Diarylquinolines
A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. (1/37)
The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase. (+info)Bactericidal activities of R207910 and other newer antimicrobial agents against Mycobacterium leprae in mice. (2/37)
As measured by a proportional bactericidal technique in the mouse footpad system, the bactericidal activity against Mycobacterium leprae of R207910 was equal to that of rifapentine, rifampin, or moxifloxacin and significantly greater than those of minocycline, PA-824, and linezolid. These data suggest that R207910 may play an important role in treatment of leprosy. (+info)In vitro and in vivo activities of rifampin, streptomycin, amikacin, moxifloxacin, R207910, linezolid, and PA-824 against Mycobacterium ulcerans. (3/37)
Seven antimicrobials were tested in vitro against 29 clinical isolates of Mycobacterium ulcerans. R207910 demonstrated the lowest MIC(50) and MIC(90), followed by moxifloxacin (MXF), streptomycin (STR), rifampin (RIF), amikacin (AMK), linezolid (LZD), and PA-824. All but PA-824 demonstrated an MIC(90) significantly less than the clinically achievable peak serum level. Administered as monotherapy to mice, RIF, STR, AMK, MXF, R207910, and LZD demonstrated some degree of bactericidal activity, whereas PA-824 failed to prevent mortality and to reduce the mean number of CFU in the footpads. Because 4 or 8 weeks of treatment by the combinations RIF-MXF, RIF-R207910, and RIF-LZD displayed bactericidal effects similar to those of RIF-STR and RIF-AMK, these three combinations might be considered as orally administered combined regimens for treatment of Buruli ulcer. Taking into account the cost, potential toxicity, and availability, the combination RIF-MXF appears more feasible for application in the field; additional experiments with mice are warranted to define further its activity against M. ulcerans. In addition, a pilot clinical trial is proposed to test the efficacy of RIF-MXF for treatment of Buruli ulcer. (+info)Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria. (4/37)
The atpE gene encoding the subunit c of the ATP synthase of Mycobacterium tuberculosis, the target of the new diarylquinoline drug R207910, has been sequenced from in vitro mutants resistant to the drug. The previously reported mutation A63P and a new mutation, I66M, were found. The genetic diversity of atpE in 13 mycobacterial species was also investigated, revealing that the region involved in resistance to R207910 is conserved, except in Mycobacterium xenopi in which the highly conserved residue Ala63 is replaced by Met, a modification that may be associated with the natural resistance of M. xenopi to R207910. (+info)Combinations of R207910 with drugs used to treat multidrug-resistant tuberculosis have the potential to shorten treatment duration. (5/37)
The objective of the present study was to identify the optimal R207910-containing regimen to administer to patients who cannot receive rifampin (RIF) and isoniazid (INH) because of multidrug-resistant tuberculosis (MDR-TB), concomitant use of antiretroviral drugs, or toxicity. Mice were infected intravenously with 5 x 10(6) CFU of the H37Rv strain and treated five times per week with R207910 alone or various combinations of R207910 with the second-line drugs amikacin (AMK), pyrazinamide (PZA), moxifloxacin (MXF), and ethionamide (ETH). All R207910-containing regimens were significantly more active than the non-R207910-containing regimens after 1 month of therapy. When given for 2 months, R207910 alone was more active than the WHO standard first-line regimen RIF-INH-PZA. When R207910 was combined with second-line drugs, the combinations were more active than the currently recommended regimen of MDR-TB AMK-ETH-MXF-PZA, and culture negativity of both the lungs and spleen was reached after 2 months of treatment in almost every case. (+info)Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis. (6/37)
In previous studies, the diarylquinoline R207910 (also known as TMC207) was demonstrated to have high bactericidal activity when combined with first- or second-line antituberculous drugs. Here we extend the evaluation of R207910 in the curative model of murine tuberculosis by assessing the activities of one-, two-, and three-drug combinations containing R207910 and isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or moxifloxacin (MXF) in the setting of a high initial bacillary load (7.2 log(10) CFU). Two months of treatment with the combinations R207910-PZA, R207910-PZA-INH, R207910-PZA-RIF, or R207910-PZA-MXF resulted in culture-negative lung homogenates in 70 to 100% of the mice, while mice treated with INH-RIF-PZA (the reference regimen) or RIF-MXF-PZA remained culture positive. Combinations including R207910 but not PZA (e.g., R207910-INH-RIF and R207910-MXF-RIF) were less active than R207910-PZA-containing regimens administered either alone or with the addition of INH, RIF, or MXF. These results reveal a synergistic interaction between R207910 and PZA. Three-drug combinations containing these two drugs and INH, RIF, or MXF have the potential to significantly shorten the treatment duration in patients, provided that these results can be confirmed in long-term experiments including periods of relapse. (+info)Location of persisting mycobacteria in a Guinea pig model of tuberculosis revealed by r207910. (7/37)
The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment. (+info)New tuberculosis therapeutics: a growing pipeline. (8/37)
Novel chemotherapeutic drugs are needed to improve tuberculosis (TB) control, especially in the developing world. Given the magnitude of the problem and the resources available in countries that have the highest burden of disease, the present standards of care for the treatment of drug-susceptible TB, drug-resistant TB, TB/human immunodeficiency virus (HIV) coinfection, and latent TB infection are all unsatisfactory. Because no truly novel compounds for the treatment of TB have been discovered in the past 40 years, the recent enhanced activity in the research and development of new TB drugs is extremely encouraging. Seven compounds are presently in clinical development specifically for the treatment of TB. Other known antibiotic compound families are being investigated preclinically, in an attempt to identify new antimicrobial drugs with specific antituberculous activity. In addition, novel targets have been identified and are the subject of efforts to validate their potential usefulness in the treatment of TB. (+info)Diarylquinolines are a class of synthetic compounds, specifically antimalarial drugs, that contain two aromatic rings connected by a quinoline moiety, with prominent members including pyronaridine and methylene blue.
Diarylquinolines are a class of antimicrobial compounds, which include drugs such as bedaquiline and TBA-354. These agents inhibit mycobacterial ATP synthase and have been used in the treatment of drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB).
Bedaquiline, for example, is a first-in-class diarylquinoline medication that was approved by the US Food and Drug Administration (FDA) in 2012 for use in combination with other antituberculosis drugs to treat adults with pulmonary MDR-TB.
It's important to note that the use of diarylquinolines should be under the guidance of a healthcare professional, as they can have potential side effects and drug interactions.
Diarylquinoline
Diaryl quinolines (DARQs) are a chemical class of drugs that treat tuberculosis. They target subunit c of mycobacterial ATP ... Although ATP synthase in bacteria is similar to its eukaryotic analogue, diarylquinoline agents (such as TMC207) are very ... Metal free synthesis of 2,4-diarylquinoline derivatives with enamides and imines (Articles with short description, Short ... 4-diaryl quinoline (phenyl and naphthyl). US FDA approval in 2012. As of 2014, the only licensed indication of the drug ...
Bedaquiline
June 2009). "The diarylquinoline TMC207 for multidrug-resistant tuberculosis". The New England Journal of Medicine. 360 (23): ... It is the first member of a new class of drugs called the diarylquinolines. Bedaquiline is bactericidal. ATP production is ... It is in the diarylquinoline antimycobacterial class of medications. It works by blocking the ability of M. tuberculosis to ...
ATP synthase subunit C
Diarylquinoline Kühlbrandt W, Davies KM (January 2016). "Rotary ATPases: A New Twist to an Ancient Machine". Trends in ...
Multidrug-resistant tuberculosis
R207910 his a diarylquinoline that has a different mechanism; this drug directly inhibits energy production, so this drug may ... "A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis". Science. 307 (5707): 223-227. Bibcode:2005Sci ...
Tibotec
"A Diarylquinoline Drug Active on the ATP Synthase of Mycobacterium tuberculosis". Science. 307 (5707): 223-7. Bibcode:2005Sci ... an diarylquinoline anti-tuberculosis drug Rilpivirine (TMC278, tradename Edurant), an NNRTI Simeprevir (TMC435, tradename ...
Koen Andries
2005), A diarylquinoline drug active on the ATP-synthase of Mycobacterium tuberculosis, Science 307 (5707): 223-27 Invention: ...
Janssen Pharmaceuticals
... an diarylquinoline anti-tuberculosis drug, discovered by Koen Andries and his team, which promises a shorter and simpler ...
Diarylquinoline - Wikipedia
Diaryl quinolines (DARQs) are a chemical class of drugs that treat tuberculosis. They target subunit c of mycobacterial ATP ... Although ATP synthase in bacteria is similar to its eukaryotic analogue, diarylquinoline agents (such as TMC207) are very ... Metal free synthesis of 2,4-diarylquinoline derivatives with enamides and imines (Articles with short description, Short ... 4-diaryl quinoline (phenyl and naphthyl). US FDA approval in 2012. As of 2014, the only licensed indication of the drug ...
Provisional CDC Guidelines for the Use and Safety Monitoring of Bedaquiline Fumarate (Sirturo) for the Treatment of Multidrug...
Bedaquiline fumarate (Sirturo or bedaquiline) is an oral diarylquinoline. On December 28, 2012, on the basis of data from two ... Bedaquiline, a diarylquinoline, is the first drug with a novel mechanism of action against M. tuberculosis that has been ... The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009;360:2397-405 10.1056/NEJMoa0808427. ...
Rates and mechanisms of resistance development in **Mycobacterium tuberculosis** to a novel diarylquinoline ATP synthase...
Copper(ii) triflate catalyzed three-component reaction for the synthesis of 2,3-diarylquinoline derivatives using aryl amines,...
Ali, S., & Khan, A. T. (2021). Copper(ii) triflate catalyzed three-component reaction for the synthesis of 2,3-diarylquinoline ... Ali, Saghir ; Khan, Abu T. / Copper(ii) triflate catalyzed three-component reaction for the synthesis of 2,3-diarylquinoline ... Ali, S & Khan, AT 2021, Copper(ii) triflate catalyzed three-component reaction for the synthesis of 2,3-diarylquinoline ... Copper(ii) triflate catalyzed three-component reaction for the synthesis of 2,3-diarylquinoline derivatives using aryl amines, ...
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A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307(5707):223-227.. View this ... Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J Biol Chem. 2008;283(37): ... Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria. Antimicrob Agents Chemother. ...
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Sirturo (bedaquiline) dosing, indications, interactions, adverse effects, and more
Diarylquinoline; inhibits mycobacterial adenosine 5-triphosphate (ATP) synthase, an enzyme essential for the generation of ... Diarylquinoline antimycobacterial indicated as part of combination therapy for pulmonary multidrug resistant tuberculosis (MDR- ... Diarylquinoline antimycobacterial indicated as part of combination therapy for pulmonary multidrug resistant tuberculosis (MDR- ...
U.S. FDA Grants Priority Review to Bedaquiline (TMC207) for Multi-Drug Resistant Tuberculosis Treatment | Johnson & Johnson
Frontiers | In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates
BDQ is a diarylquinoline that targets atpE gene, coding for the subunit c of the ATP synthase complex (Andries et al., 2005). ... 2005). A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223-227. doi: 10.1126/ ... new insights into the binding of the diarylquinoline TMC207 to the ATP synthase C-ring structure. Antimicrob. Agents Chemother. ... Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor ...
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The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is used for treatment of drug-resistant ... 2023). Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines. EMBO. J. ... which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria (Courbon ... and high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, ...
Sirturo (bedaquiline) dosing, indications, interactions, adverse effects, and more
Diarylquinoline; inhibits mycobacterial adenosine 5-triphosphate (ATP) synthase, an enzyme essential for the generation of ... Diarylquinoline antimycobacterial indicated as part of combination therapy for pulmonary multidrug resistant tuberculosis (MDR- ... Diarylquinoline antimycobacterial indicated as part of combination therapy for pulmonary multidrug resistant tuberculosis (MDR- ...
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Bedaquiline in Drug-Resistant Tuberculosis: A Mini-Review | Bentham Science
Probing the interaction of the diarylquinoline TMC207 with its target mycobacterial ATP synthase. PLoS One, 2011, 6(8), e23575. ... Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat. Chem. Biol., 2007, 3(6), 323-324.. [http://dx.doi.org/ ... A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science, 2005, 307(5707), 223-227.. [http://dx ...
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Bedaquiline - WikiProjectMed
June 2009). "The diarylquinoline TMC207 for multidrug-resistant tuberculosis". The New England Journal of Medicine. 360 (23): ... It is in the diarylquinoline antimycobacterial class of medications.[1] It works by blocking the ability of M. tuberculosis to ... It is the first member of a new class of drugs called the diarylquinolines.[19] Bedaquiline is bactericidal.[19] ATP production ...
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Gelber R, Andries K, Paredes RM, Andaya CE, Burgos J. The diarylquinoline R207910 is bactericidal against Mycobacterium leprae ... In vitro antimycobacterial spectrum of a diarylquinoline ATP synthase inhibitor. Antimicrob Agents Chemother. 2007;51:4202-4. ... Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis. ...
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Bedaquiline4
- Bedaquiline fumarate (Sirturo or bedaquiline) is an oral diarylquinoline. (cdc.gov)
- Bedaquiline is a diarylquinoline discovered by scientists at Janssen. (jnj.com)
- Bedaquiline is a diarylquinoline antimycobacterial which inhibits the proton transfer chain of mycobacterial ATP synthase, an enzyme necessary for energy generation in Mycobacterium tuberculosis . (azurewebsites.net)
- Sirturo (Bedaquiline)® is a diarylquinoline antimycobacterial drug indicated as part of combination therapy in the treatment of adult and pediatric patients (12 to less than 18 years of age and weighing at least 30 kg) with pulmonary multi-drug resistant tuberculosis (MDR-TB). (pharmacyexam.com)
Antimycobacterial1
- [9] It is in the diarylquinoline antimycobacterial class of medications. (mdwiki.org)
TMC2072
- Although ATP synthase in bacteria is similar to its eukaryotic analogue, diarylquinoline agents (such as TMC207) are very specific to the bacterial enzyme, so were expected to be safe for use in humans and other eukaryotes. (wikipedia.org)
- 6] Diacon AH, Pym A, Grobusch M, et al.The diarylquinoline TMC207 for multidrug-resistant tuberculosis[J]. N Engl J Med, 2009, 360(23): 2397-2405. (rsghb.cn)
Derivatives2
- An efficient and expedient synthetic protocol is reported for the synthesis of 2,3-diarylquinoline derivatives from readily available aryl amines, aryl aldehydes and styrene oxides using 10 mol% copper(ii) triflate by employing three-component reaction. (utmb.edu)
- Ali, S & Khan, AT 2021, ' Copper(ii) triflate catalyzed three-component reaction for the synthesis of 2,3-diarylquinoline derivatives using aryl amines, aryl aldehydes and styrene oxides ', Organic and Biomolecular Chemistry , vol. 19, no. 14, pp. 3255-3262. (utmb.edu)
Reaction1
- citation needed] The reaction of aryl aldehyde, malonodinitrile, and 3‐arylamino‐5,5‐dimethylcyclohex‐2‐enone can produce 1,4-diarylquinolines. (wikipedia.org)
Synthase3
- Although ATP synthase in bacteria is similar to its eukaryotic analogue, diarylquinoline agents (such as TMC207) are very specific to the bacterial enzyme, so were expected to be safe for use in humans and other eukaryotes. (wikipedia.org)
- The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. (nih.gov)
- Diarylquinoline inhibits ATP synthase. (nih.gov)