Development of novel 9H-carbazole-4H-chromene hybrids as dual cholinesterase inhibitors for the treatment of Alzheimer's disease.

Autor: Sharon N; Department of Chemistry, School of Science, GITAM (Deemed to Be University), Hyderabad, India., Ugale VG; Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India. vinod.ugale@rediffmail.com.; Bioprospecting Group, Agharkar Research Institute, Savitribai Phule Pune University, G. G. Agharkar Road, Pune, Maharashtra, India. vinod.ugale@rediffmail.com., Padmaja P; Centre for Semio Chemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad, India., Lokwani D; Department of Pharmaceutical Chemistry, Rajarshi Shahu College of Pharmacy, Buldana, Maharashtra, India., Salunkhe C; Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India., Shete P; Bioprospecting Group, Agharkar Research Institute, Savitribai Phule Pune University, G. G. Agharkar Road, Pune, Maharashtra, India., Reddy PN; Department of Chemistry, School of Science, GITAM (Deemed to Be University), Hyderabad, India. npedaven@gitam.edu., Kulkarni PP; Bioprospecting Group, Agharkar Research Institute, Savitribai Phule Pune University, G. G. Agharkar Road, Pune, Maharashtra, India. ppkulkarni@aripune.org.
Jazyk: angličtina
Zdroj: Molecular diversity [Mol Divers] 2024 Apr 29. Date of Electronic Publication: 2024 Apr 29.
DOI: 10.1007/s11030-024-10859-z
Abstrakt: Alzheimer's disease (AD) is a neurodegenerative disease affecting mental ability and neurocognitive functions. Cholinesterase enzymes affect concentration of acetylcholine in the brain, leading to dementia. Thus, there is an urgent need to develop novel dual cholinesterase inhibitors as possible anti-AD drugs. Herein, we have designed and synthesized a novel series of 9H-carbazole-4H-chromenes 4(a-l) through a one-pot three-component reaction of salicylaldehydes (1), hydroxycarbazole (2) and N-methyl-1-(methylthio)-2-nitroethenamine (3) using triethylamine as a catalyst in ethanol. Synthetic transformation involves the formation of two C-C bonds and one C-O bond in a single step to obtain desired analogs. The rapid one-pot reaction does not require chromatographic purification, proceeds under mild conditions, and exhibits good tolerance toward various functional groups with high synthetic yields. Synthesized compounds were screened for cytotoxicity using MTT assay in BV-2 microglial cells. These compounds were then in-vitro screened against acetylcholinesterase (AChE) and butyrylcholinestrase (BuChE) enzymes. Most of these ligands have shown dual cholinesterase inhibitory activity compared to the standard drug. In-vitro results showed that the compounds 4a and 4d have promising anticholinesterase response against both cholinesterase enzymes (4a, AChE IC 50 : 5.76 µM, BuChE IC 50 : 48.98 µM; 4d, AChE IC 50 : 3.58 µM, BuChE IC 50 : 42.73 µM). In-vitro results were validated by molecular docking and dynamic simulation at 100 ns. Molecular docking and molecular dynamics simulation study strongly supported structural features present in these analogs. Together, these analogs could be exploited to develop dual anti-cholinesterase candidates to treat AD in combination with other drugs.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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