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Vol. 35 No. 7 (2023): Vol 35 Issue 7 (2023)

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Novel Cholinesterase Inhibitors: Synthesis, in silico and in vitro Studies

https://doi.org/10.14233/ajchem.2023.27588
Effiong E. Ekerendu
Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria
https://orcid.org/0009-0002-9719-136X
Uchechukwu C. Okoro
Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria
https://orcid.org/0000-0002-4116-7144
Cosmas C. Eze
Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria Department of Chemistry, University of Nigeria, Nsukka, Enugu State, Nigeria
David S. Khanye
Department of Pharmaceutical Chemistry, Rhodes University, Makhanda 6139, South Africa
https://orcid.org/0000-0003-0725-5738
Kingsley O. Omeje
Department of Biochemistry, University of Nigeria, Nsukka, Nigeria
https://orcid.org/0000-0001-8993-4229
Narendra K. Mishra
Department of Chemistry, University of Copenhagen, Copenhagen, Denmark
https://orcid.org/0000-0001-6251-7177
David I. Ugwu
Department of Pure and Industrial Chemistry, University of Nigeria, Nsukka, Nigeria Department of Chemistry, University of the Free State, Park West, Bloemfontein 9301, South Africa
https://orcid.org/0000-0002-2370-6191

Corresponding Author(s) : David I. Ugwu

Izuchukwu.ugwu@unn.edu.ng

Asian Journal of Chemistry, Vol. 35 No. 7 (2023): Vol 35 Issue 7 (2023)

Abstract

The synthesis of new functionalized linear diaza and triaza phenothiazine and phenoxazines and their in silico and in vitro anti-Alzheimer activity is reported. Fifteen new amide derivatives (8-11 & 13-24) were synthesized by the reactions of phenothiazines/phenoxazine (6 or 12) and various aliphatic and aromatic primary amides (7) in the presence of nickel catalyst and anhydrous potassium carbonate under nitrogen atmosphere. The FTIR, 1H NMR, 13C NMR and HR-MS spectra of the synthesized compounds were in agreement with the assigned structures. All the 15 new derivatives were screened for their in silico and in vitro anti-Alzheimer’s activity using the inhibition of acetylcholinesterase and butyrylcholinesterase. The results of the in silico experiment showed that most of the synthesized derivatives had good binding energies, binding interaction and bond distances. The most active derivatives in the in silico studies was compounds 18 (-12.5 and -11.5 kcal/mol) against acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound 18 had the best in vitro inhibitory activity against acetylcholinesterase and butyrylcholinesterase (99.37% and 82.35%). The results of in silico experiment were greatly in agreement with the results of in vitro studies. The structure-activity relationship studies revealed that the phenothiazine derivatives had better in silico and in vitro activities. Furthermore, 2-substitutted phenothiazines had better activity than the unsubstituted phenothiazines. The synthesized compounds showed promising in silico and in vitro activities against acetylcholinesterase and butyrylcholinesterase and as such could be further developed for the treatment of Alzheimer’s disease.

Keywords

Acetylcholinesterase Alzheimer’s disease Butyrylcholinesterase Phenoxazines Phenothiazines
Ekerendu, E. E., Okoro, U. C., Eze, C. C., Khanye, D. S., Omeje, K. O., Mishra, N. K., & Ugwu, D. I. (2023). Novel Cholinesterase Inhibitors: Synthesis, in silico and in vitro Studies. Asian Journal of Chemistry, 35(7), 1683–1691. https://doi.org/10.14233/ajchem.2023.27588
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