- Reinvestigation of the structure-activity relationships of isoniazid
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Isoniazid (INH) remains a cornerstone for treatment of drug susceptible tuberculosis (TB), yet the quantitative structure-activity relationships for INH are not well documented in the literature. In this paper, we have evaluated a systematic series of INH analogs against contemporary Mycobacterium tuberculosis strains from different lineages and a few non-tuberculous mycobacteria (NTM). Deletion of the pyridyl nitrogen atom, isomerization of the pyridine nitrogen to other positions, replacement of the pyridine ring with isosteric heterocycles, and modification of the hydrazide moiety of INH abolishes antitubercular activity. Similarly, substitution of the pyridine ring at the 3-position is not tolerated while substitution at the 2-position is permitted with 2-methyl-INH 9 displaying antimycobacterial activity comparable to INH. To assess the specific activity of this series of INH analogs against mycobacteria, we assayed them against a panel of gram-positive and gram-negative bacteria, as well as a few fungi. As expected INH and its analogs display a narrow spectrum of activity and are inactive against all non-mycobacterial strains evaluated, except for 4, which has modest inhibitory activity against Cryptococcus neoformans. Our findings provide an updated analysis of the structure-activity relationship of INH that we hope will serve as useful resource for the community.
- Hegde, Pooja,Boshoff, Helena I.M.,Rusman, Yudi,Aragaw, Wassihun Wedajo,Salomon, Christine E.,Dick, Thomas,Aldrich, Courtney C.
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- 3. 6 - Disubstituted [1, 2, 4] triazolo [3, 4 - b] [1, 3, 4] thiadiazole compound and use thereof
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The invention discloses 3,6-disubstituted[1,2,4]triazolyl[3,4-b][1,3,4]thiadiazole compounds represented by general formula (I), and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof. The compounds can be used as a transpeptidase SrtA inhibitor of Staphylococcus aureus, Bacillus pyogenes, Bacillus anthracis, Streptococcus pneumoniae and other Gram-positive bacteria, and can be used to prepare drugs for treating pathogen infection diseases with the transpeptidase SrtA of the Gram-positive bacteria, such as Staphylococcus aureus, Bacillus pyogenes, Bacillus anthracis and Streptococcus pneumoniae as target. The compounds avoid selection pressure induced drug resistance of pathogens to a certain degree, and mitigate threat of continuous drug-resistant pathogens to the health of human.
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Paragraph 0070
(2018/11/22)
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- Design, synthesis, and pharmacological and pharmacokinetic evaluation of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives as xanthine oxidoreductase inhibitors
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In an effort to find a potent xanthine oxidoreductase (XO) inhibitor, we discovered the best compound 2-[2-(2-methoxy-ethoxy)-ethoxy]-5-[5-(2-methyl-pyridin-4-yl)-1H-[1,2,4]triazol-3-yl]-benzonitrile 28. Here, we describe the following: (1) the design, synthesis, and structure-activity relationship of a series of 3-phenyl-5-pyridyl-1,2,4-triazole derivatives by in vitro studies of XO inhibitory activity in bovine milk and in vivo studies of serum uric acid (UA) reductive activity in rats, (2) a drug interaction study by a cytochrome P450 3A4 (CYP3A4) assay, and (3) a pharmacokinetic (PK) study. Compound 28 exhibits potent XO inhibitory activity, serum UA-lowering activity in rats, weak CYP3A4 inhibitory activity, and moderate PK profile.
- Sato, Takahiro,Ashizawa, Naoki,Iwanaga, Takashi,Nakamura, Hiroshi,Matsumoto, Koji,Inoue, Tsutomu,Nagata, Osamu
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scheme or table
p. 184 - 187
(2009/05/26)
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- Discovery of 3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051-a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia
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Our previous study identified 2-[2-(2-methoxy-ethoxy)-ethoxy]-5-[5-(2-methyl-4-pyridyl)-1H-[1,2,4]triazol-3-yl]-benzonitrile (2) as a safe and potent xanthine oxidoreductase (XOR) inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(3-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole (FYX-051, compound 39) to be one of the most potent XOR inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4-inhibitory activity and a better pharmacokinetic profile than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial.
- Sato, Takahiro,Ashizawa, Naoki,Matsumoto, Koji,Iwanaga, Takashi,Nakamura, Hiroshi,Inoue, Tsutomu,Nagata, Osamu
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experimental part
p. 6225 - 6229
(2010/07/02)
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- MGluR5 modulators IV
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The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
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Page/Page column 12
(2008/06/13)
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- mGluR5 modulators III
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The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
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Page/Page column 14
(2008/06/13)
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- POLYHETEROCYCLIC COMPOUNDS AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR ANTAGONISTS
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The present invention relates to new compounds of formula (I), wherein P, Q, X1, X2, X3, X4, X5, X6, R1, R2, R3, m, n, and p are as defined as in formula (I), or salts, or hydrates thereof, processes for their preparation and new intermediates used in the preparation thereof, pharmaceutical compositions containing said compounds and to the use of said compounds in therapy.
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Page/Page column 68-69
(2010/02/13)
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- NEW COMPOUNDS
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The present invention relates to new compounds of formula I, (I) a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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Page 138-139
(2010/02/06)
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