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Synthesis, in vitro and in silico enzyme (COX-1/2 & LOX-5), free radical scavenging and cytotoxicity profiling of the 2,4-dicarbo substituted quinazoline 3-oxides

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Abstract

Series of the 3-methylquinazoline 3-oxide derivatives were evaluated through enzymatic assays in vitro and in silico for potential inhibitory effect against cyclooxygenase-1/2 (COX-1/2) and lipoxygenase-5 activities as well as for free radical scavenging potential and cytotoxicity. The 6-bromo (3k) and 6-iodo substituted 2-(4-chlorophenyl)-4-methylquinazoline 3-oxide (3q) exhibited significant inhibitory effect against both COX-1 (IC50 = 13.9 ± 3.21 µM and 9.7 ± 0.09 µM, respectively) and COX-2 (IC50 = 6.4 ± 0.74 µM and 4.6 ± 1.45 µM, respectively) compared to quercetin (IC50 = 13.84 ± 1.57 µM and 5.06 ± 2.60 µM, respectively). Their activity was, however, modest compared to the selective COX-2 inhibitor, celecoxib, with IC50 values of 7.35 ± 0.88 µM and 0.62 ± 0.74 µM against COX-1 and COX-2, respectively. The two compounds exhibited comparable effect on LOX-5 (IC50 = 15.0 µM), which is moderate compared to quercetin (IC50 = 8.04 ± 1.12 µM) and modest against zileuton (IC50 = 0.42 ± 0.51 µM). Structure–activity relationship analysis suggested that the presence of a halogen atom at the C-6 position and a 2-aryl group enhance inhibitory effect against COX-2. This observation is well supported by molecular docking studies.

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Data availability

The CIF files containing complete information on the studied structures were deposited with the Cambridge Crystallographic Data Center, 3b (CCDC 2035791) and 3c (CCDC 2035790), and are freely available upon request from the following website: www.ccdc.cam.ac.uk/datarequest/cif or by contacting the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033; email: deposit@ccdc.cam.ac.uk.

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Acknowledgements

The authors are grateful to the University of Stellenbosch Central Analytical Facility (CAF) and the University of the Witwatersrand for mass spectrometric and X-ray data, respectively.

Author contributions

Conceptualization and supervision, MJM and MMM; methodology, data curation and analyses, MJM; synthesis, EEO; bioassays, ENA; molecular docking, YSC; Writing: review & editing, MJM.

Funding

FundingThis project was funded by the University of South Africa, the National Research Foundation (NRF) in South Africa (NRF GUN: 118554), and the University Sains Malaysia (RUi grant: 1001/CIPPM/8011051). The views and opinions expressed in this article are those of the authors and not of the funding bodies.

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

    Malose J. Mphahlele, Eugene E. Onwu, Emmanuel N. Agbo & Marole M. Maluleka

  2. Department of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X06, Florida, 1710, South Africa

    Garland K. More

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

    Yee Siew Choong

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Mphahlele, M.J., Onwu, E.E., Agbo, E.N. et al. Synthesis, in vitro and in silico enzyme (COX-1/2 & LOX-5), free radical scavenging and cytotoxicity profiling of the 2,4-dicarbo substituted quinazoline 3-oxides. Med Chem Res 31, 146–164 (2022). https://doi.org/10.1007/s00044-021-02811-9

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