2. Academic Validation
  3. Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis

Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis

  • Bioorg Med Chem. 2019 Sep 15;27(18):4143-4150. doi: 10.1016/j.bmc.2019.07.045.
Wallace J Reis 1,  Ícaro A O Bozzi 1,  Matheus F Ribeiro 1,  Priscila C B Halicki 2,  Laís A Ferreira 2,  Pedro E Almeida da Silva 2,  Daniela F Ramos 3,  Carlos A de Simone 4,  Eufrânio N da Silva Júnior 5
Affiliations

Affiliations

  • 1 Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, Brazil.
  • 2 Mycobacteria Laboratory, School of Medicine, Federal University of Rio Grande, Rio Grande 96200-190, RS, Brazil.
  • 3 Mycobacteria Laboratory, School of Medicine, Federal University of Rio Grande, Rio Grande 96200-190, RS, Brazil. Electronic address: danielaramos@furg.br.
  • 4 Institute of Physics, University of São Paulo, São Carlos 13560-160, SP, Brazil.
  • 5 Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, Brazil. Electronic address: eufranio@ufmg.br.
PMID: 31378595 DOI: 10.1016/j.bmc.2019.07.045
Abstract

Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H37Rv) strain and two isoniazid-resistant strains (INHR1 and INHR2) of Mycobacterium tuberculosis. The antimycobacterial activity of the derivatives was determined based on the resazurin microtiter assay and their cytotoxicity in adhered mouse monocyte macrophage J774.A1 cells (ATCC TIB-67). Of the twenty-two compounds evaluated against the three strains of M. tuberculosis, twenty-one presented some activity against the H37Rv and INHR1 (katG S315T) or INHR2 (inhA C(-5)T) strains. Compounds 1a, 2a, and 8a were effective against the INHR1 strain, and compounds 1a, 1b, 2a, 3a, 5a, 5b and 8a were effective against the INHR2 strain, with MICs in the range of 3.12-6.25 µg/mL. Compounds 1b and 5b were the most active against H37Rv, with MIC of 0.78 µg/mL. Based on the selectivity index, 1b and 5b can be considered safe as a drug candidate compounds. These results demonstrate that quinoidal compounds can be used as promising scaffolds for the development of new anti-TB drugs and hybrids with activity against M. tuberculosis-susceptible and INH-resistant strains.

Keywords

Antimycobacterial compounds; Hybrid molecules; Isoniazid-naphthoquinone derivatives; Mycobacterium tuberculosis; Quinone; Tuberculosis.

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