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6-Substituted nicotinic acid analogues, potent inhibitors of CAIII, used as therapeutic candidates in hyperlipidemia and cancer

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Abstract

Nicotinic acid has been reported as a potential inhibitor of carbonic anhydrase III enzyme. Carbonic anhydrase III (CAIII) is an emerging new pharmacological target for the management of dyslipidemia and cancer progression. The activity of 6-substituted nicotinic acid analogs against carbonic anhydrase III was studied using a size-exclusion chromatography. The appearance of concentration-dependent vacancy peak was indicative of binding with CAIII. Chromatographic and docking studies revealed that the carboxylic acid of ligand is essential for binding via coordinate bond formation with Zn+2 ion in the enzyme active site. Moreover, the presence of a hydrophobic group, containing a hydrogen bond acceptor, at position 6 of the pyridine improves activity, e.g., 6-(hexyloxy) pyridine-3-carboxylic acid (Ki = 41.6 µM). Utilizing the weak esterase activity of CAIII, the inhibitory mode of 6-substituted nicotinic acid was confirmed.

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Acknowledgements

Part of this research was conducted during the sabbatical year granted to Dr. Muhammed Alzweiri by the University of Jordan in the academic year 2015/2016.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman, 11942, Jordan

    Haneen K. Mohammad, Muhammed H. Alzweiri, Mohammad A. Khanfar & Yusuf M. Al-Hiari

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  1. Haneen K. Mohammad
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  2. Muhammed H. Alzweiri
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  3. Mohammad A. Khanfar
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  4. Yusuf M. Al-Hiari
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Correspondence to Muhammed H. Alzweiri.

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Mohammad, H.K., Alzweiri, M.H., Khanfar, M.A. et al. 6-Substituted nicotinic acid analogues, potent inhibitors of CAIII, used as therapeutic candidates in hyperlipidemia and cancer. Med Chem Res 26, 1397–1404 (2017). https://doi.org/10.1007/s00044-017-1825-x

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  • DOI: https://doi.org/10.1007/s00044-017-1825-x

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