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Hybrid pharmacophore-based drug design, synthesis, and antiproliferative activity of 1,4-dihydropyridines-linked alkylating anticancer agents

Abstract

Two series of novel substituted 1,4-dihydropyridine derivatives incorporating nitrogen mustard pharmacophore hybrids without spacer DHP-M (4a4d) and with ethyl spacer DHP-L-M (8a8g) were designed and synthesized. They were subjected to in silico ADME prediction study to check their drug-like properties and evaluated for their cytotoxicity against: A 549 (lung), COLO 205 (colon), U 87 (glioblastoma), and IMR-32 (neuroblastoma) human cancer cell lines in vitro using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay against chlorambucil and docetaxel. Majority of the test compounds exhibited moderate to significant cytotoxic activity. The highest activity in all the investigated cancer cells was displayed by DHP-M (4a). This may be due to the less steric hindrance offered by 4a.

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Fig. 1
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Acknowledgments

The authors are thankful to the College Managing Committee, SCOP, Nangal for providing necessary facilities to carry out research work. The authors wish to express their gratitude to Dr. Manoj Kumar, Professor of Pharmaceutical Chemistry, UIPS, Panjab University, Chandigarh to carry out an ADME study at his lab. The authors are also thankful to ISFAL, ISF College of Pharmacy, Moga (Punjab) for carrying out cell line studies and SAIF, Panjab University, Chandigarh for cooperation in getting the spectral data.

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Correspondence to Rajesh K. Singh.

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Singh, R.K., Prasad, D.N. & Bhardwaj, T.R. Hybrid pharmacophore-based drug design, synthesis, and antiproliferative activity of 1,4-dihydropyridines-linked alkylating anticancer agents. Med Chem Res 24, 1534–1545 (2015). https://doi.org/10.1007/s00044-014-1236-1

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Keywords

  • 1,4-Dihydropyridine
  • Alkylating agent
  • Nitrogen mustard
  • ADME
  • MTT assay