- Synthesis and structure-activity relationship of new chalcone linked 5-phenyl-3-isoxazolecarboxylic acid methyl esters potentially active against drug resistant Mycobacterium tuberculosis
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In search of novel therapeutic agents active against emerging drug-resistant Mycobacterium tuberculosis and to counter the long treatment protocol of existing drugs, herein we present synthesis and biological evaluation of a new series of 5-phenyl-3-isoxazolecarboxylic acid methyl ester-chalcone hybrids. Among 35 synthesized compounds, 32 analogues displayed potent in-vitro activity against Mycobacterium tuberculosis H37Rv with MIC 0.12–16 μg/mL. Cell viability test against Vero cells indicated 29 compounds to be non-cytotoxic (CC50 > 20 μg/mL & SI > 10). Most potent compounds with MIC 0.12 μg/mL (7 b, 7j, 7 ab) exhibited selectivity index (SI) in excess of 320. Further studies on activity against drug-resistant Mycobacterium tuberculosis revealed 7j as the most potent compound with MIC 0.03–0.5 μg/mL. Time-kill kinetic study suggested compound 7j displaying concentration-dependent bactericidal killing activity with relatively comparable potency to that of current first-line anti-TB drugs. Taken together, 7j presents a novel hit with potential to be translated into a potent antimycobacterial.
- Sahoo, Santosh Kumar,Rani, Bandela,Gaikwad, Nikhil Baliram,Ahmad, Mohammad Naiyaz,Kaul, Grace,Shukla, Manjulika,Nanduri, Srinivas,Dasgupta, Arunava,Chopra, Sidharth,Yaddanapudi, Venkata Madhavi
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- Rational design of 5-phenyl-3-isoxazolecarboxylic acid ethyl esters as growth inhibitors of Mycobacterium tuberculosis. A potent and selective series for further drug development
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New antituberculosis (anti-TB) drugs are urgently needed to shorten the 6-12month treatment regimen and especially to battle drug-resistant Mycobacterium tuberculosis (Mtb) strains. In this study, we have continued our efforts to develop isoxazole-based a
- Lilienkampf, Annamaria,Pieroni, Marco,Wan, Baojie,Wang, Yuehong,Franzblau, Scott G.,Kozikowski, Alan P.
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scheme or table
p. 678 - 688
(2010/07/06)
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- Protein-tyrosine phosphatase inhibitors and uses thereof
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The present invention is directed to compounds of formula (I), or a pharmaceutically suitable salt or prodrug thereof, which are useful for the selective inhibition of protein tyrosine phosphatase-1B (PTP1B), and are useful for the treatment of disorders caused by overexpressed or altered protein tyrosine phosphatase 1B.
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- Fragment screening and assembly: A highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor
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Using an NMR-based fragment screening and X-ray crystal structure-based assembly, starting with millimolar ligands for both the catalytic site and the second phosphotyrosine binding site, we have identified a small-molecule inhibitor of protein tyrosine phosphatase 1B with low micromolar inhibition constant, high selectivity (30-fold) over the highly homologous T-cell protein tyrosine phosphatase, and good cellular activity in COS-7 cells.
- Liu, Gang,Xin, Zhili,Pei, Zhonghua,Hajduk, Philip J.,Abad-Zapatero, Cele,Hutchins, Charles W.,Zhao, Hongyu,Lubben, Thomas H.,Ballaron, Stephen J.,Haasch, Deanna L.,Kaszubska, Wiweka,Rondinone, Cristina M.,Trevillyan, James M.,Jirousek, Michael R.
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p. 4232 - 4235
(2007/10/03)
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