Design, synthesis and antitubercular evaluation of benzothiazinones containing an oximido or amino nitrogen heterocycle moiety

A series of 8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-ones (BTZs) bearing an oximido or amino nitrogen heterocycle moiety through modifications at the C-2 position of BTZ043 and BPTZ169 were designed and synthesized as new antitubercular agents. Many of the target compounds demonstrate excellent in vitro activity (MIC: <0.016–0.088 μg mL−1) against the drug susceptive H37Rv strain and two clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains. Compound 10a displays acceptable safety, aqueous solubility and pharmacokinetic properties, opening up a new possibility for further development.

[1]  Richard E. Lee,et al.  New agents for the treatment of drug-resistant Mycobacterium tuberculosis. , 2016, Advanced drug delivery reviews.

[2]  Bin Wang,et al.  Synthesis, antimycobacterial and antibacterial activity of 1-(6-amino-3,5-difluoropyridin-2-yl)fluoroquinolone derivatives containing an oxime functional moiety. , 2016, Bioorganic & medicinal chemistry letters.

[3]  S. Swaminathan,et al.  A Note on Derivatives of Isoniazid, Rifampicin, and Pyrazinamide Showing Activity Against Resistant Mycobacterium tuberculosis , 2016, Chemical biology & drug design.

[4]  Minghua Wang,et al.  Synthesis, antimycobacterial and antibacterial activity of fluoroquinolone derivatives containing an 3-alkoxyimino-4-(cyclopropylanimo)methylpyrrolidine moiety. , 2015, European journal of medicinal chemistry.

[5]  Nicola J. Ryan,et al.  Delamanid: First Global Approval , 2014, Drugs.

[6]  T. Buclin,et al.  Towards a new combination therapy for tuberculosis with next generation benzothiazinones , 2014, EMBO molecular medicine.

[7]  Jon Cohen,et al.  Infectious disease. Approval of novel TB drug celebrated--with restraint. , 2013, Science.

[8]  R. Read,et al.  Supplementary Materials for Structural Basis for Benzothiazinone-Mediated Killing of Mycobacterium tuberculosis , 2012 .

[9]  Lian-Shun Feng,et al.  Synthesis and antibacterial activity of naphthyridone derivatives containing mono/difluoro-methyloxime pyrrolidine scaffolds. , 2012, European journal of medicinal chemistry.

[10]  A. Baulard,et al.  Tuberculosis: the drug development pipeline at a glance. , 2012, European journal of medicinal chemistry.

[11]  L. Chiarelli,et al.  Analogous Mechanisms of Resistance to Benzothiazinones and Dinitrobenzamides in Mycobacterium smegmatis , 2011, PloS one.

[12]  P. Li,et al.  Clofazimine Analogs with Efficacy against Experimental Tuberculosis and Reduced Potential for Accumulation , 2011, Antimicrobial Agents and Chemotherapy.

[13]  Vadim Makarov,et al.  Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-β-D-ribose 2'-epimerase DprE1 of Mycobacterium tuberculosis. , 2010, Journal of the American Chemical Society.

[14]  A. Nunn,et al.  Global tuberculosis drug development pipeline: the need and the reality , 2010, The Lancet.

[15]  Stewart T. Cole,et al.  Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis , 2009, Science.

[16]  D. Schraufnagel,et al.  Global action against multidrug-resistant tuberculosis. , 2000, JAMA.

[17]  Y. Kim,et al.  Novel fluoroquinolone antibacterial agents containing oxime-substituted (aminomethyl)pyrrolidines: synthesis and antibacterial activity of 7-(4-(aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6- fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (LB20304). , 1997, Journal of medicinal chemistry.