Enantioselective synthesis of new oxazolidinylthiazolidines as enzyme inhibitors

Saiz, Cecilia; Villamil, Valentina; González, Mariano M.; Rossi, María-Agustina; Martínez, Lucy María Reidl; Suescun, Leopoldo; Vila, Alejandro J.; Mahler, Graciela

doi:10.1016/j.tetasy.2016.11.002

Cited by 8 publications

(4 citation statements)

References 17 publications

(22 reference statements)

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“…explored the preparation of oxazolidinylthiazolidine bicycles using cyclo‐chain tautomerism, which exhibited competitive inhibition of NDM‐1, K i = 1.6 ± 0.6 μM. This process involves the reversible movement of protons, transforming the open structure into a new heterocycle (Saiz et al., ). These results clearly provide hope for identifying a broader spectrum of MBL inhibitors.…”

Section: Progress In Designing Metallo‐β‐lactamase Inhibitorsmentioning

confidence: 99%

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

et al. 2019

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After more than 80 years of development, β‐lactam drugs have become the most widely used high‐efficiency, low‐toxic broad‐spectrum antibacterial drugs. However, with the widespread use and even abuse of those drugs, the resistance of major pathogens to β‐lactam drugs has increased over years, which has become a thorny problem to the public health. A common mechanism of the resistance to β‐lactams is the producing of β‐lactamases, which can hydrolyze the β‐lactam ring and inactivate these drugs. Metallo‐β‐lactamases (MBLs) are one kind of β‐lactamases that require metal ions for their catalytic activities. Although it is a well‐known strategy to recover the efficacy of β‐lactams by the combination of β‐lactamase inhibitors, there are still no MBL inhibitors that can be used in clinical practice. Therefore, it is urgent to develop MBL inhibitors. This review outlines the currently discovered MBL inhibitors with an emphasis on various strategies and approaches taken to discover MBL inhibitors, which may lead to diverse classes of inhibitors. Recent progress, particularly new screening methods, and the rational design of potent MBL inhibitors are discussed.

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Section: Progress In Designing Metallo‐β‐lactamase Inhibitorsmentioning

confidence: 99%

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

et al. 2019

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“…Bisthiazolidines ( 1 ) are enantiomerically pure bicycles previously prepared in high yields (Scheme ) . Interestingly, they display activity against Metallo‐β‐Lactamases (MBLs), a diverse set of enzymes that catalyze the hydrolysis of a broad range of β‐lactam drugs including carbapenems , .…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, they display activity against Metallo‐β‐Lactamases (MBLs), a diverse set of enzymes that catalyze the hydrolysis of a broad range of β‐lactam drugs including carbapenems , . These compounds have been recently characterized as cross‐class inhibitors against seven different MBLs, some of clinical relevance like NDM‐1, VIM‐2, and L1 , …”

Section: Introductionmentioning

confidence: 99%

Preparation and Mechanistic Studies of 2‐Substituted Bisthiazolidines by Imine Exchange

et al. 2020

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Bisthiazolidines (BTZ) are bicyclic compounds considered as penicillin analogs that inhibit the full range of Metallo‐β‐Lactamases (MBLs) and potentiate β‐lactam activity against resistant bacteria. Herein, we present a new methodology to prepare 2‐substituted bisthiazolidines by aldehyde exchange. Thirteen new bisthiazolidines were prepared using this methodology, with yields ranging from 31 to 75 %. The reaction is based on in situ imines formation, which are able to exchange side chains. The reaction intermediates were studied based on NMR experiments, and a key imine 1b‐II could be detected in the reaction mixture. Furthermore, a DFT computational analysis was performed to gain insights into the reaction mechanism, allowing us to unveil the different pathways and their activation barriers within the synthetic route. The results suggest that the most favorable route involve the formation of the thiazolidine 1b‐III by i) a N‐assisted N–C bond cleavage, and ii) a thiol‐mediated 5 endo‐trig cyclization followed by a C–N bond cleavage. In contrast with previously reported evidence, the imine metathesis was discarded as a plausible pathway. Finally, the reaction of 1b‐III with aldehyde 2a leads to bicycle 4a via the iminium ion 1b‐V.

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“…7 In this context, our group has previously prepared small libraries containing N, O-and S-fused heterocycles. 3,8 In an earlier approach, we synthesized a novel bicyclic scaffold: thiazolidinyl-2,3,4,5-tetrahydro-1,4-thiazepine 3a. The compound was prepared by condensation of azadithiane 1a and dimethylacetylene-dicarboxylate 2a through a domino process (see Scheme 1).…”

Section: Introductionmentioning

confidence: 99%