- Discovery of a Novel Mycobacterial F-ATP Synthase Inhibitor and its Potency in Combination with Diarylquinolines
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The F1FO-ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.
- Anbarasu, Sivaraj,Bates, Roderick W.,Dick, Thomas,Dr?ge, Peter,Grüber, Gerhard,Harikishore, Amaravadhi,Hotra, Adam,Kalia, Nitin Pal,Kalyanasundaram, Revathy,Lakshmanan, Umayal,Makhija, Harshyaa,Ng, Pearly Shuyi,Parthasarathy, Krupakar,Pethe, Kevin,Poulsen, Anders,Pradeep, Chaudhari Namrata,Ragunathan, Priya,Sae-Lao, Patcharaporn,Sarathy, Jickky Palmae,Saw, Wuan-Geok,Seankongsuk, Pattarakiat,Shin, Joon,Tan, Jocelyn Hui Ling
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p. 13295 - 13304
(2020/06/03)
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- PYRIMIDINE FGFR4 INHIBITORS
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Provided herein are compounds of Formula I useful as FGFR4 inhibitors, as well as methods of use of the same.
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Page/Page column 110
(2015/05/05)
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- NOVEL PROCESSES FOR THE PREPARATION OF CYCLOPROPYL-AMIDE DERIVATIVES
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The present invention is directed to novel processes for the preparation of cyclopropyl-amide derivatives, useful for the treatment of disorders and conditions mediated by the histamine receptor.
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Page/Page column 49
(2010/11/27)
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- NOVEL PROCESSES FOR THE PREPARATION OF PIPERAZINYL AND DIAZAPANYL BENZAMIDE DERIVATIVES
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The present invention is directed to novel processes for the preparation of substituted piperazinyl and diazepanyl benzamides, useful for the treatment of disorders and conditions mediated by the histamine receptor.
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Page/Page column 70
(2010/11/27)
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- PIPERAZINYL AND DIAZAPANYL BENZAMIDES AND BENZTHIOAMIDES
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Substituted piperazinyl and diazepanyl benzamides and benzthioamides of formula (I), compositions containing them, and methods of making and using them to treat histamine-mediated conditions.
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- Structure-activity relationships of the quinolone antibacterials against mycobacteria: Effect of structural changes at N-1 and C-7
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The re-emergence of tuberculosis infections which are resistant to conventional drug therapy has demonstrated the need for alternative chemotherapy against Mycobacterium tuberculosis. As part of a study to optimize the quinolone antibacterials against M. tuberculosis, we have prepared a series of N-1- and C-7-substituted quinolones to examine specific structure-activity relationships between modifications of the quinolone at these two positions and activity against mycobacteria. The compounds, synthesized by literature procedures, were evaluated for activity against Mycobacterium fortuitum and Mycobacterium smegmatis as well as Gram-negative and Gram-positive bacteria. The activity of the compounds against M. fortuitum was used as a barometer of M. tuberculosis activity. The results demonstrate that (i) the activity against mycobacteria was related more to antibacterial activity than to changes in the lipophilicity of the compounds, (ii) the antimycobacterial activity imparted by the N-1 substituent was in the order tert-butyl ≥ cyclopropyl > 2,4-difluorophenyl > ethyl ? cyclobutyl > isopropyl, and (iii) substitution with either piperazine or pyrrolidine heterocycles at C-7 afforded similar activity against mycobacteria.
- Renau,Sanchez,Gage,Dever,Shapiro,Gracheck,Domagala
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p. 729 - 735
(2007/10/03)
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