Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens

Ma, Zhenkun; He, Shijie; Yuan, Ying; Zhuang, Zhijun; Liu, Yu; Wang, Huan; Chen, Jing; Xu, Xiangyi; Ding, Charles Z.; Molodtsov, Vadim; Lin, Wei; Robertson, Gregory T.; Weiss, Jason; Pulse, Mark; Nguyen, Phung M.; Duncan, Leonard R; Doyle, Timothy B; Ebright, Richard H.; Lynch, A. Simon

doi:10.1021/acs.jmedchem.1c02045

Cited by 15 publications

(12 citation statements)

References 43 publications

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“…Besides the exploration of compounds acting on novel antibiotic targets, one avenue is to expand the utility of already existing pharmacologic motifs, such as nitroimidazoles. Ma et al recently reported about the potent dual-targeting rifamycin–nitroimidazole conjugate TNP-2198 exploiting polypharmacology against microaerophilic and anaerobic bacteria . Furthermore, the recently reported nitroimidazole indolin-2-one hybrids were shown to expand the potency of nitroimidazoles, which were classically restricted to the treatment of anaerobic bacteria, to aerobic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Ma et al recently reported about the potent dual-targeting rifamycin–nitroimidazole conjugate TNP-2198 exploiting polypharmacology against microaerophilic and anaerobic bacteria. 25 Furthermore, the recently reported nitroimidazole indolin-2-one hybrids were shown to expand the potency of nitroimidazoles, which were classically restricted to the treatment of anaerobic bacteria, to aerobic conditions. Here, we unravel an unexpected putative dual MoA of nitroimidazole indolin-2-one hybrids in pathogenic S. aureus that is potentially responsible for this gain of aerobic activity.…”

Section: Discussionmentioning

confidence: 99%

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Indolin-2-one Nitroimidazole Antibiotics Exhibit an Unexpected Dual Mode of Action

et al. 2022

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Nitroimidazoles such as metronidazole are used as anti-infective drugs against anaerobic bacteria. Upon in vivo reduction of the nitro group, reactive radicals damage DNA and proteins in the absence of oxygen. Unexpectedly, a recent study of nitroimidazoles linked to an indolin-2-one substituent revealed potent activities against aerobic bacteria. This suggests a different, yet undiscovered mode of action (MoA). To decipher this MoA, we first performed whole proteome analysis of compound-treated cells, revealing an upregulation of bacteriophage-associated proteins, indicative of DNA damage. Since DNA binding of the compound was not observed, we applied activity-based protein profiling (ABPP) for direct target discovery. Labeling studies revealed topoisomerase IV, an essential enzyme for DNA replication, as the most enriched hit in pathogenic Staphylococcus aureus cells. Subsequent topoisomerase assays confirmed the inhibition of DNA decatenation in the presence of indolin-2-one nitroimidazole with an activity comparable to ciprofloxacin, a known inhibitor of this enzyme. Furthermore, we determined significantly increased redox potentials of indolin-2-one nitroimidazoles compared to classic 5-nitroimidazoles such as metronidazole, which facilitates in vivo reduction. Overall, this study unravels that indolin-2-one-functionalized nitroimidazoles feature an unexpected dual MoA: first, the direct inhibition of the topoisomerase IV and second the classic nitroimidazole MoA of reductive bioactivation leading to damaging reactive species. Importantly, this dual MoA impairs resistance development. Given the clinical application of this compound class, the new mechanism could be a starting point to mitigate resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Indolin-2-one Nitroimidazole Antibiotics Exhibit an Unexpected Dual Mode of Action

et al. 2022

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“… ,, Initially, the silver salt AgSbF 6 reacted with [Cp*RhCl 2 ] 2 to form a cationic rhodium complex A . K 2 CO 3 -assisted concerted metalation deprotonation leads to the coordination of the nitrogen atom of the amide/sulfoximine substrate B with catalytically active rhodium species A , generating a five-membered Rh(III)-intermediate C through a reversible C(sp)-H activation reaction. Subsequently, a seven-membered rhodium metallacycle intermediate D was afforded when rhodacycle C underwent an olefin insertion with methyl 2-chloroacrylate 2 .…”

Section: Resultsmentioning

confidence: 99%

“…Nitrogen-containing heterocycles are key structural motifs in organic chemistry since numerous natural products, polymeric materials, and drugs feature these skeletons (Figure ). Tremendous efforts have been dedicated to the construction of nitrogen-containing heterocycles, resulting in C–N bond formation and C–N annulation reactions gaining significant attraction.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Isoquinolone, 1,2-Benzothiazine, and Naphtho[1′,2′:4,5]imidazo[1,2-a]pyridine Derivatives via Rhodium(III)-Catalyzed (4 + 2) Annulation

et al. 2022

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In this study, we report a novel and efficient synthetic method to construct isoquinolone scaffold via the Rh(III)-catalyzed (4 + 2) annulation of benzamide with an unreported coupling reagent methyl 2-chloroacrylate. Accordingly, other valuable 1,2-benzothiazine and naphtho[1′,2′:4,5]imidazo[1,2-a]pyridine derivatives are also obtained through a similar synthetic protocol. Thus, our developed method is highlighted by high yield and reaction versatility.

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“…[22][23][24] Previous studies on the advancement of DprE1 inhibitors proposed that high throughput screening, molecular modeling, docking, functional genomics, and proteomics are all significant in identifying novel chemical scaffolds as potential TB chemotherapy molecules. 20,25 Using the PubChem and ZINC databases, we used insilicobased virtual screening to find potential chemical compounds that can serve as DprE1 inhibitors. In the present study, a library of 100 molecules with a structural resemblance to bedaquiline (FDA approved anti-TB drug) was generated to identify novel and promising agents against the DprE1, a vulnerable drug target in Mtb.…”

Section: Introductionmentioning

confidence: 99%

Computational Studies to Identify Potential Inhibitors Targeting the DprE1 Protein in Mycobacterium tuberculosis

Sheikh

Rizvi

et al. 2022

Int J. Pharm. Investigation

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Background: DprE1, which is a flavoenzyme, is very important for cell wall biosynthesis in Mycobacterium tuberculosis (Mtb) and for the pathogenesis, virulence, lethality, and stress resistance of the host. Drug-resistant tuberculosis is a challenging global human health issue, necessitating the development of novel, more effective treatment regimens without adverse effects. DprE1 represents a potential therapeutic target. It was explored as a drug target utilizing benzothiazoles (BTZ), which are enormously potential anti-bacterial agents and are currently being explored as anti-mycobacterial entities. Materials and Methods: We used virtual screening of bioactive molecules from PubChem and ZINC databases targeting DprE1, having bioactive thousands of molecules known for anti-microbial activity. In the present study, we selected 100 compounds as the most promising candidates to act as potential DprE1 inhibitors to control this emerging condition of tuberculosis infection. To identify the six topranked compounds, molecular docking was used to calculate the binding affinities (ranging from -8.3 to 10.0 kcal/mol) between various compounds (C1-C6) and the DprE1 protein.Results: Based on the results of an ADMET analysis, these six chemicals are safer potential drug candidates, as neither AMES toxicity nor carcinogenicity is present when toxicological properties are considered. Out of 6 compounds, the top-ranked compound exhibiting the best binding affinity against the drug target DprE1 (Pdb-id;4FEH) receptor was further subjected to molecular dynamic simulation for 100 nanoseconds to check the stability and trajectories by root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) graphs and interacting coordinates using Desmond Schrodinger Software. Conclusion: Our in-silico investigation identified potent inhibitors for the DprE1 protein of Mtb, and these compounds can be considered and recommended as the lead molecules in the treatment of tuberculosis.

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Design, Synthesis, and Characterization of TNP-2198, a Dual-Targeted Rifamycin-Nitroimidazole Conjugate with Potent Activity against Microaerophilic and Anaerobic Bacterial Pathogens

Cited by 15 publications

References 43 publications

Indolin-2-one Nitroimidazole Antibiotics Exhibit an Unexpected Dual Mode of Action

Indolin-2-one Nitroimidazole Antibiotics Exhibit an Unexpected Dual Mode of Action

Synthesis of Isoquinolone, 1,2-Benzothiazine, and Naphtho[1′,2′:4,5]imidazo[1,2-a]pyridine Derivatives via Rhodium(III)-Catalyzed (4 + 2) Annulation

Computational Studies to Identify Potential Inhibitors Targeting the DprE1 Protein in Mycobacterium tuberculosis

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