Modulation of Human Acetylthiocholine Esterase Activity by Novel Fused Pyrimidine Derivatives: In vitro, Theoretical and ADMET Studies

Year 2024, Volume: 11 Issue: 3, 1197 - 1210, 30.08.2024

Zaizafoon Nasif , Zahraa Salim Al-garawi , Füreya Elif Öztürkkan

https://doi.org/10.18596/jotcsa.1327285

Abstract

Pyrimidine compounds have medicinal and biological activities as previously reported. In this work, two novel fused pyrimidine compounds were synthesized, fused pyrazolo–pyrimidine compound was synthesized by cyclization of 5-amino-4-cyano-1-phenyl pyrazole with propionic acid in the presence of POCl3, and the other fused pyrrole–pyrano-pyrimidine compound was synthesized by cyclization of ethyl(E)-N-(3-cyano-4-(4-(dimethylamino)phenyl)-7-methyl-4,5,6,7-tetrahydropyrano[2,3-b] pyrrole-2-yl) formimidate with hydrazine hydrate, in methanol. These fused pyrimidine compounds were characterized by FT-IR and 1H NMR. The effect of these compounds was studied on the activity of the human neurotransmission enzyme acetylthiocholine esterase AChE. Results indicated that these compounds significantly inhibited AChE activity at concentrations of 10-11 M. Michalis-Menton showed mixed noncompetitive inhibition of AChE activity. In conclusion, newly synthesized compounds could be promising derivatives for enhancing cholinergic neurotransmission. Among the other derivatives, derivative 4 formed H-bond interactions with key amino acid residues Tyr334, and Asp72, whereas the other electrostatic interactions formed with Tyr334, Phe330, Ile287, Tyr121, Arg289, Trp279, Gly335, and Phe288. In the case of derivatives 9, similar binding interactions with active pockets of 2ACE were observed due to the high homology of the binding site residues. In addition, we examined ADMET properties with the help of online databases to search for possible drug similarity of synthesized compounds 4 and 9 and revealed that both molecules were compatible with Lipinski's five rules.

Keywords

Fused pyrazolo–pyrimidine, AChE activity, Molecular docking, noncompetitive inhibition, ADMET

Thanks

This research was registered in the annual plan of the Department of Chemistry at Mustansiriyah University, on January 11, 2021. The authors thank Mustansiriyah University for supporting this research https://uomustansiriyah.edu.iq/. The authors are also grateful to Dr. Hamed Hashim for his useful decisions regarding FT-IR.

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