Cholinesterase inhibitory activity of highly functionalized fluorinated spiropyrrolidine heterocyclic hybrids

doi:10.1016/j.sjbs.2020.11.005

. 2021 Jan;28(1):754-761.

doi: 10.1016/j.sjbs.2020.11.005. Epub 2020 Nov 11.

Cholinesterase inhibitory activity of highly functionalized fluorinated spiropyrrolidine heterocyclic hybrids

Raju Suresh Kumar¹, Abdulrahman I Almansour¹, Natarajan Arumugam¹, D Kotresha², Thota Sai Manohar³, S Venketesh³

Affiliations

¹ Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
² Department of Studies in Botany, Davangere University, Shivagangothri, Davangere 577007, Karnataka, India.
³ Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, A.P 515 134, India.

PMID: 33424364
PMCID: PMC7783807
DOI: 10.1016/j.sjbs.2020.11.005

Cholinesterase inhibitory activity of highly functionalized fluorinated spiropyrrolidine heterocyclic hybrids

Raju Suresh Kumar et al. Saudi J Biol Sci. 2021 Jan.

. 2021 Jan;28(1):754-761.

doi: 10.1016/j.sjbs.2020.11.005. Epub 2020 Nov 11.

Authors

Raju Suresh Kumar¹, Abdulrahman I Almansour¹, Natarajan Arumugam¹, D Kotresha², Thota Sai Manohar³, S Venketesh³

Affiliations

¹ Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
² Department of Studies in Botany, Davangere University, Shivagangothri, Davangere 577007, Karnataka, India.
³ Department of Biosciences, Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, A.P 515 134, India.

PMID: 33424364
PMCID: PMC7783807
DOI: 10.1016/j.sjbs.2020.11.005

Abstract

Two series of dimethoxyindanone imbedded novel fluorinated spiropyrrolidine heterocyclic hybrids were synthesized employing two different less explored azomethine ylides and were measured for their efficiency as inhibitors for Alzheimer's disease. Among the spiropyrrolidine heterocyclic hybrids, the indole based fluorinated compound with a methoxy substituent at the meta- position of the aryl ring exhibited the utmost potent AChE and BChE inhibitory activities with an IC₅₀ of 1.97 ± 0.19 µM and 7.08 ± 0.20 µM respectively. The plausible mechanism of inhibition on ChE receptors was unveiled via molecular docking studies.

Keywords: AChE; Alzheimer’s disease; BChE; Cholinesterase inhibitory activity; Fluorinated spiroheterocyclic hybrids; Molecular docking simulation.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

**Scheme 1**
Retro synthetic approach employed in the present work.

**Scheme 2**
Synthesis of fluorinated spiropyrrolidines **4/6(a-j)**.

**Fig. 1**
(A and B) Peripheral anionic site and catalytic active site of hAChE displaying 4e.

**Fig. 2**
Active site of hBChE displaying 4e in the binding pocket of enzyme.

**Fig. 3**
(A and B) Amino acid residues of hAChE involved in the hydrogen and hydrophobic interactions with 4e at Peripheral anionic and catalytic active sites.

**Fig. 4**
Amino acid residues of hBChE involved in the hydrogen and hydrophobic interactions with **4e.**

**Fig. 5**
(A and B) Cartoon view of hAChE with **4e,** at the peripheral anionic and catalytic active sites.

**Fig. 6**
Cartoon view of hBChE with 4e.

See this image and copyright information in PMC

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References

1. Ali M.A., Yar M.S., Hasan M.Z., Ahsan M.J., Pandian S. Design, synthesis and evaluation of novel 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4-substituted phenyl methanone analogues. Bioorg. Med. Chem. Lett. 2009;19:5075–5077. - PubMed
1. Almansour A.I., Arumugam N., Kumar R.S., Kotresha D., Manohar T.S., Venketesh S. Design, synthesis and cholinesterase inhibitory activity of novel spiropyrrolidine tethered imidazole heterocyclic hybrid. Bioorg. Med. Chem. Lett. 2020;30:126789. - PubMed
1. Almansour A.I., Kumar R.S., Arumugam N., Basiri A., Kia Y., Ali M.A., Farooq M., Murugaiyah V. A facile ionic liquid promoted synthesis, cholinesterase inhibitory activity and molecular modeling study of novel highly functionalized spiropyrrolidines. Molecules. 2015;20:2296–2309. - PMC - PubMed
1. Basiri A., Murugaiyah V., Osman H., Kumar R.S., Kia Y., Ali M.A. Microwave assisted synthesis, cholinesterase enzymes inhibitory activities and molecular docking studies of new pyridopyrimidine derivatives. Bioorg. Med. Chem. 2013;21:3022–3031. - PubMed
1. Basiri A., Murugaiyah V., Osman H., Kumar R.S., Kia Y., Awang K.B., Ali M.A. An expedient, ionic liquid mediated multi-component synthesis of novel piperidone grafted cholinesterase enzymes inhibitors and their molecular modeling study. Eur. J. Med. Chem. 2013;67:221–229. - PubMed

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[1] Ali M.A., Yar M.S., Hasan M.Z., Ahsan M.J., Pandian S. Design, synthesis and evaluation of novel 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4-substituted phenyl methanone analogues. Bioorg. Med. Chem. Lett. 2009;19:5075–5077. - PubMed

[2] Ali M.A., Yar M.S., Hasan M.Z., Ahsan M.J., Pandian S. Design, synthesis and evaluation of novel 5,6-dimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl-3,4-substituted phenyl methanone analogues. Bioorg. Med. Chem. Lett. 2009;19:5075–5077. - PubMed

[3] Almansour A.I., Arumugam N., Kumar R.S., Kotresha D., Manohar T.S., Venketesh S. Design, synthesis and cholinesterase inhibitory activity of novel spiropyrrolidine tethered imidazole heterocyclic hybrid. Bioorg. Med. Chem. Lett. 2020;30:126789. - PubMed

[4] Almansour A.I., Arumugam N., Kumar R.S., Kotresha D., Manohar T.S., Venketesh S. Design, synthesis and cholinesterase inhibitory activity of novel spiropyrrolidine tethered imidazole heterocyclic hybrid. Bioorg. Med. Chem. Lett. 2020;30:126789. - PubMed

[5] Almansour A.I., Kumar R.S., Arumugam N., Basiri A., Kia Y., Ali M.A., Farooq M., Murugaiyah V. A facile ionic liquid promoted synthesis, cholinesterase inhibitory activity and molecular modeling study of novel highly functionalized spiropyrrolidines. Molecules. 2015;20:2296–2309. - PMC - PubMed

[6] Almansour A.I., Kumar R.S., Arumugam N., Basiri A., Kia Y., Ali M.A., Farooq M., Murugaiyah V. A facile ionic liquid promoted synthesis, cholinesterase inhibitory activity and molecular modeling study of novel highly functionalized spiropyrrolidines. Molecules. 2015;20:2296–2309. - PMC - PubMed

[7] Basiri A., Murugaiyah V., Osman H., Kumar R.S., Kia Y., Ali M.A. Microwave assisted synthesis, cholinesterase enzymes inhibitory activities and molecular docking studies of new pyridopyrimidine derivatives. Bioorg. Med. Chem. 2013;21:3022–3031. - PubMed

[8] Basiri A., Murugaiyah V., Osman H., Kumar R.S., Kia Y., Ali M.A. Microwave assisted synthesis, cholinesterase enzymes inhibitory activities and molecular docking studies of new pyridopyrimidine derivatives. Bioorg. Med. Chem. 2013;21:3022–3031. - PubMed

[9] Basiri A., Murugaiyah V., Osman H., Kumar R.S., Kia Y., Awang K.B., Ali M.A. An expedient, ionic liquid mediated multi-component synthesis of novel piperidone grafted cholinesterase enzymes inhibitors and their molecular modeling study. Eur. J. Med. Chem. 2013;67:221–229. - PubMed

[10] Basiri A., Murugaiyah V., Osman H., Kumar R.S., Kia Y., Awang K.B., Ali M.A. An expedient, ionic liquid mediated multi-component synthesis of novel piperidone grafted cholinesterase enzymes inhibitors and their molecular modeling study. Eur. J. Med. Chem. 2013;67:221–229. - PubMed

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Cholinesterase inhibitory activity of highly functionalized fluorinated spiropyrrolidine heterocyclic hybrids

Affiliations

Cholinesterase inhibitory activity of highly functionalized fluorinated spiropyrrolidine heterocyclic hybrids

Authors

Affiliations

Abstract

Conflict of interest statement

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