Design and development of novel N-(4-aminobenzoyl)- l-glutamic acid conjugated 1,3,5-triazine derivatives as Pf-DHFR inhibitor: An in-silico and in-vitro study.

Autor: Adhikari N; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India., Choudhury AAK; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India., Shakya A; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India., Ghosh SK; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India., Patgiri SJ; Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Dibrugarh, Assam, India., Singh UP; Drug Design & Discovery Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology & Sciences, Prayagraj, Uttar Pradesh, India., Bhat HR; Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India.
Jazyk: angličtina
Zdroj: Journal of biochemical and molecular toxicology [J Biochem Mol Toxicol] 2023 Apr; Vol. 37 (4), pp. e23290. Date of Electronic Publication: 2022 Dec 21.
DOI: 10.1002/jbt.23290
Abstrakt: In the present work, a library of 120 compounds was prepared using various aliphatic and aromatic amines. Finally, 10 compounds were selected through in silico screening carrying 4-aminobenzoyl-l-glutamic acid and 1,3,5-triazine moiety. The docking results of compounds 4d16 and 4d38 revealed higher binding interaction with amino acids Asp54 (-537.96 kcal/mol) and Asp54, Phe116 (-618.22 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR inhibitors and were comparable to standard WR99210. These compounds were developed by facile and microwave-assisted synthesis via nucleophilic substitution reaction and characterized by different spectroscopic methods. In vitro antimalarial assay results also suggested that these two compounds were having higher antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain out of the ten synthesized compounds with IC 50 13.25 μM and 14.72 μM, respectively. These hybrid scaffolds might be useful in the lead discovery of a new class of Pf-DHFR inhibitors.
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Databáze: MEDLINE
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