ANTITUBERCULOSIS ACTIVITIES OF CLOFAZIMINE AND ITS NEW ANALOGS B4154 AND B4157

In our efforts to develop new drugs for the treatment of tuberculosis, especially that caused by multidrug-resistant strains, we investigate d clofazimine (CFM) and two of its analogs, B4154 and B4157 for their antituberculosis activities. Twenty M. tuberculosis strains were teste d, including 16 drug-resistant strains (strains resistant to one or mo re antituberculosis drugs), for their susceptibilities to these three agents, All of the strains were found to be susceptible to B4154 and B 4157, and one strain showed moderate resistance to CFM. The MICs of B4 154, B4157, and CFM at which 90% of strains were inhibited were 0.25, 0.12, and less than or equal to 1.0 mu g/ml, respectively, The intrace llular activities of CFM and B4157 were superior to that of B4154, The chemotherapeutic activities of the three compounds were evaluated in C57BL/6 mice. At a dose of 20 mg/kg of body weight, the activity of CF M was slightly superior to that of B4157; however, both compounds prev ented mortality and caused a significant reduction in the numbers of C FU in the lungs and spleens, The animals treated with B4157 showed les s pigmentation than animals treated with CFM. The chemotherapeutic act ivity of CFM was comparable to those of rifampin and isoniazid. Comple te susceptibility of multidrug-resistant strains to CFM and B4157 and the therapeutic efficacies of these compounds against mouse tuberculos is make these drugs attractive agents for the treatment of drug-resist ant tuberculosis.