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

[1]  Bilge Debelec Butuner,et al.  Design, synthesis, and in vitro biological evaluation of novel thiazolopyrimidine derivatives as antileishmanial compounds. , 2020, Archiv der Pharmazie.

[2]  S. Rizk,et al.  Synthesis, DFT study, molecular docking and insecticidal evaluation of some pyrazole-based tetrahydropyrimidine derivatives , 2020 .

[3]  R. Zabihollahi,et al.  Design, synthesis and evaluation of cytotoxic, antimicrobial, and anti-HIV-1 activities of new 1,2,3,4-tetrahydropyrimidine derivatives , 2019, Research in pharmaceutical sciences.

[4]  B. Liu,et al.  Multicomponent synthesis and anticancer activity studies of novel 6-(Trifluoromethyl)-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate derivatives , 2018, Synthetic Communications.

[5]  K. Selvakumar,et al.  Heteropoly acid supported on activated natural clay-catalyzed synthesis of 3,4-dihydropyrimidinones/thiones through Biginelli reaction under solvent-free conditions , 2018 .

[6]  Z. Benzekri,et al.  A Green and Simple Protocol one-pot Biginelli Condensation using Dicalcium Phosphate as Reusable Catalyst , 2017 .

[7]  A. M. El-Naggar,et al.  Design, synthesis of new pyrimidine derivatives as anticancer and antimicrobial agents , 2017 .

[8]  R. Arenas,et al.  Leishmaniasis: a review , 2017, F1000Research.

[9]  S. Bahekar,et al.  Simple and efficient synthesis of 3,4-dihydropyrimidin-2(1H)-thiones utilizing l-proline nitrate as a proficient, recyclable and eco-friendly catalyst , 2017 .

[10]  Olivier Michielin,et al.  SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules , 2017, Scientific Reports.

[11]  Xianhai Hu,et al.  Gallium (III) chloride-catalyzed synthesis of 3,4-dihydropyrimidinones for Biginelli reaction under solvent-free conditions , 2017 .

[12]  S. Shafi,et al.  An efficient one-pot multicomponent synthesis of 3,4-dihydropyrimidine-2-(1H)-ones/thiones/imines via a Lewis base catalyzed Biginelli-type reaction under solvent-free conditions , 2016 .

[13]  U. Rashid,et al.  Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents. , 2016, European journal of medicinal chemistry.

[14]  J. Votýpka,et al.  A Historical Overview of the Classification, Evolution, and Dispersion of Leishmania Parasites and Sandflies , 2016, PLoS neglected tropical diseases.

[15]  Xiaomei Zhang,et al.  An Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones and Thiones Catalyzed by a Novel Brønsted Acidic Ionic Liquid under Solvent-Free Conditions , 2015, Molecules.

[16]  N. Kaur.  Greener and Expeditious Synthesis of Fused Six-Membered N,N-Heterocycles Using Microwave Irradiation , 2015 .

[17]  Suman Gupta,et al.  Design, synthesis and biological evaluation of aryl pyrimidine derivatives as potential leishmanicidal agents. , 2013, Bioorganic & medicinal chemistry letters.

[18]  B. N. P. Kumar,et al.  Synthesis and biological activity of some pyrimidine derivatives. , 2013 .

[19]  R. M. Gleiser,et al.  Synthesis and antimosquito properties of 2,6-substituted benzo[d]thiazole and 2,4-substituted benzo[d]thiazole analogues against Anopheles arabiensis. , 2013, European journal of medicinal chemistry.

[20]  R. Mohan,et al.  Iron(III) tosylate catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones via the Biginelli reaction , 2013 .

[21]  Yong-mei Wang,et al.  Highly enantioselective Biginelli reaction catalyzed by a simple chiral primary amine catalyst: asymmetric synthesis of dihydropyrimidines , 2012 .

[22]  J. Cano,et al.  Leishmaniasis Worldwide and Global Estimates of Its Incidence , 2012, PloS one.

[23]  S. Narahari,et al.  Synthesis of dihydropyrimidinones via Biginelli multi-component reaction , 2012 .

[24]  K. Bahrami,et al.  Highly Efficient Solvent-Free Synthesis of Dihydropyrimidinones Catalyzed by Zinc Oxide , 2009 .

[25]  Z. Yao,et al.  Efficient synthesis of pyrimidinone derivatives by ytterbium chloride catalyzed Biginelli-type reaction under solvent-free conditions , 2009 .

[26]  B. Carboni,et al.  Ca(NO3)2·4H2O‐catalysed Biginelli Reaction: One‐pot Synthesis of 1,2,3,4‐Tetrahydropyrimidin‐2‐ones/pyrimidine‐2‐thiones under Solvent‐free Conditions , 2008 .

[27]  S. Tala,et al.  Synthesis of Some New 1,2,3,4-Tetrahydropyrimidine-2- thiones and Their Thiazolo[3,2-a]pyrimidine Derivatives as Potential Biological Agents , 2008 .

[28]  L. Yadav,et al.  Chiral ionic liquid-catalyzed Biginelli reaction : stereoselective synthesis of polyfunctionalized perhydropyrimidines , 2008 .

[29]  C. Mukhopadhyay,et al.  Microwave-induced bismuth nitrate-catalyzed synthesis of dihydropyrimidones via Biginelli condensation under solventless conditions , 2007 .

[30]  M. P. Kaushik,et al.  Synthesis of 4-aryl substituted 3,4-dihydropyrimidinones using silica-chloride under solvent free conditions. , 2007, Molecules.

[31]  Jide Wang,et al.  One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-(thio)ones using strontium(II) nitrate as a catalyst , 2006 .

[32]  Ashutosh,et al.  Dihydropyrido[2,3-d]pyrimidines as a new class of antileishmanial agents. , 2005, Bioorganic & medicinal chemistry.

[33]  Ashok Kumar,et al.  Synthesis, anti-inflammatory and analgesic activities evaluation of some mono, bi and tricyclic pyrimidine derivatives. , 2005, Bioorganic & medicinal chemistry.

[34]  W. Su,et al.  One-pot synthesis of dihydropyrimidiones catalyzed by strontium(II) triflate under solvent-free conditions , 2005 .

[35]  Suman Gupta,et al.  Synthesis and antileishmanial profile of some novel terpenyl pyrimidines. , 2004, European journal of medicinal chemistry.

[36]  A. Chakraborty,et al.  In(OTf)3-catalysed one-pot synthesis of 3,4-dihydropyrimidin-2(lH)-ones , 2004 .

[37]  P. Murphy,et al.  The guanidine metabolites of Ptilocaulis spiculifer and related compounds; isolation and synthesis , 2010 .

[38]  C. Kappe,et al.  Design and Synthesis of a Conformationally Rigid Mimic of the Dihydropyrimidine Calcium Channel Modulator SQ 32,926 , 2000 .

[39]  M. F. Bean,et al.  Novel Alkaloids from the Sponge Batzella sp.: Inhibitors of HIV gp120-Human CD4 Binding , 1995 .