NH-1,2,3-Triazole Inhibitors of the VIM-2 Metallo-β-Lactamase

Weide, Timo; Saldanha, S. Adrian; Minond, Dmitriy; Spicer, Timothy; Fotsing, Joseph R.; Spaargaren, Michael; Frère, Jean‐Marie; Bebrone, Carine; Sharpless, K. Barry; Hodder, Peter; Fokin, Valery V.

doi:10.1021/ml900022q

Cited by 83 publications

(40 citation statements)

References 11 publications

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“…The biggest challenges are the metallo-␤-lactamases. However, some progress has been made in identifying potential inhibitors (cephalosporin-derived reverse hydroxamates and oximes, phthalic acid derivatives, mitoxantrone, 4-chloromercuribenzoic acid, sulfonyl-triazole analogs, and NH-1,2,3-triazole-based compounds) (66,84,138,202,248). Alternative inhibitors can include carbapenems with different stereochemistries.…”

Section: Discussionmentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

Endimiani

Taracila

et al. 2011

Antimicrob Agents Chemother

1,181

962

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In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the ␤-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most ␤-lactamases, in some cases act as "slow substrates" or inhibitors of ␤-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting ␤-lactamases serves as a major rationale for expansion of this class of ␤-lactams. We describe the initial discovery and development of the carbapenem family of ␤-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.Carbapenems play a critically important role in our antibiotic armamentarium. Of the many hundreds of different ␤-lactams, carbapenems possess the broadest spectrum of activity and greatest potency against Gram-positive and Gram-negative bacteria. As a result, they are often used as "last-line agents" or "antibiotics of last resort" when patients with infections become gravely ill or are suspected of harboring resistant bacteria (23,(174)(175)(176)229). Unfortunately, the recent emergence of multidrug-resistant (MDR) pathogens seriously threatens this class of lifesaving drugs (189). Several recent studies clearly show that resistance to carbapenems is increasing throughout the world (35,64,73,123,151,155,173,200). Despite this menacing trend, our understanding of how to best use these agents is undergoing a renaissance, especially concerning their role with regard to ␤-lactamase inhibition. In this context, we view the number, type, and diversity of carbapenems as compelling reasons to explore these compounds for new insights into drug development.

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Section: Discussionmentioning

confidence: 99%

Carbapenems: Past, Present, and Future

Papp-Wallace

Endimiani

Taracila

et al. 2011

Antimicrob Agents Chemother

1,181

962

View full text Add to dashboard Cite

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“…On the other hand, such properties are highly welcome when NH-1,2,3-triazoles were synthesized as biologically active agents by the cascade method. [32][33][34][35][36][38][39][40][41][42]45 …”

Section: Discussionmentioning

confidence: 99%

“…Thus, the methods have already been applied to prepare some N-unsubstituted 1,2,3-triazoles. [32][33][34][35][36][37][38][39][40][41][42][43][44][45] Our previous studies were focused on the mechanisms to explain the formation of these heterocycles. [28][29][30][31] …”

Section: Introductionmentioning

confidence: 99%

Synthesis of N-unsubstituted 1,2,3-triazoles via a cascade including propargyl azides, allenyl azides, and triazafulvenes

Banert¹,

Hagedorn²,

Hemeltjen³

et al. 2016

Arkivoc

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About thirty NH-1,2,3-triazoles with at least one additional functional group in a side chain at C-4 were prepared from propargyl substrates. These reactions included propargyl azides and their [3,3]-sigmatropic rearrangement to generate short-lived allenyl azides, which cyclized to form triazafulvenes that could be trapped by addition of N-or O-nucleophiles. In most cases, simple substrates and cheap sodium azide were utilized as starting compounds, and the syntheses were performed by using a one-pot procedure without isolation of any dangerous azides. This method to prepare NH-1,2,3-triazoles turned out to be compatible with quite different substitution patterns of the propargyl substrate.

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“…Finally, employing click chemistry, compounds 2a,b were cyclized with 3a-i, respectively, to give target compounds 4a-r in good yields. In recent years, the 1,2,3-triazole scaffold became a highlight fragment with the emergence of click chemistry and the 1,2,3-triazole-containing compounds were reported to possess a variety of biological activities [24][25][26][27][28], especially as antifungal agents [29][30][31]. Furthermore, the hybridizations of the 1,2,3-triazole moiety with other antifungal agents were reported.…”

Section: Chemistrymentioning

confidence: 99%

“…Among them, benzofuran inhibitors showed high selectivity and powerful antifungal activity [16][17][18][19] (Figure 1). Furthermore, the benzofuran core itself possessed a definite antifungal activity and numbers of benzofuran derivatives were reported without indicating the targets [20][21][22][23] In recent years, the 1,2,3-triazole scaffold became a highlight fragment with the emergence of click chemistry and the 1,2,3-triazole-containing compounds were reported to possess a variety of biological activities [24][25][26][27][28], especially as antifungal agents [29][30][31]. Furthermore, the hybridizations of the 1,2,3-triazole moiety with other antifungal agents were reported.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Antifungal Activity of Novel Benzofuran-Triazole Hybrids

Liang

Tian

et al. 2016

Molecules

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Abstract:A series of novel benzofuran-triazole hybrids was designed and synthesized by click chemistry, and their structures were characterized by HRMS, FTIR and NMR. The in vitro antifungal activity of target compounds was evaluated using the microdilution broth method against five strains of pathogenic fungi. The result indicated that the target compounds exhibited moderate to satisfactory activity. Furthermore, molecular docking was performed to investigate the binding affinities and interaction modes between the target compound and N-myristoyltransferase. Based on the results, preliminary structure activity relationships (SARs) were summarized to serve as a foundation for further investigation.

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NH-1,2,3-Triazole Inhibitors of the VIM-2 Metallo-β-Lactamase

Cited by 83 publications

References 11 publications

Carbapenems: Past, Present, and Future

Carbapenems: Past, Present, and Future

Synthesis of N-unsubstituted 1,2,3-triazoles via a cascade including propargyl azides, allenyl azides, and triazafulvenes

Design, Synthesis and Antifungal Activity of Novel Benzofuran-Triazole Hybrids

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