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  2. Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors

Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors

  • Eur J Med Chem. 2020 Aug 1;199:112402. doi: 10.1016/j.ejmech.2020.112402.
Şengül Dilem Doğan 1 Miyase Gözde Gündüz 2 Hilal Doğan 3 Vagolu Siva Krishna 4 Christian Lherbet 5 Dharmarajan Sriram 4
Affiliations

Affiliations

  • 1 Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, 38039, Kayseri, Turkey. Electronic address: dogandilem@gmail.com.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye, 06100, Ankara, Turkey.
  • 3 Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, 38039, Kayseri, Turkey.
  • 4 Department of Pharmacy, Birla Institute of Technology and Science-Pilani, 500078, Hyderabad, India.
  • 5 LSPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118, route de Narbonne, 236 Cours Eugene Cosserat, 31062, Toulouse Cedex, France.
Abstract

Tuberculosis remains the most deadly infectious disease worldwide due to the emergence of drug-resistant strains of Mycobacterium tuberculosis. Hence, there is a great need for more efficient treatment regimens. Herein, we carried out rational molecular modifications on the chemical structure of the urea-based co-crystallized ligand of enoyl acyl carrier protein reductase (InhA) (PDB code: 5OIL). Although this compound fulfills all structural requirements to interact with InhA, it does not inhibit the Enzyme effectively. With the aim of improving the inhibition value, we synthesized thiourea-based derivatives by one-pot reaction of the amines with corresponding isothiocyanates. After the structural characterization using 1H NMR, 13C NMR, FTIR and HRMS, the obtained compounds were initially tested for their abilities to inhibit Mycobacterium tuberculosis growth. The results revealed that some compounds exhibited promising antitubercular activity, MIC values at 0.78 and 1.56 μg/mL, combined with low cytotoxicity. Moreover, the most active compounds were tested against latent as well as dormant forms of the bacteria utilizing nutrient starvation model and Mycobacterium tuberculosis infected macrophage assay. Enzyme inhibition assay against enoyl-acyl carrier protein reductase identified InhA as the important target of some compounds. Molecular docking studies were performed to correlate InhA inhibition data with in silico results. Finally, theoretical calculations were established to predict the physicochemical properties of the most active compounds.

Keywords

Antimycobacterial; Antitubercular; Docking; Enoyl-ACP reductase; Molecular modeling.

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