Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis

Bin-na, Liu; Li, Kai; Lu, Yu; Zhang, Dongfeng; Yang, Taowei; Li, Xuan; Ma, Chen; Zheng, Meiqin; Wang, Bin; Zhang, Gang; Wang, Fei; Ma, Zhenkun; Li, Chun; Huang, Haihong; Yin, Daqiang

doi:10.3390/molecules17044545

Cited by 23 publications

(25 citation statements)

References 8 publications

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“…An excessively long half-life (t 1/2 ) (over 70 days in humans) and accumulation in fat and skin tissues lead to unwelcome skin discoloration (16)(17)(18). A systematic structure-activity study of more than 500 newly synthesized CFZ analogs was conducted to identify new generation compounds with equivalent or better efficacy than CFZ and at the same time incur reduced skin pigmentation potential (19)(20)(21).…”

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confidence: 99%

In Vitro and In Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis

Wang

et al. 2019

Antimicrob Agents Chemother

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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 ϫ 10 Ϫ7 in wild strains of M. tuberculosis. TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular M. tuberculosis and in lowdose 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.

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confidence: 99%

In Vitro and In Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis

Wang

et al. 2019

Antimicrob Agents Chemother

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“…However, it reduces the macrophage half-life, which might lead to reduction of bacterial clearance, and produces minor adverse effects. Still, several analogs have shown improved properties and reduced adverse effects that could be used in the drugs combination [115].…”

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confidence: 99%

Considerations on clinical trials of leprosy treatment: need of novel drug combinations

Illarramendi¹,

Oliveira²,

Sales³

et al. 2013

Clinical Investigation

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Considering that after 30 years of using multidrug therapy (MDT), leprosy eradication has still not been achieved, leprosy treatment must remain on the drug discovery agenda. Due to the complexities inherent in leprosy disease and the many methodological issues involved in clinical trials, the task of translating the bench findings into clinical practice has been arduous. While the effectiveness of reducing the currently recommended MDT remains controversial, a number of highly bactericidal antibiotics and immune-modulatory drugs have emerged as prospective candidates to improve patient adherence and quality of life, reduce adverse effects and prevent resistance. To replace the standard WHO-MDT, the new combination must be the shortest, simplest and, consequently, most affordable treatment possible.

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“…However, if phenyl ring at C‐2 position is substituted by a pyridyl group lipophilicity decreases and potency increases. The decrease in lipophilicity reduces the pigmentation potential . Substituting the same C‐2 position with a methoxypyridylamino group improves pharmacokinetics with retention of potency.…”

Section: Clofaziminementioning

confidence: 99%

“…The decrease in lipophilicity reduces the pigmentation potential. 175 Substituting the same C-2 position F I G U R E 1 0 Structure-activity relationship of clofazimine. TB, tuberculosis with a methoxypyridylamino group improves pharmacokinetics with retention of potency.…”

Section: Structure-activity Relationship Of Clofaziminementioning

confidence: 99%

An overview of new antitubercular drugs, drug candidates, and their targets

Bahuguna

Rawat

2019

Medicinal Research Reviews

131

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The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug‐resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four‐drug treatment regimen was introduced 40 years ago but the emergence of multidrug‐resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti‐TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug‐target interactions, and their structure‐activity relationship.

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Systematic Evaluation of Structure-Activity Relationships of the Riminophenazine Class and Discovery of a C2 Pyridylamino Series for the Treatment of Multidrug-Resistant Tuberculosis

Cited by 23 publications

References 8 publications

In Vitro and In Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis

In Vitro and In Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis

Considerations on clinical trials of leprosy treatment: need of novel drug combinations

An overview of new antitubercular drugs, drug candidates, and their targets

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