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KMID : 0043320170400020168
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Archives of Pharmacal Research
2017 Volume.40 No. 2 p.168 ~ p.179
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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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Abdu Allah Hajjaj H. M.
Youssif Bahaa G. M.
Abdelrahman Mostafa H.
Abdel Hamid Mohammed K.
Reshma Rudraraju Srilakshmi
Yogeeswari Perumal
Sriram Dharmarajan
Aboul Fadl Tarek
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Abstract
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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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KEYWORD
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Antitubercular, p-Aminosalicylic, Dormant TB, Triazole, Isatin, Hydazide and modeling
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