hydrazinecarbothioamide (63) emerged as the premier candidates with good ChE inhibitory activities (IC₅₀ values of 1.37 µM and 1.18 µM for hAChE, IC₅₀ values of 2.69 µM and 3.31 µM for EqBuChE, 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

Keywords:

• Acetylcholinesterase
• butyrylcholinesterase
• metal chelation
• MTDL
• carbazole
• Alzheimer’s disease

Additional information

Funding

Kishan B. Patel is thankful to the AICTE, New Delhi for awarding PG Scholarship (GPAT) [ID-1-3526872437]. Dushyant V. Patel greatly acknowledges the DST-INSPIRE, New Delhi for awarding Research Fellowship (IF-150660).