Synthesis of 2-Thio-Substituted 1,6-Diazabicyclo[3.2.1]octane Derivatives, Potent β-Lactamase Inhibitors

Fujiu, Motohiro; Yokoo, Katsuki; Aoki, Toshiaki; Shibuya, Satoru; Sato, Jun; Komano, Kazuo; Kusano, Hiroki; Sato, Soichiro; Ogawa, Masayoshi; Yamawaki, Kenji

doi:10.1021/acs.joc.0c00980

Cited by 13 publications

(25 citation statements)

References 28 publications

(65 reference statements)

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“…This fact is further strengthened by comparing the data of compounds 5j and 5k, where later showed better activity due to the presence of CF 3 -group at the para position of benzene ring, instead of p-toluene. The influence of the electron-withdrawing groups at C2 position of the DBO ring is already reported in the literature [13]. The compounds 5l and 5m with pyridine substituents proved the most active compounds among all of the synthesized compounds as well as the control IMI.…”

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confidence: 52%

Sulfonylamidine‐substituted derivatives of avibactam: Synthesis and antibacterial activity

Zhai

Sun

et al. 2021

Journal of Heterocyclic Chem

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Avibactam is a clinically approved non-β-lactam based β-lactamase inhibitor. Derivatization of this scaffold with improved inhibition profile is the demand of the day to cope with the future challenges. We successfully synthesized new derivatives of avibactam containing sulfonylamidine moieties at C2 position of the diazabicyclooctane ring. We tested in vitro antibacterial activities of newly synthesized compounds against 10 bacterial strains expressing variable β-lactamases. All compounds did not exhibit antimicrobial profile when assayed individually; however, all compounds minimized the MIC value of the imipenem in combination. Compound 5l proved most potent against all 10 bacterial strains, and showed improved inhibition against six bacterial strains as compared with the control inhibitor, relebactam. The compound 5l may be a lead hit for future development.

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confidence: 52%

Sulfonylamidine‐substituted derivatives of avibactam: Synthesis and antibacterial activity

Zhai

Sun

et al. 2021

Journal of Heterocyclic Chem

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Section: Durlobactam Prodrugs Etx1317 and Etx0282mentioning

confidence: 99%

“…To access the sulfide derivatives, commercially available carboxylic acid 17 was subjected to a photo-induced Barton decarboxylative thiolation reaction with appropriate thiolating agents in the presence of 2-mercaptopyridine-1-oxide and ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC . HCl) [69,70] Thio-substituted DBOs: Researchers from Shiniogi pharmaceuticals reported a series of thio-substituted DBO derivatives in which the C2 position of DBO was transformed into sulfide, which was then oxidized to sulfinates and sulfones. To access the sulfide derivatives, commercially available carboxylic acid 17 was subjected to a photo-induced Barton decarboxylative thiolation reaction with appropriate thiolating agents in the presence of 2mercaptopyridine-1-oxide and Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl) [69,70] This research group also prepared thio-substituted DBOs in which the N-hydroxy position of DBO was activated with fluoroacetate derivatives instead of sulfonic acid.…”

Section: Durlobactam Prodrugs Etx1317 and Etx0282mentioning

confidence: 99%

“…HCl) [69,70] Thio-substituted DBOs: Researchers from Shiniogi pharmaceuticals reported a series of thio-substituted DBO derivatives in which the C2 position of DBO was transformed into sulfide, which was then oxidized to sulfinates and sulfones. To access the sulfide derivatives, commercially available carboxylic acid 17 was subjected to a photo-induced Barton decarboxylative thiolation reaction with appropriate thiolating agents in the presence of 2mercaptopyridine-1-oxide and Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl) [69,70] This research group also prepared thio-substituted DBOs in which the N-hydroxy position of DBO was activated with fluoroacetate derivatives instead of sulfonic acid. Thus compounds 27 and 31 were synthesized via two different synthetic routes.…”

Section: Durlobactam Prodrugs Etx1317 and Etx0282mentioning

confidence: 99%

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Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

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Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

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“…A 12-step synthetic scheme and its optimization were reported for obtaining the DBO precursor containing the azido group at position C2 (DBO 3 ; Figure D). Other teams functionalized the C 2 position with groups containing heteroatoms, sulfur or fluorine . Recently, a series of amidine substituted-DBOs have been reported .…”

mentioning

confidence: 99%

Traceless Staudinger Ligation To Introduce Chemical Diversity on β-Lactamase Inhibitors of Second Generation

et al. 2021

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We explored the traceless Staudinger ligation for the functionalization of the C2 position of second generation β-lactamase inhibitors based on a diazabicyclooctane (DBO) scaffold. Our strategy is based on the synthesis of phosphine phenol esters and their ligation to an azido-containing precursor. Biological evaluation showed that this route provided access to a DBO that proved to be superior to commercial relebactam for inhibition of two of the five β-lactamases that were tested.

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Synthesis of 2-Thio-Substituted 1,6-Diazabicyclo[3.2.1]octane Derivatives, Potent β-Lactamase Inhibitors

Cited by 13 publications

References 28 publications

Sulfonylamidine‐substituted derivatives of avibactam: Synthesis and antibacterial activity

Sulfonylamidine‐substituted derivatives of avibactam: Synthesis and antibacterial activity

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

Traceless Staudinger Ligation To Introduce Chemical Diversity on β-Lactamase Inhibitors of Second Generation

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