Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents

Liu, Lingfeng; Kong, Chengcheng; Fumagalli, Marco; Savková, Karin; Xu, Yiwen; Huszár, Stanislav; Sammartino, José Camilla; Fan, Dongguang; Chiarelli, Laurent R.; Mikušová, Katarı́na; Sun, Zhonghe; Qiao, Chunhua

doi:10.1016/j.ejmech.2020.112773

Cited by 26 publications

(22 citation statements)

References 22 publications

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“…This phenotype was described for other DprE1 inhibitors and can be attributed to the deficiency in the synthesis of the arabinan polymer in bacteria upon drug treatment. In this situation, the mycolic acids lack an acceptor in the mycobacterial cell wall core and therefore they accumulate in the form of extractable lipids TMM and TDM. , These data suggest that compounds 6 and 38 are acting by the inhibition of the DprE1 target in M. tuberculosis H37Rv.…”

Section: Results and Discussionmentioning

confidence: 98%

Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents

et al. 2021

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The benzothiazinone (BTZ) scaffold compound PBTZ169 kills Mycobacterium tuberculosis by inhibiting the essential flavoenzyme DprE1, consequently blocking the synthesis of the cell wall component arabinans. While extraordinarily potent against M. tuberculosis with a minimum inhibitory concentration (MIC) less than 0.2 ng/mL, its low aqueous solubility and bioavailability issues need to be addressed. Here, we designed and synthesized a series of 6-methanesulfonyl substituted BTZ analogues; further exploration introduced five-member aromatic heterocycles as linkers to attach an aryl group as the side chain. Our work led to the discovery of a number of BTZ derived compounds with potent antitubercular activity. The optimized compounds 6 and 38 exhibited MIC 47 and 30 nM, respectively. Compared to PBTZ169, both compounds displayed increased aqueous solubility and higher stability in human liver microsomes. This study suggested that an alternative side-chain modification strategy could be implemented to improve the druglike properties of the BTZ-based compounds.

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Section: Results and Discussionmentioning

confidence: 98%

Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents

et al. 2021

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“…PBTZ169 was reduced and covalently bound with Cys387 at the binding site of DprE1 by 8‐NO 2 group (Figure 2B) [9] . When we prepared this manuscript, Qiao and co‐workers reported the compound CN01 and its proposed mechanism of action [15] . They used methyl thioglycolate to mimic Cys387 of DprE1 in PBS (PH 7.4) to react with CN01 and detected the target mass by MS.…”

Section: Resultsmentioning

confidence: 99%

Molecular Insight into the Discrepancy of Antitubercular Activity between 8‐Nitro and 8‐Cyano Benzothiazinones

et al. 2020

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Benzothiazinones with 8-NO 2 group is a novel class of compounds with potent antitubercular activity, especially BTZ043 and PBTZ169, which covalently inhibit DprE1. 8-CN benzothiazinones is reported as another type of benzothiazinones with potent antitubercular activity. Taking this as the starting point, a series of 8-CN benzothiazinones are synthesized and evaluated for their antitubercular activity. To better understand the antitubercular activity of this series of benzothiazinones, the difference between the molecular structures of CN01 and PBTZ169 in crystal are analyzed. CN01 and PBTZ169 show completely different conformations of the piperazine ring. Density functional theory analysis (DFT) and molecular dynamics (MD) simulation are performed to provide more details to explain the different antitubercular activity. All the analysis based on crystallography, quantum chemistry, and molecular modeling lay a foundation for the subsequent structural optimization of 8-CN benzothiazinones.

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“…DprE1 is one of the enzymes responsible for the cell wall biosynthesis, catalyzing the formation of decaprenyl-phosphoarabinose from decaprenyl-phosphoribose [176]. This target has been extensively explored as several scaffolds have been discovered and optimized for its inhibition [177][178][179][180]. In 2018, a family of triazole-diindolylmethane derivatives was designed from a molecular hybridization approach, by combining different pharmacophores.…”

Section: Other Targetsmentioning

confidence: 99%

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

Campaniço

Harjivan

Warner

et al. 2020

IJMS

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Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the bacteria to coexist in a state of asymptomatic latency. This last state can be sustained for years or even decades, waiting for a breach in the immune system to become active again. Furthermore, most current therapies are not efficacious against this state, failing to completely clear the infection. Over the years, a series of experimental methods have been developed to mimic the latent state, currently used in drug discovery, both in vitro and in vivo. Most of these methods focus in one specific latency inducing factor, with only a few taking into consideration the complexity of the granuloma and the genomic and proteomic consequences of each physiological factor. A series of targets specifically involved in latency have been studied over the years with promising scaffolds being discovered and explored. Taking in account that solving the latency problem is one of the keys to eradicate the disease, herein we compile current therapies and diagnosis techniques, methods to mimic latency and new targets and compounds in the pipeline of drug discovery.

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Design, synthesis and evaluation of covalent inhibitors of DprE1 as antitubercular agents

Cited by 26 publications

References 22 publications

Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents

Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents

Molecular Insight into the Discrepancy of Antitubercular Activity between 8‐Nitro and 8‐Cyano Benzothiazinones

Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

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