Abstract
Clofazimine, a member of the riminophenazine class, is one of the few antibiotics that are still active against multidrug-resistant Mycobacterium tuberculosis (M. tuberculosis). However, the clinical utility of this agent is limited by its undesirable physicochemical properties and skin pigmentation potential. With the goal of maintaining potent antituberculosis activity while improving physicochemical properties and lowering skin pigmentation potential, a series of novel riminophenazine derivatives containing a 2-methoxypyridylamino substituent at the C-2 position of the phenazine nucleus were designed and synthesized. These compounds were evaluated for antituberculosis activity against M. tuberculosis H37Rv and screened for cytotoxicity. Riminophenazines bearing a 3-halogen- or 3,4-dihalogen-substituted phenyl group at the N-5 position exhibited potent antituberculosis activity, with MICs ranging from 0.25~0.01 μg/mL. The 3,4-dihalogen- substituted compounds displayed low cytotoxicity, with IC50 values greater than 64 μg/mL. Among these riminophenazines, compound 15 exhibited equivalent in vivo efficacy against M. tuberculosis infection and reduced skin discoloration potential in an experimental mouse infection model as compared to clofazimine. Compound 15, as compared to clofazimine, also demonstrated improved physicochemical properties and pharmacokinetic profiles with a short half-life and less drug tissue accumulation. This compound is being evaluated as a potential drug candidate for the treatment of multidrug resistant tuberculosis.
Highlights
Tuberculosis (TB) has become a global public health emergency due to the rapid development of multidrug-resistant tuberculosis (MDR-TB)
Against M. tuberculosis H37Rv, the majority of compounds exhibited potent activity equal or better than CFZ and TBI-1004 with minimum inhibitory concentration (MIC) values ranging from 0.01 to 0.1 μg/mL. It appears that the number, type and position of the halogen atoms on the phenyl ring at the N-5 position have no significant impact on the antituberculosis activity
A systematic structure-activity relationship study was conducted based on riminophenazine pharmacophore containing a 2-methoxypyridylamino group at the C-2 position
Summary
Tuberculosis (TB) has become a global public health emergency due to the rapid development of multidrug-resistant tuberculosis (MDR-TB). World Health Organization in 2013, an estimated 8.6 million people developed TB and 1.3 million people died from TB in 2012, including 320,000 deaths among HIV-positive people [1]. Some progress has been made to develop new TB drugs. The global TB drug pipeline consists of about 10 new or repurposed drugs in Phase II or Phase III clinical trials. Administration (FDA) for the treatment MDR-TB in more than 40 years [1,2,3]. There is still an urgent need for new and more effective therapy for the treatment MDR-TB and repurposing or optimizing existing antibiotics has been proved an effective approach in identifying new TB drugs [2,4]
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