Novel N-substituted aminobenzamide scaffold derivatives targeting the dipeptidyl peptidase-IV enzyme

Qosay A Al-Balas1 Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, JordanCorrespondence[email protected] [email protected]

Munia F Sowaileh1 Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, JordanCorrespondence[email protected] [email protected]

Mohammad A Hassan1 Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

Amjad M Qandil1 Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan;2 Pharmaceutical Sciences Department, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia

Karem H Alzoubi3 Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

Nizar M Mhaidat3 Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

Ammar M Almaaytah4 Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

Omar F Khabour5 Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan

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Abstract

Background

The dipeptidyl peptidase-IV (DPP-IV) enzyme is considered a pivotal target for controlling normal blood sugar levels in the body. Incretins secreted in response to ingestion of meals enhance insulin release to the blood, and DPP-IV inactivates these incretins within a short period and stops their action. Inhibition of this enzyme escalates the action of incretins and induces more insulin to achieve better glucose control in diabetic patients. Thus, inhibition of this enzyme will lead to better control of blood sugar levels.

Methods

In this study, computer-aided drug design was used to help establish a novel N-substituted aminobenzamide scaffold as a potential inhibitor of DPP-IV. CDOCKER software available from Discovery Studio 3.5 was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the DPP-IV enzyme. The designed compounds were synthesized and tested against a DPP-IV enzyme kit provided by Enzo Life Sciences. The synthesized compounds were characterized using proton and carbon nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and determination of melting point.

Results

Sixty-nine novel compounds having an N-aminobenzamide scaffold were prepared, with full characterization. Ten of these compounds showed more in vitro activity against DPP-IV than the reference compounds, with the most active compounds scoring 38% activity at 100 μM concentration.

Conclusion

The N-aminobenzamide scaffold was shown in this study to be a valid scaffold for inhibiting the DPP-IV enzyme. Continuing work could unravel more active compounds possessing the same scaffold.

Keywords:

Supplementary materials

Figure S1 Infrared spectrum of compound 78.

Figure S2 Infrared spectrum of compound 83.

Figure S3 Infrared spectrum of compound 90.

Figure S4 Infrared spectrum of compound 93.

Figure S5 Infrared spectrum of compound 98.

Acknowledgments

This work was supported by the Scientific Research Fund, Ministry of Higher Education and Scientific Research, The Hashemite Kingdom of Jordan (grant TS/3/14/2008) and the Scientific Research Deanship, Jordan University of Science and Technology (grant 11/2012).

Disclosure

The authors report no conflicts of interest in this work.