Цзяньчжоу Мэн, Цин Хэ, Сяо Ван, Ян Гуань, Ишуан Лю и Чуньлин Сяо
Aim: This study aimed to discover new Anti-Mycobacterium Tuberculosis (MTB) chemicals for treating drugresistant MTB.
Method: A phenotypic screening model was construed using MTB H37Rv (ATCC27294) for searching antituberculosis chemicals. Minimal inhibitory concentrations (MICs) of the positive compounds to sensitive and resistant MTB strains were detected to confirm antibacterial activities. The pharmacokinetic and metabolic properties and intracor-poral anti-MTB activity of the promising compound were determined in mice to assess drug suitability.
Results: HMPP, an acyl hydrazone Schiff base derivative of these compounds, was obtained based on this model. HMPP potently inhibited H37Rv (MIC, 0.72 μM) and a multiple drug-resistant MTB strain (MIC, 45 μM). The half maximal inhibitory concentrations (IC50) for Vero and HepG2 were 457.06 μM and 720.86 μM, respectively. The IC50 value which inhibited the tail current of hERG channels was much >higher than 30 μM. Based on the mini-Ames experiment, HMPP did not induce>a 3-fold increase in reverse mutations. The elimination factor of HMPP was 7.75 L/h/kg, and the half-life (t1/2) was 0.37 h and 1.82 h for Intravenous (iv) and Oral (po) administration in Sprague- Dawley rats. After one-hour incubation in murine plasma, HMPP hydrolyzed completely into M1 and M2 83.36%) HMPP reduced the load of MTB in mice lungs from 3.83 × 105 Colony Forming Units (CFU) to 3.32 × 103 CFU at a dose of 100 mg/kg.
Conclusion: These results indicate that HMPP is a promising antibacterial agent for treating mycobacterium tuberculosis.