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An in vitro study of the 5-methyl- and 5-bromo/chloro substituted 2-hydroxy-3-nitrochalcones as α-glucosidase and/or α-amylase inhibitors with potential anti-inflammatory activity

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Abstract

Series of the 5-methyl-, 5-bromo- and 5-chloro substituted 2-hydroxy-3-nitrochalcones (2a–d), (2e–h) and (2i–l), respectively, have been synthesized and characterized using a combination of spectroscopic and single crystal X-ray diffraction techniques. The compounds were, in turn, evaluated through enzymatic assays in vitro for inhibitory effect against α-glucosidase and α-amylase activities. Most of the test compounds exhibited increased inhibitory activity against α-glucosidase compared to the anti-diabetic drug, acarbose. Chalcones 2a, 2c, 2d, and 2g–j exhibited dual inhibitory effect against both enzymes with minimal cytotoxicity against the Raw-264,7 macrophage (Murine) cells compared to the anticancer drug, curcumin. Derivatives 2e and 2k exhibited increased inhibitory activity and selectivity against α-amylase with significantly reduced cytotoxicity against the Raw-264,7 cells. Chalcones 2a, 2i, and 2j showed the capability to increase the phagocytic ability of Raw-264,7 cells in the presence of lipopolysaccharide (LPS) stimuli. Molecular docking has been performed on the most active derivatives to predict the hypothetical protein–ligand binding modes into the α-glucosidase and α-amylase binding sites. Selected compounds were also docked into the Toll-like receptor-myeloid differentiation factor 2 (TLR4-MD2) active sites to determine their binding energies at least at theoretical level. The key aspects of the pharmacokinetics of these compounds, namely, absorption, distribution, metabolism, and excretion have also been simulated.

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Data availability

The CIF file containing complete information on the studied structure of 2k was deposited with the Cambridge Crystallographic Data Center, CCDC 2192594, and is freely available upon request from the following website: www.ccdc.cam.ac.uk/datarequest/cif or by contacting the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB2 1EZ, UK; fax: + 44-1223-336033; email: deposit@ccdc.cam.ac.uk.

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Acknowledgements

We thank University of the Witwatersrand for X-ray diffraction data using the single-crystal diffractometer purchased through the NRF Equipment Program (UID:78572). HRMS analysis was conducted on Sciex X500R TOF-MS of the University of Limpopo, funded by the South African National Research Foundation (NRF), grant number: 120326.

Funding

This project received financial support from the University of South Africa, University of Limpopo and the National Research Foundation (NRF) in South Africa (NRF GUN’s: 118554 & 138285), South African Medical Research Council (SAMRC) (Division of Research Capacity Development) (SAMRC Project Code Number: 57009 & 57039) as well as Malaysia Ministry of Higher Education Fundamental Research Grant Scheme (203/CIPPM/6711680; FRGS/1/2018/STG05/USM/02/1).

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Authors and Affiliations

  1. Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida, 1710, South Africa

    Malose J. Mphahlele

  2. Department of Chemistry, Faculty of Science and Agriculture, School of Physical and Mineral Science, University of Limpopo, Private Bag X1106, Sovenga, 0727, South Africa

    Marole M. Maluleka

  3. Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia

    Yee Siew Choong

  4. Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Private Bag X1106, Sovenga, 0727, South Africa

    Bernice A. Monchusi & Vusi G. Mbazima

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Contributions

M.J.M.: Conceptualization, Formal analysis, Writing–original draft, Methodology, Writing– review & editing; M.M.M.: Conceptualization, Methodology, Investigation, Writing– original draft. Y.S.C.: Formal analysis, Methodology, Writing– review & editing. B.A.M.: Formal analysis, Methodology, Writing– original draft; V.G.M.: Writing– review & editing.

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Correspondence to Malose J. Mphahlele.

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Mphahlele, M.J., Maluleka, M.M., Choong, Y.S. et al. An in vitro study of the 5-methyl- and 5-bromo/chloro substituted 2-hydroxy-3-nitrochalcones as α-glucosidase and/or α-amylase inhibitors with potential anti-inflammatory activity. Med Chem Res 31, 2243–2259 (2022). https://doi.org/10.1007/s00044-022-02980-1

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