title: Synthesis and anti-mycobacterial activity of 4-(4-phenyl-1H-1,2,3-triazol-1-yl)salicylhydrazones: revitalizing an old drug.
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.
authors.affiliation: Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt. hagag.abdallah@pharm.au.edu.eg.
authors.forename: Hajjaj H M
authors.identifier: http://orcid.org/0000-0002-4474-9086
authors.initials: HH
authors.lastname: Abdu-Allah
authors.affiliation: Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.|Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka, 42421, Saudi Arabia.
authors.forename: Bahaa G M
authors.initials: BG
authors.lastname: Youssif
authors.affiliation: Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt.
authors.forename: Mostafa H
authors.initials: MH
authors.lastname: Abdelrahman
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.
authors.forename: Mohammed K
authors.initials: MK
authors.lastname: Abdel-Hamid
authors.affiliation: Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, Telangana, 500078, India.
authors.forename: Rudraraju Srilakshmi
authors.initials: RS
authors.lastname: Reshma
authors.affiliation: Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, Telangana, 500078, India.
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.
authors.forename: Tarek
authors.initials: T
authors.lastname: Aboul-Fadl
authors.affiliation: Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, Telangana, 500078, India. dsriram@hyderabad.bits-pilani.ac.in.
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D010131:Aminosalicylic Acid / Q000737:chemistry*; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004977:Ethambutol / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007538:Isoniazid / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D021281:Quantitative Structure-Activity Relationship; D012293:Rifampin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D006835:Hydrazones; D014230:Triazoles; D010131:Aminosalicylic Acid; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin
keywords: Antitubercular; Dormant TB; Hydazide and modeling; Isatin; Triazole; p-Aminosalicylic