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Synthesis and biological evaluations of novel pyrazinoic acid derivatives as anticancer agents

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Abstract

Pyrazinoic acid or pyrazine-2-carboxylic acid (PA), due to its nitrogenous heteroaromatic ring, can be explored as an anticancer agent. Here, a series of twenty novels PA derivatives have been synthesized and characterized using IR, NMR, and mass spectrums. Their cytotoxic activity was evaluated against three different cancer cell lines, including lung (A549), breast (MCF-7), and colon (HT-29). P16, the most potent compound, showed moderate cytotoxicity with IC50 of 6.11, 10.64, and 14.92 μM, against the A549, MCF-7, and HT-29 cell lines, respectively. Furthermore, the effect of this compound against MRC5 as a non-tumoral lung cell line, exhibited a selectivity index of 9.02. The apoptotic induction activity of P16 was also performed on the A549 cell line. The results showed that as the concentration of the compound increases (from 3 to 6 μM), the percentage of induction of apoptosis increases from 8.54% to 72.4%. Electrophoretic gel mobility shift assays showed that P16 was able to reactive oxygen species (ROS) induce DNA cleavage in the presents of H2O2 (1.0 mM) in high doses. Molecular docking was also applied to anticipate the binding locations and the binding of the synthesized compound with Bcl-2 apoptosis regulator and DNA as their proposed targets.

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Acknowledgements

The authors would like to thank research deputy Ahvaz Jundishapur University of Medical Sciences who support this work. Collaboration of Toxicology Research Center and Medicinal Chemistry department, school of pharmacy, Ahvaz Jundishapur University of Medical Sciences, in providing the required facilities for this work is greatly acknowledged. This article was extracted from thesis by Shiva Akhlaghi (Grant No: TRC-9902, Ethics: IR.AJUMS.REC.1399.051).

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Authors and Affiliations

  1. Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Shiva Akhlaghi, Hadi Kalantar & Masood Fereidoonnezhad

  2. Department of Medicinal Chemistry, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Shiva Akhlaghi, Azar Mostoufi & Masood Fereidoonnezhad

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  1. Shiva Akhlaghi
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  2. Azar Mostoufi
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Correspondence to Masood Fereidoonnezhad.

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IR.AJUMS.REC.1399.051.

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Akhlaghi, S., Mostoufi, A., Kalantar, H. et al. Synthesis and biological evaluations of novel pyrazinoic acid derivatives as anticancer agents. Med Chem Res 31, 580–593 (2022). https://doi.org/10.1007/s00044-022-02858-2

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  • DOI: https://doi.org/10.1007/s00044-022-02858-2

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