Synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors

Vidaillac, Céline; Guillon, Jean; Moreau, Stéphane; Arpin, Corinne; Lagardère, Annie; Larrouture, Stéphane; Dallemagne, Patrick; Caignard, Daniel‐Henri; Quentin, Claudine; Jarry, Christian

doi:10.1080/14756360701485406

Cited by 14 publications

(3 citation statements)

References 39 publications

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“…Pharmacological Inhibitors, also known as Efflux Pumps Inhibitors (EPIs). These are chemical compounds used: i) to interfere with the assembly or function of efflux pumps [176] (for instance, in the case of the tripartite RND systems, blocking of the OM channel may lead to the inhibition of efflux pump activity [177]); ii) in combination therapy to increase the antibiotic concentration inside a pathogenic cell [10,67,116,161,162]. EPIs of this latter class act by competitive/non-competitive inhibition of the pump, rendering antibiotics more effective, and might prevent accumulation of other resistance mechanisms over time.…”

Section: Strategies To Overcome Efflux-mediated Mdrmentioning

confidence: 99%

RND Efflux Pumps: Structural Information Translated into Function and Inhibition Mechanisms

Ruggerone¹,

Murakami²,

Pos³

et al. 2013

CTMC

127

120

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Efflux pumps of the Resistance Nodulation Division (RND) superfamily play a major role in the intrinsic and acquired resistance of Gram-negative pathogens to antibiotics. Moreover, they are largely responsible for multi-drug resistance (MDR) phenomena in these bacteria. The last decade has seen a sharp increase in the number of experimental and computational studies aimed at understanding their functional mechanisms. Most of these studies focused on the RND drug/proton antiporter AcrB, part of the AcrAB-TolC efflux pump actively recognizing and expelling noxious agents from the interior of bacteria. These studies have been focused on the dynamical interactions between AcrB and its substrates and inhibitors, on the details of the proton translocation mechanisms, and on the way AcrB assembles with protein partners to build up a functional pump. In this review we summarize these advances focusing on the role of AcrB.

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Section: Strategies To Overcome Efflux-mediated Mdrmentioning

confidence: 99%

RND Efflux Pumps: Structural Information Translated into Function and Inhibition Mechanisms

Ruggerone¹,

Murakami²,

Pos³

et al. 2013

CTMC

127

120

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“…Reported classes of NorA inhibitors include flavones and flavonolignans,7 pyrroloquinoxalines,8 4-arylpyridine-3,5-dicarboxylate esters,9 N-aryl ureas,10 and indoles 11…”

mentioning

confidence: 99%

Structure–activity relationships of 2-aryl-1H-indole inhibitors of the NorA efflux pump in Staphylococcus aureus

Ambrus

Kelso

Bremner

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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The synthesis of 22 2-aryl-1H-indoles, including 12 new compounds, has been achieved via Pd-or Rh-mediated methodologies, or selective electrophilic substitution. All three methods were based on elaborations from simple indole precursors. SAR studies on these indoles and 2-phenyl-1H-indole in S. aureus as NorA efflux pump inhibitors indicated 5-nitro-2-(3-methoxycarbonyl)phenyl-1H-indole was a slightly more potent inhibitor than the lead INF55. A promising new antibacterial lead compound against S. aureus, (2-phenyl-1H-indol-5-yl)-methanol, was also found. Keywords 2-Arylindoles; NorA efflux pump inhibitors; AntibacterialEfflux pumps compromise the efficacy of a wide range of antibiotics by actively extruding them from bacterial cells. 1,2 The pumps can be expressed in many different forms in both Gram-positive 3 and Gram-negative bacteria 4 and for some species a variety of pumps may be present with different or overlapping substrates. For the important community and nosocomially acquired human pathogen Staphylococcus aureus a number of pumps have been identified, including NorA, which has been shown to play a role in the development of clinical multidrug resistance (MDR) by this organism. 5 One promising strategy for combating MDR in S. aureus is to treat infections with a combination of a NorA efflux pump inhibitor and a conventional antibiotic, with the pump inhibitor serving to restore the antibiotic's potency by reducing its efflux from bacterial cells. 6Reported classes of NorA inhibitors include flavones and flavonolignans, 7 pyrroloquinoxalines, 8 4-arylpyridine-3,5-dicarboxylate esters, 9 N-aryl ureas, 10 and indoles. 11From the indole class, 5-nitro-2-phenylindole (2, INF55) (Scheme 1) represents a promising lead structure capable of producing a 4-fold increase in S. aureus susceptibility to ciprofloxacin when co-administered with the antibiotic at a concentration of 1.5 µg/mL. 11 *Corresponding author. Tel.: +612 42214255; fax +612 42214287; email: john_bremner@uow.edu.au. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. potentiates berberine activity to the same degree at the higher concentration of 3.0 µg/mL). NIH Public AccessThe current work discloses our latest systematic SAR exploration around the 2-aryl ring of INF55 and details the first experimental description of the effects of substituting the indole 5-nitro group. The goal of this study was to obtain a deeper understanding of the SAR of INF55 and analogues with a view to increasing potency against NorA in S. aureus. Furthermore, we sought to broaden our knowledge of substituent tolerance aro...

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“…If phosgene or triphosgene is used as synthetic equivalent of the synthon R 2 C 2+ during construction of the pyrroloquinoxaline system from derivatives of 1-(2-aminophenyl)pyrrole 4,5-dihydropyrrolo[1,2-a]quinoxalin-4-ones 65 with a highly reactive carbamoyl function are formed. Syntheses of a series of functionally substituted derivatives of pyrrolo[1,2-a]quinoxalines 65 of pharmacological interest by this method have been described [8,10,[38][39][40][41][42][43][44][45].…”

Section: Type B1 Production Methodsmentioning

confidence: 99%

Pyrrolo[1,2-a]quinoxalines based on pyrroles (Review)

Калинин

Мамедов

2011

Chem Heterocycl Comp

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Published data on methods for the synthesis of pyrrolo [1,2-a]quinoxalines, based on derivatives of pyrroles and also on compounds not originally derivatives of quinoxalines or pyrroles, are reviewed and classified. Keywords: pyrroles, pyrrolo[1,2-a]quinoxalines. In a continuation of the previous review [1], where possible methods for the construction of pyrrolo-[1,2-a]quinoxalines based on quinoxalines were examined, data are presented here on methods of synthesis based on pyrroles and other systems that are not derivatives of either quinoxalines or pyrroles. N N Pyrrolo[1,2-a]quinoxalines 1 2 3 4 5 6 7 8 9Various possible methods based on pyrroles for the construction of the pyrrolo[1,2-a]quinoxaline system are given below.

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Synthesis of new 4-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]quinoxaline and 5-[2-(alkylamino)ethylthio]pyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives, as potential bacterial multidrug resistance pump inhibitors

Cited by 14 publications

References 39 publications

RND Efflux Pumps: Structural Information Translated into Function and Inhibition Mechanisms

RND Efflux Pumps: Structural Information Translated into Function and Inhibition Mechanisms

Structure–activity relationships of 2-aryl-1H-indole inhibitors of the NorA efflux pump in Staphylococcus aureus

Pyrrolo[1,2-a]quinoxalines based on pyrroles (Review)

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