Synthesis of Pyrazole-Thiobarbituric Acid Derivatives: Antimicrobial Activity and Docking Studies

A one-pot reaction was described that results in various pyrazole-thiobarbituric acid derivatives as new pharmacophore agents. These new heterocycles were synthesized in high yields with a broad substrate scope under mild reaction conditions in water mediated by NHEt2. The molecular structures of the synthesized compounds were assigned based on different spectroscopic techniques. The new compounds were evaluated for their antibacterial and antifungal activity. Compounds 4h and 4l were the most active compounds against C. albicans with MIC = 4 µg/L. Compound 4c exhibited the best activity against S. aureus and E. faecalis with MIC = 16 µg/L. However, compounds 4l and 4o were the most active against B. subtilis with MIC = 16 µg/L. Molecular docking studies for the final compounds and standard drugs were performed using the OpenEye program.

[1]  D. Schuster,et al.  Evaluation of selected 3D virtual screening tools for the prospective identification of peroxisome proliferator-activated receptor (PPAR) γ partial agonists. , 2016, European journal of medicinal chemistry.

[2]  M. García-Arencibia,et al.  Tricyclic pyrazoles. Part 8. Synthesis, biological evaluation and modelling of tricyclic pyrazole carboxamides as potential CB2 receptor ligands with antagonist/inverse agonist properties. , 2016, European journal of medicinal chemistry.

[3]  J. Berger,et al.  Crystal structure and stability of gyrase–fluoroquinolone cleaved complexes from Mycobacterium tuberculosis , 2016, Proceedings of the National Academy of Sciences.

[4]  M. Islam,et al.  Molecular structure investigation and biological evaluation of Michael adducts derived from dimedone , 2016, Research on Chemical Intermediates.

[5]  Y. Mabkhot,et al.  Synthesis of novel 5-monoalkylbarbiturate derivatives: new access to 1,2-oxazepines , 2015 .

[6]  Sajda Ashraf,et al.  Synthesis and dynamics studies of barbituric acid derivatives as urease inhibitors , 2015, Chemistry Central Journal.

[7]  M. Egorov,et al.  Non-catalytic multicomponent rapid and efficient approach to 10-(2,4,6-trioxohexahydropyrimidin-5-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-ones from salicylaldehydes, dimedone, and barbituric acids , 2015, Monatshefte für Chemie - Chemical Monthly.

[8]  J. Tyndall,et al.  Structural Insights into Binding of the Antifungal Drug Fluconazole to Saccharomyces cerevisiae Lanosterol 14α-Demethylase , 2015, Antimicrobial Agents and Chemotherapy.

[9]  J. Snyder,et al.  Pyrazolo-Piperidines Exhibit Dual Inhibition of CCR5/CXCR4 HIV Entry and Reverse Transcriptase. , 2015, ACS medicinal chemistry letters.

[10]  R. Gainetdinov,et al.  Further Insights Into the Pharmacology of the Human Trace Amine‐Associated Receptors: Discovery of Novel Ligands for TAAR1 by a Virtual Screening Approach , 2014, Chemical biology & drug design.

[11]  Y. Mabkhot,et al.  Zwitterionic pyrimidinium adducts as antioxidants with therapeutic potential as nitric oxide scavenger. , 2014, European journal of medicinal chemistry.

[12]  N. Sharma,et al.  Structures of kibdelomycin bound to Staphylococcus aureus GyrB and ParE showed a novel U-shaped binding mode. , 2014, ACS chemical biology.

[13]  Y. Mabkhot,et al.  Tandem Aldol-Michael reactions in aqueous diethylamine medium: a greener and efficient approach to dimedone-barbituric acid derivatives , 2014, Chemistry Central Journal.

[14]  Y. Mabkhot,et al.  An efficient and green procedure for synthesis of rhodanine derivatives by aldol-thia-Michael protocol using aqueous diethylamine medium , 2014 .

[15]  Y. Mabkhot,et al.  A Greener, Efficient Approach to Michael Addition of Barbituric Acid to Nitroalkene in Aqueous Diethylamine Medium , 2014, Molecules.

[16]  Y. Mabkhot,et al.  Tandem Aldol-Michael Reactions in Aqueous Diethylamine Medium: A Greener and Efficient Approach to Bis-Pyrimidine Derivatives , 2013, International journal of molecular sciences.

[17]  G. Klebe,et al.  Secreted aspartic protease in complex with ritonavir , 2012 .

[18]  P. Fossa,et al.  Docking-based 3D-QSAR analyses of pyrazole derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors , 2012, Journal of Molecular Modeling.

[19]  A. Bazgir,et al.  Chromeno[2,3-d]pyrimidine-triones synthesis by a three-component coupling reaction. , 2010, Chemical & pharmaceutical bulletin.

[20]  B. Trost,et al.  Asymmetric Syntheses of Oxindole and Indole Spirocyclic Alkaloid Natural Products , 2009 .

[21]  B. Trost,et al.  Asymmetric Syntheses of Oxindoleand Indole Spirocyclic Alkaloid Natural Products , 2009 .

[22]  P. Yogeeswari,et al.  A facile synthesis and antimycobacterial evaluation of novel spiro-pyrido-pyrrolizines and pyrrolidines. , 2009, European journal of medicinal chemistry.

[23]  Salman A. Khan,et al.  Pyridinium 5-[(1,3-diethyl-6-hydroxy-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)(2-methoxyphenyl)methyl]-1,3-diethyl-4,6-dioxo-2-thioxopyrimidin-5-ide , 2009, Acta crystallographica. Section E, Structure reports online.

[24]  S. Heymsfield,et al.  Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions , 2009, International Journal of Obesity.

[25]  P. Fossa,et al.  Rational design, synthesis and biological evaluation of new 1,5-diarylpyrazole derivatives as CB1 receptor antagonists, structurally related to rimonabant. , 2008, European journal of medicinal chemistry.

[26]  A. Bazgir,et al.  One-pot synthesis and antibacterial activities of pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-dione derivatives. , 2008, Bioorganic & medicinal chemistry letters.

[27]  H. Hassaneen,et al.  Synthesis and Antimicrobial Activity of Some New Pyrazole, Fused Pyrazolo[3,4-d]-pyrimidine and Pyrazolo[4,3-e][1,2,4]-triazolo[1,5-c]pyrimidine Derivatives , 2008, Molecules.

[28]  K. Gudmundsson,et al.  Pyrazolopyridines with potent activity against herpesviruses: effects of C5 substituents on antiviral activity. , 2008, Bioorganic & medicinal chemistry letters.

[29]  M. Jachak,et al.  Synthesis of novel dipyrazolo[3,4-b:3,4-d]pyridines and study of their fluorescence behavior , 2007 .

[30]  J. Hawkinson,et al.  Preparation and optimization of a series of 3-carboxamido-5-phenacylaminopyrazole bradykinin B1 receptor antagonists. , 2007, Journal of medicinal chemistry.

[31]  C. Lamberth.  Pyrazole chemistry in crop protection , 2007 .

[32]  J. Cai,et al.  A New Class of Metal-Free Catalysts for Direct Diastereo- and Regioselective Mannich Reactions in Aqueous Media. , 2005 .

[33]  B. Jursic,et al.  Preparation of 5,5′-Pyrilidene and 5,5′-Quinolidene Bis-barbituric Acid Derivatives. , 2003 .

[34]  R. Simon,et al.  The safety of celecoxib in patients with aspirin-sensitive asthma. , 2002, Arthritis and rheumatism.

[35]  D. Lesieur,et al.  Three-dimensional quantitative structure-activity relationships of cyclo-oxygenase-2 (COX-2) inhibitors: a comparative molecular field analysis. , 2001, Journal of medicinal chemistry.

[36]  Rajender S. Varma,et al.  Solvent-free organic syntheses. using supported reagents and microwave irradiation , 1999 .

[37]  V. K. Ahluwalia,et al.  One-Pot Syntheses of 5-Oxo-1,4,5,6,7,8-hexahydroquinolines and Pyrimido(4,5-b)quinolines Using Microwave Irradiation and Ultrasound. , 1997 .

[38]  V. Garg,et al.  Reaction of 5‐Amino‐4‐formyl‐3‐methyl(or phenyl)‐1‐phenyl‐1H‐pyrazoles with Active Methylene Compounds: Synthesis of Fused Heterocyclic Rings. , 1997 .

[39]  V. K. Ahluwalia,et al.  One-pot Syntheses of 5-Oxo-1,4,5,6,7,8-hexahydroquinolinesand Pyrimido[4,5-b]quinolines using MicrowaveIrradiation and Ultrasound , 1997 .

[40]  K. Paull,et al.  5-(N-phenylcarboxamido)-2-thiobarbituric acid (NSC 336628), a novel potential antitumor agent. , 1985, Biochemical pharmacology.