Identification of Less Lipophilic Riminophenazine Derivatives for the Treatment of Drug-Resistant Tuberculosis

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(50) 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.

Synthesis and Biological Evaluation of Novel 2-Methoxypyridylamino-Substituted Riminophenazine Derivatives as Antituberculosis Agents

“…This series of compounds, exemplified by TBI-1004 (Figure 1), displayed potent antituberculosis activity, reduced lipophilicity, and improved pharmacokinetic profiles as compared to CFZ [8]. We also concluded that an electron-withdrawing group at the para-position of the phenyl ring at the N-5 position was beneficial to antituberculosis activity [9]. Previously, O'Sullivan and coworkers found that compounds bearing a 3,4-dichlorophenyl or 3,4,5-trichlorophenyl group at the N-5 position and a tetramethylpiperidyl group at the C-3 position, such as compound B4100 (Figure 1), possessed improved antituberculosis activity as compared to CFZ [10,11].…”

“…The most compounds were prepared based on the previously published protocols [9,12]. Nitro compounds 2a-d were synthesized from commercially available 2-fluoronitrobenzene (1) and aryl amines via aromatic nucleophilic substitution.…”

“…This agent has demonstrated excellent activity against MDR-TB both in vitro and in vivo, and has been used in clinical trials for the treatment of MDR-TB [6]. We have conducted a systematic structural modification on CFZ to address the skin discoloration problem, which is one of the major obstacles for its clinical use [7][8][9]. We have identified a novel series of riminophenazine derivatives containing a 2-methoxypyridylamino substituent at the C-2 position of the phenazine nucleus.…”

“…Hence, we kept the phenazine nucleus with the 2-methoxypyridylamino group at the C-2 position intact. Our previous work indicated that the 2-methoxypyridylamino group is a privileged moiety [9]. We focused our investigation on the halogen effect of the N-5 phenyl group.…”

Computational Approach for Locating Effective Cyanobacterial Compounds against Mycobacterium Tuberculosis

“…[4][5][6] Mainly, Mtb developed resistance to pyrazinamide with alteration(s) in cell wall synthesis. 7,8 In this scenario, the development of a novel well-tolerated and emulating anti-mycobacterial agent, for the control of MDR, XDR or TDR Mtb, is a dire necessity. Peptidoglycan layer is the major component of Mtb bacterial cell wall providing shape and rigidity, as in eubacteria.…”