| Tuberculosis (TB) is presently regarded as one of the most dangerous infectious diseases worldwide and one of the major AIDS-associated infections. It has been estimated that more than 9.2 million people worldwide develop active TB, and 1.7 million die every year. However, no new anti-TB drugs have been introduced over the past 40 years.;JM-24 was found to have an excellent antituberculosis activity against both replicating and non-replicating bacilli, with a minimum inhibitory concentration (MIC) of 0.9 muM and 12.2 muM, respectively. Its activity appeared to be very specific for Mycobacterium tuberculosis, and it effected significant reductions in CFU in infected macrophages with an EC90 of 4.1 muM. More importantly, the increased in vitro antituberculosis activity of the corresponding acid at pH6.0 strongly suggested that it may be active in vivo because the acidic pH environment is possibly produced during the active inflammation in the lungs of TB patients. However, both metabolism and pharmacokinetic study suggested that JM-24 was rapidly converted to an inactive metabolite M1 (2, 8-bis-trifluoromethylquinoline-4-ol). In order to improve the metabolic stability of this series, chemistry efforts were focused on the modification of the ether linker of JM-24. Compound 25d with an alkene linker turned out to be both more metabolically stable and potent than JM-24, with a MIC of 0.2 muM, only 2-fold higher than that of rifampin. Furthermore, the oral area under the curve (AUC) of compound 25d acid is 70-fold higher than JM-24 acid.;The further chemistry efforts demonstrated that structure activity relationships (SARs) in the ether linker series could not apply to the new alkene linker series. The pharmacophore model indicated that the position(s) for substitution(s) in the alkene linker series played an important rote in the antituberculosis activity, which led to discover potent antituberculosis ligands 25k and 25l. This new series may hold promise to clinical candidates for the treatment of tuberculosis. |
