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

• Published in: Synthetic communications Vol. 52; no. 2; pp. 190 - 204
• Main Authors: Rode, Nitin, Tantray, Aafaq, Shelar, Amruta, Patil, Rajendra, Terdale, Santosh
• Format: Journal Article
• Language: English
• Published: Taylor & Francis 17.01.2022
• Subjects: Amino acid ionic liquid; antileishmanial activity; dihydropyrimidin-2(1H)-(thio)one; prolinium hydrogen sulfate
• ISSN: 0039-7911; 1532-2432
• DOI: 10.1080/00397911.2021.2010757

The synthesis of 3,4-dihydropyrimidin-2(1H)-(thio)one (DHPM) derivatives involving aromatic aldehyde, β-ketoesters and urea/thiourea using prolinium hydrogen sulfate (ProHSO 4 ) 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 IC 50 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.