Structure-Based Drug Design and Characterization of Sulfonyl-Piperazine Benzothiazinone Inhibitors of DprE1 from Mycobacterium tuberculosis

Antimicrobial Agents and Chemotherapy
Jérémie PitonStewart T Cole

Abstract

Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis As part of the MCZ backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile, and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ, and covalent adducts with the active-site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group, no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

References

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Citations

Mar 6, 2019·Current Topics in Medicinal Chemistry·Marcus Vinicius Nora de Souza, Thais Cristina Mendonça Nogueira
Apr 2, 2020·Frontiers in Pharmacology·Abed El-Hakim El-KadiryMoutih Rafei
Aug 29, 2018·Antimicrobial Agents and Chemotherapy·Jin ShiYu Pang
Nov 17, 2020·European Journal of Medicinal Chemistry·Pankaj S GiraseRajshekhar Karpoormath
Jan 20, 2021·Medicinal Chemistry Research : an International Journal for Rapid Communications on Design and Mechanisms of Action of Biologically Active Agents·Gang ZhangCourtney C Aldrich
Apr 20, 2021·ACS Omega·Vallabhaneni S MurthyVijayaparthasarathi Vijayakumar
May 1, 2021·Pharmaceutics·Filia StephanieUsman Sumo Friend Tambunan
Jun 30, 2021·Current Opinion in Pharmacology·Michele MondoniGiovanni Sotgiu
Jul 31, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Vallabhaneni S MurthyVijayaparthasarathi Vijayakumar
Oct 6, 2021·Journal of Medicinal Chemistry·Dongguang FanChunhua Qiao

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Software Mentioned

Hyperchem
SwissADME webserver
Prism
GraphPad
coot
XDS
MCZ
SwissADME
GraphPad Prism
PHENIX

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