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Synthesis of N-(3-picolyl)-based 1,3,2λ5-benzoxazaphosphinamides as potential 11β-HSD1 enzyme inhibitors

Abstract

Inhibition of 11β-HSD1 enzymatic action is perceived as a potential target for the treatment of metabolic syndromes like cardiovascular diseases, obesity, and diabetes. In an attempt to formulate potential organophosphorus compounds against 11β-HSD1 enzyme inhibition, we report novel 6-bromo-3-(6-methyl-2-pyridyl)-2-alkyl/arylamino-3,4-dihydro-2H-1,3,2λ5-benzoxazaphosphinin-2-ones 22a22n as good in vitro inhibitors of HEK 293 cell lines. The in vivo acute and sub-acute investigations sustain them as good antidiabetic compounds. The computational docking studies performed on them also supported the binding mode of compounds 22a and 22h with 11β-HSD1 protein. The blood glucose level lowering effect of the target compounds 22a22n screened on the streptozotocin-induced diabetic rats revealed that the target compounds are potential by antidiabetic when compared to the potency of standard glibenclamide drug. In addition, the calculated QSAR parameters, predicted ADMET properties, evaluated bioactivity properties and toxicity risk studies authorize drug like properties to the synthesized compounds.

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Fig. 1
Scheme 1
Fig. 2

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Acknowledgments

We thank University Grants Commission (UGC), New Delhi, INDIA for providing financial support through UGC-BSR-RFSMS (Research Fellowship In Sciences For Meritorious Students) Fellowship (F.4-1/2011, BSR-RFSMS-BSK) and for providing financial assistance through the Major Research Project (F. No.: 42-281/2013 (SR), Dated: 12-03-2013). We also thank Dr. V. Koteswara Rao, Post doctoral Fellow, Kansas University, Kansas, USA for providing MOE software for QSAR and Molecular docking studies.

Conflict of interest

We state that none of the authors have any conflict of interest in the context of this communication.

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Correspondence to Suresh Reddy Cirandur.

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Supplementary material 1 (PDF 1811 kb) Supporting Information Additional Supporting Information may be found in the online version of this article containing Structure Activity Relationship correlation studies as Fig. (3), binding mode parameters of ligands with the 11β-HSD1 binding site in Table 10 and spectra of compound 22e

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Balam, S.K., Krishnammagari, S.K., Soora Harinath, J. et al. Synthesis of N-(3-picolyl)-based 1,3,2λ5-benzoxazaphosphinamides as potential 11β-HSD1 enzyme inhibitors. Med Chem Res 24, 1119–1135 (2015). https://doi.org/10.1007/s00044-014-1194-7

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Keywords

  • 11β-HSD1 inhibition
  • ADMET properties
  • Benzoxazaphosphinamides
  • In vivo antidiabetic activity
  • In vitro HEK 293 cell inhibition
  • QSAR studies