Amino acid ionic liquid-catalyzed synthesis, anti-Leishmania activity, molecular docking, molecular dynamic simulation, and ADME study of 3,4-dihydropyrimidin-2(1H)-(thio)ones

Abstract

The synthesis of 3,4-dihydropyrimidin-2(1H)-(thio)one (DHPM) derivatives involving aromatic aldehyde, β-ketoesters and urea/thiourea using prolinium hydrogen sulfate (ProHSO₄) as a catalyst has been studied. A variety of DHPM derivatives were obtained in high yield under solvent-free conditions in a short reaction time. The in-vitro screening of antileishmanial activity of both the oxo and the thioxo compounds showed significant activity against extracellular promastigotes. The aldehyde substituted at C-4 position with methyl (4g) in the oxo series and chloro (4m), methyl (4n) in the thioxo series imparted good bioactivity, with >80% reduction in viability at 50 µg/mL, with IC₅₀ values 29.3, 29.3, and 28.3 µg/mL, respectively. Molecular docking study of the compound 4m displayed −6.4 kcal/mol binding energy. According to 50 ns molecular dynamics simulation study Leishmania major pteridine reductase 1 (PTR1) interacts well with the amino acid residues Phe-109, Leu-222, and Val-226. The in silico ADME study showed good drug-likeness properties.

Graphical Abstract

Keywords:

• Amino acid ionic liquid
• antileishmanial activity
• dihydropyrimidin-2(1H)-(thio)one
• prolinium hydrogen sulfate

Supporting Information

The general experimental procedure for synthesis, in-vitro study, molecular docking, molecular dynamic simulation study, spectroscopic data 1H-NMR, 13C-NMR, FT-IR spectra, and HRMS data of all synthesized compounds can be found in the online version.

Acknowledgments

The authors are thankful to the Department of Zoology, SPPU, Pune for providing the culture.