title: Organocatalytic multicomponent reaction for the acquisition of a selective inhibitor of mPTPB, a virulence factor of tuberculosis.
abstract: Mycobacterium protein tyrosine phosphatase B (mPTPB) is essential for the survival and persistence of Mycobacterium in the host. Thus small molecule inhibitors of mPTPB are potential anti-TB agents. We developed an efficient organocatalytic multicomponent reaction (MCR) between pyrrole, formaldehyde and aniline, affording a potent and selective mPTPB inhibitor with an IC(50) value of 1.5 μM and >50-fold specificity. Our studies provide a successful example of using organocatalysis as a discovery tool for the acquisition of PTP inhibitors.
authors: Department of Biochemistry and Molecular Biology, Chemical Genomics Core Facility, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
authors: Rongjun
authors: R
authors: He
authors: Li-Fan
authors: LF
authors: Zeng
authors: Yantao
authors: Y
authors: He
authors: Li
authors: L
authors: Wu
authors: Andrea Michelle
authors: AM
authors: Gunawan
authors: Zhong-Yin
authors: ZY
authors: Zhang
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005557:Formaldehyde / Q000737:chemistry; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C414465:MptpA protein, Mycobacterium tuberculosis; D011758:Pyrroles; D037521:Virulence Factors; D005557:Formaldehyde; D017027:Protein Tyrosine Phosphatases; C023650:aniline
references: J Am Chem Soc. 2007 Aug 8;129(31):9613-5
references: 17636914
references: Bioorg Med Chem. 2012 Mar 15;20(6):1940-6
references: 22133902
references: Mol Microbiol. 2003 Nov;50(3):751-62
references: 14617138
references: Chemistry. 2004 Oct 25;10(21):5323-31
references: 15390208
references: Drug Discov Today. 2007 Jan;12(1-2):8-27
references: 17198969
references: Angew Chem Int Ed Engl. 2005 Jun 20;44(25):3814-39
references: 15900534
references: Chem Commun (Camb). 2010 Apr 14;46(14):2504-6
references: 20309476
references: Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4573-8
references: 20167798
references: Chem Soc Rev. 2008 Jan;37(1):29-41
references: 18197331
references: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13420-5
references: 9391040
references: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10606-11
references: 16809424
references: Org Biomol Chem. 2007 Apr 7;5(7):1018-20
references: 17377652
references: Chem Soc Rev. 2009 Aug;38(8):2178-89
references: 19623342
references: Angew Chem Int Ed Engl. 2009;48(40):7387-90
references: 19739182
references: J Bacteriol. 2000 Oct;182(19):5425-32
references: 10986245
references: J Am Chem Soc. 2009 Oct 28;131(42):15301-10
references: 19785440
references: Chembiochem. 2005 Oct;6(10):1749-53
references: 16196020
references: Lancet. 2010 Jun 12;375(9731):2100-9
references: 20488518
references: J Org Chem. 2010 Jan 1;75(1):74-85
references: 19954143
references: Lancet. 1976 Dec 18;2(7999):1349-50
references: 63815
references: Org Biomol Chem. 2011 Mar 7;9(5):1277-300
references: 21120241
references: Org Lett. 2002 Jan 24;4(2):217-20
references: 11796054
references: Chem Soc Rev. 2010 Nov;39(11):4402-21
references: 20601998
references: Org Lett. 2009 Nov 19;11(22):5102-5
references: 19852491
references: J Med Chem. 2010 Mar 25;53(6):2333-44
references: 20000419