The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis
| Autor: | Ruben C. Hartkoorn, Anthony Vocat, Katarína Mikušová, Elena Kazakova, João Neres, Trent M. Conroy, O. B. Ryabova, Jérémie Piton, Michal Šarkan, Vadim Makarov, Stanislav Huszár, Gaëlle S. Kolly, Stewart T. Cole |
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| Předmět: |
Male
medicine.drug_class Stereochemistry Pyridines Antitubercular Agents Thiazines Microbial Sensitivity Tests Biology Antimycobacterial Piperazines Mycobacterium tuberculosis Mice Structure-Activity Relationship Bacterial Proteins In vivo Catalytic Domain medicine Animals Humans Tuberculosis Pharmacology (medical) Experimental Therapeutics Pyrroles Spiro Compounds IC50 ADME Pharmacology Mice Inbred BALB C Hep G2 Cells biology.organism_classification In vitro Alcohol Oxidoreductases Disease Models Animal Infectious Diseases Mechanism of action Covalent bond medicine.symptom |
| Popis: | 8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β- d -ribose 2′-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro . Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml against M. tuberculosis . These compounds inhibit DprE1 with 50% inhibitory concentration (IC 50 ) values of in vitro absorption-distribution-metabolism-excretion/toxicity (ADME/T) and in vivo pharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency. |
| Databáze: | OpenAIRE |
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