Furthermore, in humans, INH is metabolized and in this way deactivated by N-acetyltransferase type 2 (NAT2). Therefore, the clinical efficacy of INH in the treatment of drug-resistant TB is restricted due to mutations in katG or inhA and its promoter. As a prodrug, INH needs to be oxidized by the enzyme catalase-peroxidase (KatG) to inhibit its biological target enoyl-acyl carrier protein reductase (InhA), a critical enzyme employed in the biosynthesis of mycolic acids. Isoniazid (isonicotinic acid hydrazide, INH) is the cornerstone drug of modern TB therapy. The successful control of TB by the current chemotherapeutic regimen, mainly consisting of four first-line drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol), is often endangered by emerging drug-resistant Mtb strains. TB is one of the leading infectious agent-related causes of mortality, as confirmed by the data presented in the latest World Health Organization (WHO) Global TB Report. Mycobacterium tuberculosis ( Mtb) is the primary causative agent of the contagious disease tuberculosis (TB) that has devastated humankind for centuries. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1–SIH13 adhered to Lipinski’s rule of five. Although most of the synthesized compounds are hosted by the InhA binding pocket, SIH1–SIH13 do not primarily show their antitubercular activities by direct InhA inhibition. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH.
Moreover, the stability of the hydrazone moiety in the chemical structure of the final compounds was confirmed by using UV/Vis spectroscopy in both aqueous medium and DMSO. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. Additionally, the cytotoxic effects of SIH1–SIH13 were assessed on three different healthy host cell lines HEK293, IMR-90, and BEAS-2B.
Following structural characterization by FTIR, 1H NMR, 13C NMR, and HRMS, all compounds were screened for their antitubercular activity against Mtb H37Rv strain and INH-resistant clinical isolates carrying katG and inhA mutations. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge ( SIH1–SIH13). In the present study, we aimed to chemically tailor INH to overcome this resistance. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis ( Mtb). Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide.
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