Identification of Less
Lipophilic Riminophenazine Derivatives for the Treatment of Drug-Resistant
Tuberculosis
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Abstract
Clofazimine (CFZ), a member of the riminophenazine class,
has been studied in clinical trials for the treatment of multidrug-resistant
tuberculosis (MDR-TB). CFZ has several side effects which can be attributed
to its extremely high lipophilicity. A series of novel riminophenazine
analogues bearing a C-2 pyridyl substituent was designed and synthesized
with the goal of maintaining potent activity against Mycobacterium tuberculosis (M. tuberculosis) while improving upon its safety profile by lowering the lipophilicity.
All compounds were evaluated for their in vitro activity and cytotoxicity.
The results demonstrated that many new compounds had potent activity
against M. tuberculosis with MICs of
less than 0.03 μg/mL and low cytotoxicity with IC<sub>50</sub> values greater than 64 μg/mL. Some compounds were tested for
in vivo efficacy against MDR-TB in an experimental mouse infection
model. Two compounds demonstrated equivalent or better efficacy than
CFZ in this model with significantly reduced skin discoloration potential