Design of hybrid molecules as antimycobacterial compounds: Synthesis of isoniazid-naphthoquinone derivatives and their activity against susceptible and resistant strains of Mycobacterium tuberculosis.
Reis WJ, Bozzi ÍAO, Ribeiro MF, Halicki PCB, Ferreira LA, Almeida da Silva PE, Ramos DF, de Simone CA, da Silva Júnior EN.
Isoniazid-naphthoquinone hybrids were synthesized and evaluated against a susceptible (H<sub>37</sub>Rv) strain and two isoniazid-resistant strains (INH<sub>R1</sub> and INH<sub>R2</sub>) 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 H<sub>37</sub>Rv and INH<sub>R1</sub> (katG S315T) or INH<sub>R2</sub> (inhA C(-5)T) strains. Compounds 1a, 2a, and 8a were effective against the INH<sub>R1</sub> strain, and compounds 1a, 1b, 2a, 3a, 5a, 5b and 8a were effective against the INH<sub>R2</sub> strain, with MICs in the range of 3.12-6.25 µg/mL. Compounds 1b and 5b were the most active against H<sub>37</sub>Rv, 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.