Docking, Synthesis and Evaluation of the Antifungal Activity of Pyrimido[4,5-b]Quinolins

Document Type: Research article

Authors

1 Department of Chemistry, College of Science, Yazd University, Yazd, Iran.

2 Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz,.Iran.

3 Center of Basic Researches in Infectious Diseases, Department of Medical Mycology and Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz,.Iran.

Abstract

Aims: In order to expand the application of Fe3O4@SiO2-SnCl4 in the synthesis of heterocyclic compounds, in this study, we wish to report the use of one-pot three component synthesis of pyrimido[4,5-b]quinolone derivatives (D1-D16) through reaction of 6-amino-2-(methylthio)pyrimidin-4(3H)-one, dimedone, or 1,3- cyclohexadione and aldehydes in the presence of Fe3O4@SiO2-SnCl4 as an efficient eco-friendly catalyst under ultrasound irradiation. The final aim of this study is evaluation of antifungal activity of resulted products.
Method: Synthesis of pyrimido[4,5-b]quinolin derivatives were done via three components coupling reaction of aldehyde, dimedone or 1,3-cyclohexadione and 6-amino-2-(methylthio)pyrimidin-4(3H)-one in the presence of Fe3O4@SiO2-SnCl4 under ultrasonic irradiation in water at 60 oC. The products structure were studied by FT-IRI, 1H NMRII and 13C NMRII. All the compounds were screened for antimicrobial activity by broth microdilution methods as recommended by CLSIIII.
Results: Considering our results showed that compound (D13) had the most antifungal activity against C. dubliniensis, C. Albicans, C. Tropicalis and C. Neoformance at concentrations ranging (MIC90) from 1-4 μg/mL. Compounds (D9), (D10), (D14) and (D15) had significant inhibitory activities against C. dubliniensis at concentrations ranging (MIC90) from 4-8 μg/mL respectively.
Conclusion:5-(3,4-dihydroxyphenyl)-8,8-dimethyl-2-(methylthio)-5,8,9,10 tetrahydropyrimido[4,5-b]quinoline-4,6(3H,7H)-dione (D13) exhibited inhibitory and fungicidal activities against the tested yeasts. The specific binding mode or the binding orientation of more efficient compounds to CYP51 active site, have been also performed by molecular modeling investigations and showed that there is a good correlation with biological test.

Graphical Abstract

Docking, Synthesis and Evaluation of the Antifungal Activity of Pyrimido[4,5-b]Quinolins

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