- The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition
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In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R2 site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC50 > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.
- Chen, Hui,Wang, Bin,Li, Peng,Yan, Hong,Li, Gang,Huang, Haihong,Lu, Yu
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supporting information
(2021/03/26)
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- Synthesis and structure-activity relationships of antitubercular 2-nitroimidazooxazines bearing heterocyclic side chains
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Recently described biphenyl analogues of the antituberculosis drug PA-824 displayed improved potencies against M. tuberculosis but were poorly soluble. Heterobiaryl analogues of these, in which the first phenyl ring was replaced with various 5-membered ring heterocycles, were prepared with the aim of identifying potent new candidates with improved aqueous solubility. The compounds were constructed by coupling the chiral 2-nitroimidazooxazine alcohol with various halomethyl-substituted arylheterocycles, by cycloadditions to a propargyl ether derivative of this alcohol, or by Suzuki couplings on haloheterocyclic methyl ether derivatives. The arylheterocyclic compounds were all more hydrophilic than their corresponding biphenyl analogues, and several showed solubility improvements. 1-Methylpyrazole, 1,3-linked-pyrazole, 2,4-linked-triazole, and tetrazole analogues had 3- to 7-fold higher MIC potencies against replicating M. tb than predicted by their lipophilicities. Two pyrazole analogues were >10-fold more efficacious than the parent drug in a mouse model of acute M. tb infection, and one displayed a 2-fold higher solubility. 2009 American Chemical Society.
- Sutherland, Hamish S.,Blaser, Adrian,Kmentova, Iveta,Franzblau, Scott G.,Wan, Baojie,Wang, Yuehong,Ma, Zhenkun,Palmer, Brian D.,Denny, William A.,Thompson, Andrew M.
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experimental part
p. 855 - 866
(2010/06/15)
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- Synthesis of Pyrazolo[3,4-c][1,2]thiazin-4(3H)-one 2,2-Dioxides, New Heterocycles
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The reaction of substituted ethyl 5-aminopyrazole-4-carboxylatcs with two equivalents of methanesulfonyl chloride gave the substituted ethyl 5-[bis(methylsufonyl)amino]-1H-pyrazole-4-carboxylates II. Removal of one of the methanesulfonyl groups, followed
- Coppo, Frank T.,Fawzi, Maged M.
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p. 1693 - 1697
(2007/10/03)
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