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Triple-negative breast cancer (TNBC) is a cancer subtype critically dependent upon excessive activation of Wnt pathway. The anti-mycobacterial drug clofazimine is an efficient inhibitor of canonical Wnt signaling in TNBC, reducing tumor cell proliferation in vitro and in animal models. These properties make clofazimine a candidate to become first targeted therapy against TNBC. In this work, we optimized the clofazimine structure to enhance its water solubility and potency as a Wnt inhibitor. After extensive structure-activity relationships investigations, the riminophenazine 5-(4-(chlorophenyl)-3-((2-(piperazin-1-yl)ethyl)imino)-N-(pyridin-3-yl)-3,5-dihydrophenazin-2-amine (MU17) was identified as the new lead compound for the riminophenazine-based targeted therapy against TNBC and Wnt-dependent cancers. Compared to clofazimine, the water-soluble MU17 displayed a 7-fold improved potency against Wnt signaling in TNBC cells resulting in on-target suppression of tumor growth in a patient-derived mouse model of TNBC. Moreover, allowing the administration of reduced yet effective dosages, MU17 displayed no adverse effects, most notably no clofazimine-related skin coloration. ispartof: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol:222 ispartof: location:France status: published

Clofazimine (CLO) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising antituberculosis activity in vitro and in animal models and is currently under phase I clinical development for the treatment of tuberculosis in China. To identify an optimal dosing regimen to support further clinical development of TBI-166, the efficacies of CLO and TBI-166 were evaluated in two aerosol infection models utilizing BALB/c and C3HeB/FeJNju mice. TBI-166 and CLO were dosed at 20 mg/kg daily for 2 weeks, followed by QD (once daily), TIW (thrice weekly), and BIW (twice weekly) for an additional 10 weeks at the same dose level. The bactericidal activities of TBI-166 and clofazimine via QD, TIW, and BIW dosing regimens were determined after treatment. Once-daily administration of CLO and TBI-166 appeared to be more efficacious than the two intermittent dosing regimens. Once-daily administration of TBI-166 increased the bactericidal activity by approximately 1 log(10) CFU in the lung and spleen compared with TIW or BIW dosing after 12 weeks of treatment, while once-daily administration of CLO increased the bactericidal activity by 1.27 to 1.90 log(10) CFU/lung and by 1.61 to 2.22 log(10) CFU/spleen in the BALB/c mouse model compared to the intermittent therapies. The differences between QD and TIW and between QD and BIW were significant (P

Tuberculosis is one of the leading cause of death in the world, mainly due to the increasing number of multidrug‐resistant TB (MDR‐TB) and extensively drug‐resistant TB (XDR‐TB) strains. Factors such as the HIV pandemic contribute further. Also, the ineffectiveness of the chemotherapy in current use increases the mortality rate. Therefore, new and repurposed antituberculosis drugs are urgently needed for the treatment of MDR‐TB, and riminophenazines are among those drugs that are being reinvestigated for their potential in the treatment of TB. This review delivers a brief historical account of riminophenazines, their general synthesis, mechanisms of action, and their physicochemical properties. The discussion is limited to those studies that investigated the activity of these compounds as antituberculosis agents. Given their unique properties, this review will be of great significance in giving direction towards the design and development of new riminophenazine analogues., Riminophenazines innovation: Substituents on the phenazine nucleus afford novel molecules with improved antituberculosis potency. This review outlines developments in the riminophenazine analogues and summarizes synthesis, mechanism of action and physicochemical properties.

Clofazimine (CFZ), an old hydrophobic riminophenazine, has a wide range of antimycobacterial activity ranging from leprosy to nontuberculous mycobacterial diseases. CFZ has several advantages such as a favorable pharmacokinetic profile, dose-dependent side effects as well as low price. In this narrative review, we have assessed the clinical development of CFZ, starting from the potential in vitro mechanism of actions, to the spectrum of side effects and potential drug–drug interactions, highlighting its current place in therapy and future possible use in leprosy, nontuberculous mycobacterial diseases and drug-resistant tuberculosis.

The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog, TBI-166, was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort. Here, we evaluated the activity of TBI-166 against Mycobacterium tuberculosis and its potential to accumulate and discolor skin. The in vitro activity of TBI-166 against both drug-sensitive and drug-resistant M. tuberculosis is more potent than that of CFZ. Spontaneous mutants resistant to TBI-166 were found at a frequency of 2.3 × 10(−7) in wild strains of M. tuberculosis. TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular M. tuberculosis and in low-dose aerosol infection models of acute and chronic murine tuberculosis. Most importantly, TBI-166 causes less skin discoloration than does CFZ despite its higher tissue accumulation. The efficacy of TBI-166, along with its decreased skin pigmentation, warrants further study and potential clinical use.

A set of novel riminophenazine derivatives has been synthesized and evaluated for in vitro activity against chloroquine–sensitive (CQ-S) and chloroquine–resistant (CQ-R) strains of Plasmodium falciparum and against different species of Leishmania promastigotes. Most of the new compounds inhibited the growth of Leishmania promastigotes as well as CQ-S and CQ-R strains of P. falciparum with IC50 in submicromolar range, resulting in the best cases 1–2 orders of magnitude more potent than the parent compound clofazimine.