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Designing, synthesis, and characterization of some novel coumarin derivatives as probable anticancer drugs

Abstract

Coumarin is a naturally occurring oxygen heterocyclic having multifarious medicinal properties, hence used as a lead compound for designing new potent analogs. Based on the X-ray crystal structure of complexes of inhibitors containing coumarin nucleus with human NAD(P)H:quinone oxidoreductase-1 and human phosphodiesterase 4B enzymes, some novel coumarin derivatives have been designed as probable inhibitors specifically for pancreatic cancer. These two enzymes are overexpressed in various tumors, the former specifically in pancreatic cancer. The computational analysis by e-pharmacophore and docking studies suggested that specific groups at position 8 of 4-methyl-7-hydroxycoumarin have anticancer activity against skin cancer in mice and can enhance the anti-tumor activity. The chemical syntheses of 4-methyl-7-hydroxycoumarin and its 8-formyl derivative were carried out using Pechmann’s condensation followed by Duffs reaction. Treatment of the 8-formyl derivative with nine different N,N-di substituted cyanoacetamides in the presence of piperidine afforded the corresponding nine new 8-substituted-4-methyl-7-hydroxycoumarin derivatives. These compounds were characterized by IR, 1H, 13C NMR, mass spectra and elemental analysis. Intriguingly, molecular docking suggested a remarkable binding pose for all the nine coumarin derivatives vis-a-vis coumarin itself, opening further options for designing inhibitors for tumor suppression. From the docking simulation study, it was concluded that the derived coumarin derivatives are active against more than one proteins and most importantly addition of substituents at the 8th position of 4-methyl-7-hydroxycoumarin support the possibility of new coumarin derivatives having comparatively higher binding affinity and therefore more potent inhibitors.

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Acknowledgments

The author [RKK] wishes to express his grateful thanks to director IIIT, Allahabad for providing necessary facilities to carry out computational work smoothly and [DMM] expresses his grateful thanks to Prof. C.S. Reddy, Department of Chemistry, Sri Venkateswara University, Tirupati, for his helpful discussions.

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Correspondence to Krishna Misra.

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Manidhar, D.M., Kesharwani, R.K., Reddy, N.B. et al. Designing, synthesis, and characterization of some novel coumarin derivatives as probable anticancer drugs. Med Chem Res 22, 4146–4157 (2013). https://doi.org/10.1007/s00044-012-0299-0

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Keywords

  • Coumarin
  • Docking
  • E-pharmacophore
  • Human NAD(P)H:quinone oxidoreductase-1
  • Human phosphodiesterase 4Bl
  • Cancer