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Synthesis and anti-mycobacterial activity of 4-(4-phenyl-1H-1,2,3-triazol-1-yl)salicylhydrazones: revitalizing an old drug

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Abstract

The antitubercular drug; para-aminosalicylic acid (PAS) was used as the core scaffold for the design of a series of 1H-1,2,3-triazolylsalicylhydrazones upon coupling with triazole and arylhydrazone moietis to furnish a single molecular architecture. The obtained derivatives were screened against Mycobacterium tuberculosis H37Rv revealing good to high activity for the active compounds (MIC values of 0.39–1.5 μg/mL) compared to the marketed drugs isoniazid, rifampicin and ethambutol. Moreover, the most active analogue N-(1-(4-chlorobenzyl)-2-oxoindolin-3-ylidene)-2-hydroxy-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-benzohydrazide (20) was found to be ten-fold more potent than PAS and equipotent to rifampicin (MIC 0.39 µg/mL), while exhibiting low cytotoxicity with a selectivity index of >128. In addition, this compound was shown to be active against persistent forms of mycobacteria comparable to standard drugs in nutrient starvation model. Accordingly, we introduce compound 20 as a valuable lead for further development. A 3D-QSAR study was also conducted to help in explaining the observed activity and to serve as a tool for further development.

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Acknowledgement

This work was supported by Faculty of Pharmacy, Assiut University.

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Authors and Affiliations

  1. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt

    Hajjaj H. M. Abdu-Allah & Bahaa G. M. Youssif

  2. Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka, 42421, Saudi Arabia

    Bahaa G. M. Youssif

  3. Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt

    Mostafa H. Abdelrahman

  4. Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt

    Mohammed K. Abdel-Hamid & Tarek Aboul-Fadl

  5. Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, Telangana, 500078, India

    Rudraraju Srilakshmi Reshma, Perumal Yogeeswari & Dharmarajan Sriram

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  1. Hajjaj H. M. Abdu-Allah
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  2. Bahaa G. M. Youssif
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  3. Mostafa H. Abdelrahman
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  4. Mohammed K. Abdel-Hamid
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  7. Tarek Aboul-Fadl
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  8. Dharmarajan Sriram
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Correspondence to Hajjaj H. M. Abdu-Allah or Dharmarajan Sriram.

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Abdu-Allah, H.H.M., Youssif, B.G.M., Abdelrahman, M.H. et al. Synthesis and anti-mycobacterial activity of 4-(4-phenyl-1H-1,2,3-triazol-1-yl)salicylhydrazones: revitalizing an old drug. Arch. Pharm. Res. 40, 168–179 (2017). https://doi.org/10.1007/s12272-016-0882-x

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