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

• Published in: Archives of pharmacal research Vol. 40; no. 2; pp. 168 - 179
• Main Authors: Abdu-Allah, Hajjaj H. M., Youssif, Bahaa G. M., Abdelrahman, Mostafa H., Abdel-Hamid, Mohammed K., Reshma, Rudraraju Srilakshmi, Yogeeswari, Perumal, Aboul-Fadl, Tarek, Sriram, Dharmarajan
• Format: Journal Article
• Language: English
• Published: Seoul Pharmaceutical Society of Korea 01-02-2017; 대한약학회
• Subjects: Aminosalicylic Acid - chemistry; Antitubercular Agents - chemical synthesis; Antitubercular Agents - chemistry; Antitubercular Agents - pharmacology; Drug Design; Ethambutol - pharmacology; HEK293 Cells; Humans; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - pharmacology; Isoniazid - pharmacology; Medicine; Microbial Sensitivity Tests; Mycobacterium tuberculosis - drug effects; Pharmacology/Toxicology; Pharmacy; Quantitative Structure-Activity Relationship; Research Article; Rifampin - pharmacology; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; 약학; Dormant TB; Triazole; Aminosalicylic; Antitubercular; Isatin; Hydazide and modeling; p-Aminosalicylic
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/s12272-016-0882-x

The antitubercular drug;
para
-aminosalicylic acid (PAS) was used as the core scaffold for the design of a series of 1
H
-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-1
H
-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.