3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones as novel antibacterial scaffolds against methicillin-resistant Staphylococcus aureus

Cusumano, Alexander Q.; Pierce, Joshua G.

doi:10.1016/j.bmcl.2018.02.047

Cited by 21 publications

(20 citation statements)

References 16 publications

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“…3‐Hydroxy‐1,5‐dihydro‐2 H ‐pyrrol‐2‐ones have become the focus of attention in medicinal chemistry in the last years [1–4] . For example, 3‐hydroxy‐1,5‐dihydro‐2 H ‐pyrrol‐2‐ones were found to be valuable antibacterial scaffolds including methicillin‐resistant Staphylococcus aureus [5–7] . These scaffolds were developed via a structure optimization of marine natural products, phenopyrrozin [8] and p ‐hydroxyphenopyrrozin [9] (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Reaction of Hetareno[e]pyrrole‐2,3‐diones with Thiols: An Approach to Two Distinct 5‐Thio‐Substituted Pyrrole‐2‐one Derivatives

et al. 2021

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Recently, 3‐hydroxy‐1,5‐dihydro‐2H‐pyrrol‐2‐ones have become an object of close scrutiny in medicinal chemistry due to their diverse biological activity. In the present paper, we describe a substrate‐switchable reaction of hetareno[e]pyrrole‐2,3‐diones with aromatic and aliphatic thiols that afforded two series of novel 5‐thio‐substituted 3‐hydroxy‐1,5‐dihydro‐2H‐pyrrol‐2‐ones. The reaction of pyrroloquinaxolinetriones with thiols led to the formation of adducts. The initially formed adducts of pyrrolobenzoxazinetriones with thiols were subjected to hydrolysis with the oxazine ring opening and decarboxylation. Based on the latter reaction, a synthetic approach to pharmaceutically interesting monocyclic non‐fused 3‐hydroxy‐1,5‐dihydro‐2H‐pyrrol‐2‐ones bearing conformationally free thio‐substituents at C‐5 was proposed for the first time. The synthesized compounds were screened in vitro for their antimicrobial activity. Some of them were found to exhibit moderate activity against S. aureus and C. albicans. Thus, the results of current study confirm that the search for new biologically active compounds among 5‐thio‐substituted 3‐hydroxy‐1,5‐dihydro‐2H‐pyrrol‐2‐ones is promising.

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Section: Introductionmentioning

confidence: 99%

Reaction of Hetareno[e]pyrrole‐2,3‐diones with Thiols: An Approach to Two Distinct 5‐Thio‐Substituted Pyrrole‐2‐one Derivatives

et al. 2021

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“…We subsequently optimized the preparation of these heterocycles via a three-component reaction under extremely mild and scalable conditions to yield a variety of monocyclic and bicyclic heterocycles (Figure B). − This multicomponent reaction (MCR) is extremely functional-group-tolerant and has been successfully conducted on a 10 g scale, followed by subsequent conversion to a number of value-added products such as β-lactams and β-amino acids. Furthermore, this MCR has also provided direct access to natural-product-like cores such as bicyclic γ-lactams as well as an efficient route to quaternary substituted hydroindole scaffolds present within crinane alkaloids and enabled the total synthesis of the marine natural product phenopyrrozin and analogues. − As part of these efforts, we also evaluated the antimicrobial activities of the 2,3-pyrrolidinedione heterocycles and were pleased to find that a number of them had modest activity against a panel of Gram-positive bacteria (Figure C) . We are currently expanding the SAR of this class and further evaluating the properties of these molecules, but these results highlight the new chemistry that can emerge from ongoing natural product synthesis projects and the unexpected biology that can subsequently result.…”

Section: 3-pyrrolidinedione Heterocyclesmentioning

confidence: 99%

Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence

et al. 2021

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Conspectus Antimicrobial resistance to existing antibiotics represents one of the greatest threats to human health and is growing at an alarming rate. To further complicate treatment of bacterial infections, many chronic infections are the result of bacterial biofilms that are tolerant to treatment with antibiotics because of the presence of metabolically dormant persister cell populations. Together these threats are creating an increasing burden on the healthcare system, and a “preantibiotic” age is on the horizon if significant action is not taken by the scientific and medical communities. While the golden era of antibiotic discovery (1940s–1960s) produced most of the antibiotic classes in clinical use today, followed by several decades of limited development, there has been a resurgence in antibiotic drug discovery in recent years fueled by the academic and biotech sectors. Historically, great success has been achieved by developing next-generation variants of existing classes of antibiotics, but there remains a dire need for the identification of novel scaffolds and/or antimicrobial targets to drive future efforts to overcome resistance and tolerance. In this regard, there has been no more valuable source for the identification of antibiotics than natural products, with 69–77% of approved antibiotics either being such compounds or being derived from them. Our group has developed a program centered on the chemical synthesis and chemical microbiology of marine natural products with unusual structures and promising levels of activity against multidrug-resistant (MDR) bacterial pathogens. As we are motivated by preparing and studying the biological effects of these molecules, we are not initially pursuing a biological question but instead are allowing the observed phenotypes and activities to guide the ultimate project direction. In this Account, our recent efforts on the synoxazolidinone, lipoxazolidinone, and batzelladine natural products will be discussed and placed in the context of the field’s greatest challenges and opportunities. Specifically, the synoxazolidinone family of 4-oxazolidinone-containing natural products has led to the development of several chemical methods to prepare antimicrobial scaffolds and has revealed compounds with potent activity as adjuvants to treat bacterial biofilms. Bearing the same 4-oxazolidinone core, the lipoxazolidinones have proven to be potent single-agent antibiotics. Finally, our synthetic efforts toward the batzelladines revealed analogues with activity against a number of MDR pathogens, highlighted by non-natural stereochemical isomers with superior activity and simplified synthetic access. Taken together, these studies provide several distinct platforms for the development of novel therapeutics that can add to our arsenal of scaffolds for preclinical development and can provide insight into the biochemical processes and pathways that can be targeted by small molecules in the fight against antimicrobial-resistant and -tolerant infections. We hope that this work will s...

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“…The 3-hydroxy-1,5-dihydro-2 H -pyrrol-2-one (HDP) motif ( Figure 1 ) is a valuable scaffold in drug discovery. Inhibitors of p53–MDM2 protein–protein interaction [ 1 , 2 ], inhibitors of HIV integrase [ 3 , 4 ], antibacterial agents against methicillin-resistant Staphylococcus aureus [ 5 ], dengue virus helicase inhibitors [ 6 ], P2X3 receptor antagonists [ 7 ], and other potential pharmaceuticals [ 8 , 9 ] have been developed on its basis.…”

Section: Introductionmentioning

confidence: 99%

Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones

et al. 2021

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The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, 3-amino-1,5-dihydro-2H-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2H-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were prepared via their reaction with carbodiimides.

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3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones as novel antibacterial scaffolds against methicillin-resistant Staphylococcus aureus

Cited by 21 publications

References 16 publications

Reaction of Hetareno[e]pyrrole‐2,3‐diones with Thiols: An Approach to Two Distinct 5‐Thio‐Substituted Pyrrole‐2‐one Derivatives

Reaction of Hetareno[e]pyrrole‐2,3‐diones with Thiols: An Approach to Two Distinct 5‐Thio‐Substituted Pyrrole‐2‐one Derivatives

Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence

Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones

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