Introduction of a Thio Functional Group to Diazabicyclooctane: An Effective Modification to Potentiate the Activity of β-Lactams against Gram-Negative Bacteria Producing Class A, C, and D Serine β-Lactamases

Abstract

By the emergence and worldwide spread of multi-drug-resistant Gram-negative bacteria, there have been growing demands for efficacious drugs to cure these resistant infections. The key mechanism for resistance to β-lactam antibiotics is the production of β-lactamases, which hydrolyze and deactivate β-lactams. Diazabicyclooctane (DBO) analogs play an important role as one of the new classes of β-lactamase inhibitors (BLIs), and several compounds such as avibactam (AVI) have been approved by the FDA, along with many derivatives under clinical or preclinical development. Although these compounds have a similar amide substituent at the C2 position, we have recently reported the synthesis of novel DBO analogs which possess a thio functional group. This structural modification enhances the ability to restore the antimicrobial activities of cefixime (CMF) against pathogens producing classes A, C, and D serine β-lactamases compared with AVI and expands the structural tolerance at the six position. Furthermore, some of these analogs showed intrinsic microbial activities based on multipenicillin binding protein (PBP) inhibition. This is the unique feature which has never been observed in DBOs. One of our DBOs had a pharmacokinetic profile comparable to that of other DBOs. These results indicate that the introduction of a thio functional group into DBO is a novel and effective modification to discover a clinically useful new BLI.

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

“…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] ANT3310: ANT3310 is the derivative of avibactam in which the carboxamide group of avibactam has been replaced with fluorine atoms (Scheme 4). This compound has been useful in restoring the carbapenem activity against OXA-CRAB as well as other SBLcarrying carbapenem-resistant Acinetobacter baumannii strains in in vivo mouse infection models [68].…”

“…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.…”

“…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.…”

Discovery of 2-Sulfinyl-Diazabicyclooctane Derivatives, Potential Oral β-Lactamase Inhibitors for Infections Caused by Serine β-Lactamase-Producing Enterobacterales

“…We have recently reported that a thio-functional group, such as sulfone, sulfoxide, or sulfonamide, at the C2 position of DBO enhances the ability to restore antimicrobial activities of βlactam against pathogens producing various serine β-lactamases and expands structural tolerance for β-lactamase inhibition at the 6-position. 18 In designing oral agents, carboxylic acid ester prodrugs are preferred to sulfate esters because they have been a proven strategy for oral administration. Although we have already ascertained that replacing the sulfate at the 6-position with fluoroacetic acid maintains β-lactamase inhibition potential, they were unstable in serum and showed high clearance in rats.…”

“…We have recently reported the fundamental structure−activity relationship (SAR) of thio-functionalized DBOs. 18 The representative compounds and their profiles are summarized in Table 1. The sulfone and sulfoxide derivatives exhibited better inhibition against β-lactamases.…”