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Design and synthesis of novel 4-hydrazone functionalized/1,2,4-triazole fused pyrido[2,3-d]pyrimidine derivatives, their evaluation for antifungal activity and docking studies

  • Nooka Ratnam Appna
  • Ravi Kumar Nagiri
  • Raghu Babu Korupolu
  • Sirisha Kanugala
  • Ganesh Kumar Chityal
  • Ganapathi Thipparapu
  • Narsaiah BandaEmail author
Original Research
  • 21 Downloads

Abstract

A series of novel 2-substituted 4-hydrazone functionalized pyrido[2,3-d]pyrimidine (8af and 9ae) and 1,2,4-triazole fused pyrido[2,3-d]pyrimidine derivatives (10af and 11ae) were prepared starting from ethyl 2-amino-6-(trifluoromethyl)nicotinate 3 via acylation, cyclization, chlorination, hydrazine reaction, hydrazone formation followed by intramolecular cyclization. All the final products were screened against various Candida strains for determining the antifungal activity, minimum fungicidal concentration and inhibition of ergosterol biosynthesis. Among the screened, compounds 8c, 8f, 9c, 10f, 11d and 11e were identified as promising antifungal agents. From a mechanistic perspective, the concomitant treatment of 10f, 11d and 11e on different Candida strains showed inhibition of ergosterol biosynthesis, which also revealed the possible antifungal action of these compounds on the ergosterol biosynthetic pathway. The binding mode of active compounds by docking studies showed that they fit well into the active site cavity of target protein. Further, the SAR and molecular docking studies data presumed that the presence of fluoro, trifluoromethyl, bromo and nitro groups on phenyl and furyl rings in pyrido[2,3-d]pyrimidine were found to be crucial to promote antifungal activity. All the strains for Miconazole a control drug showed MIC values equal to 3.9 μg/mL. Lipinski’s parameters of all compounds are within the acceptable range defined for human use thereby indicating their potential as drug-like molecules.

Keywords

Pyrido[2,3-d]pyrimidine 4-hydrazone Triazole Antifungal activity Ergosterol Molecular docking 

Notes

Acknowledgements

N.R.A. is thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India for the award of Senior Research Fellowship. N.R.A., N.R.K., K.S. and T.G. are also thankful to Council of Scientific and Industrial Research (CSIR), New Delhi, India for providing financial assistance in the form of Research Fellowship and contingency grant.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Nooka Ratnam Appna
    • 1
    • 2
  • Ravi Kumar Nagiri
    • 2
  • Raghu Babu Korupolu
    • 1
  • Sirisha Kanugala
    • 3
  • Ganesh Kumar Chityal
    • 3
  • Ganapathi Thipparapu
    • 4
  • Narsaiah Banda
    • 2
    Email author
  1. 1.Andhra University College of EngineeringVisakhapatnamIndia
  2. 2.Fluoroorganic division, CSIR-Indian Institute of Chemical Technology, TarnakaHyderabadIndia
  3. 3.Medicinal Chemistry and Pharmacology DivisionCSIR-Indian Institute of Chemical Technology, TarnakaHyderabadIndia
  4. 4.Stem Cell Research Division, Department of BiochemistryICMR-National Institute of Nutrition (NIN)HyderabadIndia

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