Synthesis, in silico study and antimalarial activity of 2-thioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide derivatives

Abstract

The present study mainly focused on synthesizing novel 2-thioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide derivatives using multicomponent reaction. Further, the potential of the synthesized compounds against Plasmodium falciparum dihydrofolate reductase (Pf-DHFR) inhibitors was evaluated by in vitro antimalarial activity, and the results of the study showed moderate to good antimalarial profile of synthesized entities. In-silico research of all the synthesized compounds was conducted using Schrödinger LLC-2020-3 software to explain the binding mode and interactions between molecules and the Pf-DHFR enzyme. To study the drug likeliness of molecules, 3D QSAR and pharmacokinetic studies have been carried out, and the results obtained showed good pharmacokinetics profile of two compounds, namely AMPS-26 and AMPS-28, having good IC₅₀ values concerning standard drugs. Further, the in vitro enzyme inhibition assay results suggested that the synthesized compound interacts nicely with the enzyme and might be used as a potent antimalarial agent.

Graphical abstract

The current study presents a synthesis of the novel 2-thioxo-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide derivatives using multicomponent reaction. A series of 30 compounds is synthesized. Amongst them, AMPS-28 (IC₅₀ value 0.028 µg/mL) is found to be the most potent against Pf-DHFR enzyme, which is based on its molecular docking studies and IC₅₀ values, comparable to pyrimethamine having IC₅₀ value 0.035 µg/mL.