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

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Abstract

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 IC50: 5.76 µM, BuChE IC50: 48.98 µM; 4d, AChE IC50: 3.58 µM, BuChE IC50: 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.

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Acknowledgements

VGU acknowledges the financial support from Department of Science and Technology (DST)-Science and Engineering Research Board (SERB), New Delhi, India (Ref. no. TAR/2021/000140). VGU is thankful to the Principal, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra (India) for providing necessary facilities.PNR acknowledges GITAM (Deemed to be University) for research facilities. PP acknowledges the financial support of the Department of Science and Technology (DST) through the grant WOS-A (No.SR/WOS-A/CS-2/2019). PPK acknowledges the support from DST, India [Ref. no. CRG/2022/004365] and Agharkar Research Institute, Pune for providing research facilities. PS acknowledges the financial support from University Grants Commission, New Delhi, India through senior research fellowship. Authors thank the Director, Agharkar Research Institute, Pune for the support.

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Authors and Affiliations

  1. Department of Chemistry, School of Science, GITAM (Deemed to Be University), Hyderabad, India

    Nissi Sharon & Pedavenkatagari Narayana Reddy

  2. Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India

    Vinod G. Ugale & Chandradeep Salunkhe

  3. Bioprospecting Group, Agharkar Research Institute, Savitribai Phule Pune University, G. G. Agharkar Road, Pune, Maharashtra, India

    Vinod G. Ugale, Padmaja Shete & Prasad P. Kulkarni

  4. Centre for Semio Chemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad, India

    Pannala Padmaja

  5. Department of Pharmaceutical Chemistry, Rajarshi Shahu College of Pharmacy, Buldana, Maharashtra, India

    Deepak Lokwani

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  1. Nissi Sharon
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Contributions

NS: Methodology, Investigation; VGU: Conceptualization, Methodology, Investigation, Writing- Original draft preparation, Writing - Review & Editing; PP: Visualization, Data Curation; PNR: Methodology, Conceptualization, Interpretation, Resources, Review & Editing; PS: Investigation, Formal analysis; CS: Methodology, Investigation; DL: Methodology, Investigation; PPK: Supervision, Conceptualization, Methodology, Visualization, Writing - Review & Editing. All authors reviewed the manuscript.

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Correspondence to Vinod G. Ugale, Pedavenkatagari Narayana Reddy or Prasad P. Kulkarni.

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Sharon, N., Ugale, V.G., Padmaja, P. et al. Development of novel 9H-carbazole-4H-chromene hybrids as dual cholinesterase inhibitors for the treatment of Alzheimer’s disease. Mol Divers (2024). https://doi.org/10.1007/s11030-024-10859-z

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