- 8-cyanobenzothiazinone analogs with potent antitubercular activity
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8-Nitrobenzothiazinones (BTZs) exemplified by macozinone are a new class of antitubercular agents with exceptionally potent activity. The aryl nitro group has been considered indispensable for activity since this is bioactivated within mycobacteria by the flavoenzyme DprE1 to a reactive nitroso metabolite that covalently labels Cys387. However, the aryl nitro group is a potential liability with regards to safety, stability, and resistance. In this paper, we introduced a nitrile as a bioisosteric replacement of the nitro group, which we hypothesize can maintain a similar covalent mechanism of inhibition, but mitigate against the aforementioned concerns. 8-cyanobenzothiazinone 1d displayed potent antitubercular activity with an MIC of 130 nM and had an improved volume of distribution in mice that increased the intrinsic half-life by twofold compared to macozinone. Analysis of the C-2 substituent of 1d revealed similar structure–activity relationships as observed for macozinone. Overall, the results confirm the 8-nitro group of benzothiazinones can be successfully replaced with a nitrile to retain useful activity and favorable pharmacokinetic properties. [Figure not available: see fulltext.].
- Zhang, Gang,Sheng, Li,Hegde, Pooja,Li, Yan,Aldrich, Courtney C.
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- Benzothiazinone derivative with 6-position substituted with trifluoromethyl as well as preparation method and application thereof
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The invention discloses a benzothiazinone derivative with the 6-position substituted with trifluoromethyl as well as a preparation method and application of the benzothiazinone derivative. According to the invention, benzene ring of a benzothiazinone framework is creatively changed, particularly a substituent group is creatively changed, a series of compounds are obtained, and unexpected technical effects are achieved; and specifically, compared with other benzothiazinone derivatives, the benzothiazinone derivative with the 6-position substituted with trifluoromethyl is more stable to liver microsomal enzyme, the metabolic half-life period T1/2 is longer, and the water solubility is better.
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Paragraph 0010; 0018
(2021/07/17)
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- Benzoxazinone derivatives and their use as antibacterial agents
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The invention discloses benzoxazinone derivatives, a synthesis method and applications thereof. The derivatives can be used as an antibacterial agent for treating infectious diseases caused by bacteria, especially tuberculosis (TB) caused by mycobacterium. Specifically, the invention relates to compounds represented by the formula (I), pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the provided compounds; wherein the R1 to R4 are defined in the description. The invention aim to prepare novel compounds capable of inhibiting the mycobacterium activity, the compounds can be used as a potential novel drug for treating infectious diseases caused by bacteria, moreover, the compounds can be used to treat or prevent tuberculosis (TB) caused by mycobacterium, at the same time the problems related with drug resistance can be solved, and the drug metabolism property can be improved on the basis that the mycobacterium tuberculosis resistant activity is not influenced.
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Paragraph 0113-0116
(2018/09/12)
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- BENZOTHIAZINONE DERIVATIVES AS ANTI -TUBERCULOSIS AGENTS
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Novel benzothiazinone derivatives of formula (I) or pharmaceutically acceptable salts or solvates thereof have been found to be effective against Mycobacterium tuberculosis strains and may thus be useful in the treatment of tuberculosis: wherein EWG (electron withdrawing group) = NO2, CN, CF3, F, Cl, Br, OCF3, OH, OR, OCHF2, COOR, wherein R is hydrogen or a straight or branched C1-C4 alkyl group, X = a bond or a straight or branched C1-C4 alkylene group which may be substituted with a group selected from F, Cl, Br, I or C1-C4 alkoxy; Y = hydrogen, a straight or branched C1-C4 alkyl group, OH or OR, wherein R is hydrogen or a straight or branched C1-C4 alkyl group; n = 0, 1 or 2; R1, R2 = hydrogen or substituent (s) which may be the same or different from each other and are selected from the group consisting of D, F, Cl, Br, CF3, a straight or branched C1-C4 alkyl group, a phenyl group, OR, SR, NR3R4, wherein R, R3, R4 may be the same or different from each other and are hydrogen or a straight or branched C1-C4 alkyl group or a phenyl group.
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Page/Page column 12
(2013/03/28)
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- Benzothiazinone compounds and their use as anti-tuberculosis agents
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Novel benzothiazinone derivatives of formula (I) or a pharmaceutically acceptable salt or solvate thereof have been found to be effective against Mycobacterium tuberculosis strains and may thus be useful in the treatment of tuberculosis
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Page/Page column 6-7
(2012/07/03)
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- NOVEL ANTI-TUBERCULOSIS AGENTS
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Novel benzothiazinone derivatives of formula (I) or a pharmaceutically acceptable salt or solvate thereof have been found to be effective against Mycobacterium tuberculosis strains and may thus be useful in the treatment of tuberculosis (I) wherein, EWG (electron withdrawing group) = N02, CN, CF3, F, CI, Br, OCF3, OH, OR, OCHF2, COOR, wherein R is hydrogen, or a straight or branched C1-C4 alkyl group, X = a bond, or a straight or branched C1-C4 alkylene group; Y = a bond, or a straight or branched C1-C4 alkylene group; wherein either one of X or Y is a bond and the other is a Ci-C4-alkylene group, Z = N or C, n = 1 or 2; R1 = hydrogen, a straight or branched C1-C6 alkyl group, or a C3-C6 cycloalkyl group, which may be substituted with a group selected from F, CI, Br, I or a C1-C4 alkoxy; R2 = a phenyl group, a naphthyl group or a thienyl group, each of which may be unsubstituted or substituted with one or more substituent(s) which may be the same or different from each other, selected from the group consisting of F, CI, Br, I, CN, NO2, or a straight or branched C1-C6 alkyl or phenyl group, which may be substituted with a group selected from F, CI, Br, I, or C1-C4 alkoxy.
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Page/Page column 7
(2012/07/13)
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- TRIFLUOROMETHYLBENZAMIDE DERIVATIVES AND THERAPEUTIC USES THEREOF
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Compounds of the formula (I), in which the radicals R1 to R3 and AR are as defined in the description, processes for the preparation thereof, the use thereof in the treatment of cardiovascular diseases, and pharmaceutical compositions comprising them.
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Page/Page column 19
(2008/06/13)
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- Substituted diphenyl ethers
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A compound of the formula: STR1 and salts and esters thereof, useful as intermediates for the preparation of compounds of the formula STR2 wherein R1 is an alkyl group optionally substituted by one or more fluorine atoms or by an optionally substituted phenyl group R2 is No2 or Cl and R6 is a hydrogen atom or an alkyl group of 1 to 4 carbon atoms.
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