Abstract
New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates. Importantly, no antagonism interaction was found with any two-drug combinations tested in the present study and the combination of SKLB-TB1001 with rifampicin (RMP) was proved to be synergistic. Furthermore, benzothiazinethione showed superb in vivo antitubercular efficacy in an acute Mtb infection mouse model, significantly better than that of BTZ043. These data combined with the bioavailability and safety profiles of benzothiazinethione indicates SKLB-TB1001 is a promising preclinical candidate for the treatment of drug-resistant tuberculosis.
Highlights
IntroductionMost advanced scaffold among these NCEs. And BTZ043, which acts by forming a covalent bond with Cys[387] in the active site pocket of DprE1, is nearing phase I clinical trials with a Minimum inhibitory concentrations (MICs) of 1 ng/mL20
We investigated a series of compounds with representative properties and used the microplate alamar blue assay to screen for activity against M. tuberculosis (Supplementary Table S1)
DprE1 enzyme and Benzothiazinone analogues have displayed some promising results for tuberculosis treatments
Summary
Most advanced scaffold among these NCEs. And BTZ043, which acts by forming a covalent bond with Cys[387] in the active site pocket of DprE1, is nearing phase I clinical trials with a MIC of 1 ng/mL20. The pre-clinical candidate arose from lead optimizations, PBTZ169, has shown great promise for the treatment of tuberculosis and is poised to enter clinical trials[27]. The SAR studies and the detailed mechanistic studies indicate that the NO2 group at position 8 and the sulfur atom at position 1 were critical for activity and the trifluoromethyl at position 6 plays an important role in maintaining anti-tubercular activity[20,28,29,30]. Inspired by the promising results from BTZ043, PBTZ169 and the antitubercular potential of the sulfur rich heterocycles in our earlier studies, we explored the antitubercular potential of a new sulfureous scaffold benzothiazinethione
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