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Molecular hybridization based design and synthesis of new benzo[5,6]chromeno[2,3-b]-quinolin-13(14H)-one analogs as cholinesterase inhibitors

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Abstract

A Series of new tacrine analogs were designed, synthesized, characterized by respective spectral data and evaluated for cholinesterase inhibitory activity to be useful in Alzheimer’s disease. Most of the synthesized compounds showed good in vitro inhibitory activities toward acetyl cholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Among the compounds, 6i, 6o and 6r with increased saturated carboxylic ring size attached to the pyridine moiety and having 3,4-dihydroxy, 3,4,5-trimethoxy substituents on the aromatic ring attached at the stereogenic center have shown equal potency to that of tacrine with IC50values 0.65 ± 0.06, 1.32 ± 0.02 and 0.85 ± 0.05, 1.65 ± 0.12 and 0.92 ± 0.03, 1.91 ± 0.12 μM against AChE and BuChE, respectively. Standard drug tacrine exhibited IC50 values of 0.47 ± 0.02 and 0.65 ± 0.08, while Donepezil showed IC50 0.71 ± 0.06 and 0.31 ± 0.04 μM against AChE and BuChE, respectively. Docking studies of all the molecules disclosed close hydrogen bond interactions with the binding site.

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Acknowledgements

One of the authors BM expresses thank to the University Grants Commission, New Delhi for financial support of this study. Authors thank the Principal, University College of Pharmaceutical Sciences, Kakatiya University, Warangal for providing necessary facilities. Authors RK and CB express gratitude Mr. Raghu Rangaswami and Dr. Prajwal Nandekar, Schrodinger, Bangalore for granting free one-monthlicense of Schrodinger Suite 2019 for docking studies. Both RK and CB appreciate the Principal and Management of Bharati Vidyapeeth’s Poona College of Pharmacy, Pune for providing all computational facilities.

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Authors and Affiliations

  1. Medicinal Chemistry Division, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, Telangana, 506009, India

    Baswaraju Macha, Raghuramrao Akkinepally & Achaiah Garlapati

  2. Bharati Vidyapeeth’s Poona College of Pharmacy, Paud Road, Erandawane, Pune, 411038, India

    Ravindra Kulkarni & Chandrakant Bagul

  3. Jayamukhi Institute of Pharmaceutical Sciences, Narsampet, Warangal, 506332, India

    Anil Kumar Garige

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  1. Baswaraju Macha
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Macha, B., Kulkarni, R., Bagul, C. et al. Molecular hybridization based design and synthesis of new benzo[5,6]chromeno[2,3-b]-quinolin-13(14H)-one analogs as cholinesterase inhibitors. Med Chem Res 30, 685–701 (2021). https://doi.org/10.1007/s00044-020-02670-w

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