Development of potent nanosized isatin-isonicotinohydrazide hybrid for management of Mycobacterium tuberculosis

[Display omitted] Inspired by the antitubercular activity of isoniazid (INH) and 5-bromoisatin, isatin–INH hybrid (WF-208) has been synthesized as a potent agent against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. In silico molecular docking studies ind...

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Published in:International journal of pharmaceutics 2022-01, Vol.612, p.121369-121369, Article 121369
Main Authors: Eldehna, Wagdy M., El Hassab, Mahmoud A., Abdelshafi, Nahla A., Al-Zahraa Sayed, Fatma, Fares, Mohamed, Al-Rashood, Sara T., Elsayed, Zainab M., Abdel-Aziz, Marwa M., Elkaeed, Eslam B., Elsabahy, Mahmoud, Eissa, Noura G.
Format: Article
Language:English
Subjects:
Antitubercular Agents - pharmacology
DprE1 inhibitors
Isatin - pharmacology
Isoniazid
Isoniazid - pharmacology
Molecular docking
Molecular Docking Simulation
Mycobacterium tuberculosis
Niosomes
Stability
Tuberculosis
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Summary:[Display omitted] Inspired by the antitubercular activity of isoniazid (INH) and 5-bromoisatin, isatin–INH hybrid (WF-208) has been synthesized as a potent agent against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. In silico molecular docking studies indicated that DprE1, a critical enzyme in the synthesis of M. tuberculosis cell wall, is a potential enzymatic target for WF-208. The synthesized WF-208 was incorporated into a nanoparticulate system to enhance stability of the compound and to sustain its antimicrobial effect. Nanosized spherical niosomes (hydrodynamic diameter of ca. 500–600 nm) could accommodate WF-208 at a high encapsulation efficiency of 74.2%, and could impart superior stability to the compound in simulated gastric conditions. Interestingly, WF-208 had minimal inhibitory concentrations (MICs) of 7.8 and 31.3 µg/mL against MDR and XDR M. tuberculosis, respectively, whereas INH failed to demonstrate bacterial growth inhibition at the range of the tested concentrations. WF-208-loaded niosomes exhibited a 4-fold increase in the anti-mycobacterial activity as compared to the free compound (MIC of 1.9 vs. 7.8 µg/mL) against H37Rv M. tuberculosis, after three weeks of incubation with WF-208-loaded niosomes. Incorporation of the compound into nanosized vesicles allowed for a further increase in stability, potency and sustainability of the anti-mycobacterial activity, thus, providing a promising strategy for management of tuberculosis.
ISSN:0378-5173
1873-3476
DOI:10.1016/j.ijpharm.2021.121369