Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity

Date

2022-10-01

Author

KOÇAK ASLAN, EBRU
HAN, MUHAMMED İHSAN
Krishna, Vagolu Siva
Tamhaev, Rasoul
Dengiz, Çağatay
DOĞAN, ŞENGÜL DİLEM
Lherbet, Christian
Mourey, Lionel
Tonjum, Tone
GÜNDÜZ, MİYASE GÖZDE

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Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In the present study, we aimed to chemically tailor INH to overcome this resistance. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge (SIH1-SIH13). Following structural characterization by FTIR, H-1 NMR, C-13 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. Additionally, the cytotoxic effects of SIH1-SIH13 were assessed on three different healthy host cell lines; HEK293, IMR-90, and BEAS-2B. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. 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. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH. 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. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1-SIH13 adhered to Lipinski's rule of five. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb.

Subject Keywords

antimycobacterial, Mycobacterium tuberculosis, drug-resistant clinical isolates, molecular modeling, InhA, MYCOBACTERIUM-TUBERCULOSIS, N-ACETYLTRANSFERASE, INHA INHIBITORS, DRUG, LIGANDS, AGENTS, TOOL

URI

https://hdl.handle.net/11511/100459

Journal

PHARMACEUTICALS

DOI

https://doi.org/10.3390/ph15101301

Collections

Department of Chemistry, Article

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Citation Formats

E. KOÇAK ASLAN et al., “Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity,” PHARMACEUTICALS, vol. 15, no. 10, pp. 0–0, 2022, Accessed: 00, 2022. [Online]. Available: https://hdl.handle.net/11511/100459.