Efficient Synthesis of Benzothiazinone Analogues with Activity Against Intracellular Mycobacterium Tuberculosis

Overview

Journal ChemMedChem

Specialties Chemistry
Pharmacology

Date 2021 Dec 23

PMID 34939744

Citations 4

Authors

Adrian Richter

Gagandeep Narula

Ines Rudolph

Rudiger W Seidel

Christoph Wagner

Yossef Av-Gay

Peter Imming

Affiliations

Soon will be listed here.

Abstract

8-Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence-based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high-throughput macrophage infection assay.

Citing Articles

A Comparative Pharmacokinetics Study of Orally and Intranasally Administered 8-Nitro-1,3-benzothiazin-4-one (BTZ043) Amorphous Drug Nanoparticles.

Li F, Marwitz F, Rudolph D, Gauda W, Cohrs M, Neumann P ACS Pharmacol Transl Sci. 2024; 7(12):4123-4134.

PMID: 39698258 PMC: 11651166. DOI: 10.1021/acsptsci.4c00558.

Recent Advances of DprE1 Inhibitors against : Computational Analysis of Physicochemical and ADMET Properties.

Amado P, Woodley C, Cristiano M, ONeill P ACS Omega. 2022; 7(45):40659-40681.

PMID: 36406587 PMC: 9670723. DOI: 10.1021/acsomega.2c05307.

BTZ-Derived Benzisothiazolinones with In Vitro Activity against .

Richter A, Seidel R, Goddard R, Eckhardt T, Lehmann C, Dorner J ACS Med Chem Lett. 2022; 13(8):1302-1310.

PMID: 35982823 PMC: 9380706. DOI: 10.1021/acsmedchemlett.2c00215.

Efficient Synthesis of Benzothiazinone Analogues with Activity against Intracellular Mycobacterium tuberculosis.

Richter A, Narula G, Rudolph I, Seidel R, Wagner C, Av-Gay Y ChemMedChem. 2021; 17(6):e202100733.

PMID: 34939744 PMC: 9303563. DOI: 10.1002/cmdc.202100733.

References

Stossel A, Schlenk M, Hinz S, Kuppers P, Heer J, Gutschow M . Dual targeting of adenosine A(2A) receptors and monoamine oxidase B by 4H-3,1-benzothiazin-4-ones. J Med Chem. 2013; 56(11):4580-96. DOI: 10.1021/jm400336x. View

Larsson M, Lerm M, Angeby K, Nordvall M, Jureen P, Schon T . A luciferase-based assay for rapid assessment of drug activity against Mycobacterium tuberculosis including monitoring of macrophage viability. J Microbiol Methods. 2014; 106:146-150. DOI: 10.1016/j.mimet.2014.08.015. View

Brecik M, Centarova I, Mukherjee R, Kolly G, Huszar S, Bobovska A . DprE1 Is a Vulnerable Tuberculosis Drug Target Due to Its Cell Wall Localization. ACS Chem Biol. 2015; 10(7):1631-6. DOI: 10.1021/acschembio.5b00237. View

Trefzer C, Rengifo-Gonzalez M, Hinner M, Schneider P, Makarov V, Cole S . Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-β-D-ribose 2'-epimerase DprE1 of Mycobacterium tuberculosis. J Am Chem Soc. 2010; 132(39):13663-5. DOI: 10.1021/ja106357w. View

Collins J, Blanchard S, Boswell G, Charifson P, Cobb J, Henke B . N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 2. Structure-activity relationship and optimization of the phenyl alkyl ether moiety. J Med Chem. 1998; 41(25):5037-54. DOI: 10.1021/jm980413z. View

Sorrentino F, Gonzalez Del Rio R, Zheng X, Presa Matilla J, Torres Gomez P, Martinez Hoyos M . Development of an Intracellular Screen for New Compounds Able To Inhibit Mycobacterium tuberculosis Growth in Human Macrophages. Antimicrob Agents Chemother. 2015; 60(1):640-5. PMC: 4704166. DOI: 10.1128/AAC.01920-15. View

Peng C, Gao C, Wang N, You X, Zhang L, Zhu Y . Synthesis and antitubercular evaluation of 4-carbonyl piperazine substituted 1,3-benzothiazin-4-one derivatives. Bioorg Med Chem Lett. 2015; 25(7):1373-6. DOI: 10.1016/j.bmcl.2015.02.061. View

Chauhan A, Kumar M, Kumar A, Kanchan K . Comprehensive review on mechanism of action, resistance and evolution of antimycobacterial drugs. Life Sci. 2021; 274:119301. DOI: 10.1016/j.lfs.2021.119301. View

Eckhardt T, Goddard R, Lehmann C, Richter A, Sahile H, Liu R . Crystallographic evidence for unintended benzisothiazolinone 1-oxide formation from benzothiazinones through oxidation. Acta Crystallogr C Struct Chem. 2020; 76(Pt 9):907-913. PMC: 7474187. DOI: 10.1107/S2053229620010931. View

10.

Karoli T, Becker B, Zuegg J, Mollmann U, Ramu S, Huang J . Identification of antitubercular benzothiazinone compounds by ligand-based design. J Med Chem. 2012; 55(17):7940-4. DOI: 10.1021/jm3008882. View

11.

Richter A, Rudolph I, Mollmann U, Voigt K, Chung C, Singh O . Novel insight into the reaction of nitro, nitroso and hydroxylamino benzothiazinones and of benzoxacinones with Mycobacterium tuberculosis DprE1. Sci Rep. 2018; 8(1):13473. PMC: 6128881. DOI: 10.1038/s41598-018-31316-6. View

12.

Macrae C, Sovago I, Cottrell S, Galek P, McCabe P, Pidcock E . : from visualization to analysis, design and prediction. J Appl Crystallogr. 2020; 53(Pt 1):226-235. PMC: 6998782. DOI: 10.1107/S1600576719014092. View

13.

Madikizela B, Eckhardt T, Goddard R, Richter A, Lins A, Lehmann C . Synthesis, structural characterization and antimycobacterial evaluation of several halogenated non-nitro benzothiazinones. Med Chem Res. 2021; 30(8):1523-1533. PMC: 8192043. DOI: 10.1007/s00044-021-02735-4. View

14.

Lupien A, Vocat A, Foo C, Blattes E, Gillon J, Makarov V . Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169). Antimicrob Agents Chemother. 2018; 62(11). PMC: 6201121. DOI: 10.1128/AAC.00840-18. View

15.

Mdluli K, Kaneko T, Upton A . The tuberculosis drug discovery and development pipeline and emerging drug targets. Cold Spring Harb Perspect Med. 2015; 5(6). PMC: 4448709. DOI: 10.1101/cshperspect.a021154. View

16.

Zhang , Chung , OLDENBURG . A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J Biomol Screen. 2000; 4(2):67-73. DOI: 10.1177/108705719900400206. View

17.

Richter A, Narula G, Rudolph I, Seidel R, Wagner C, Av-Gay Y . Efficient Synthesis of Benzothiazinone Analogues with Activity against Intracellular Mycobacterium tuberculosis. ChemMedChem. 2021; 17(6):e202100733. PMC: 9303563. DOI: 10.1002/cmdc.202100733. View

18.

Makarov V, Manina G, Mikusova K, Mollmann U, Ryabova O, Saint-Joanis B . Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science. 2009; 324(5928):801-4. PMC: 3128490. DOI: 10.1126/science.1171583. View

19.

Stanley S, Barczak A, Silvis M, Luo S, Sogi K, Vokes M . Identification of host-targeted small molecules that restrict intracellular Mycobacterium tuberculosis growth. PLoS Pathog. 2014; 10(2):e1003946. PMC: 3930586. DOI: 10.1371/journal.ppat.1003946. View

20.

Sun J, Lau A, Wang X, Liao T, Zoubeidi A, Hmama Z . A broad-range of recombination cloning vectors in mycobacteria. Plasmid. 2009; 62(3):158-65. DOI: 10.1016/j.plasmid.2009.07.003. View