Novel Piperazine Arylideneimidazolones Inhibit the AcrAB-TolC Pump in Escherichia coli and Simultaneously Act as Fluorescent Membrane Probes in a Combined Real-Time Influx and Efflux Assay

Q2 · MEDICINE

Article

Author: Handzlik, Jadwiga ; Kern, Winfried V. ; Olejarz, Agnieszka ; Kaczor, Aneta ; Kieć-Kononowicz, Katarzyna ; Bohnert, Jürgen A. ; Karcz, Tadeusz ; Schuster, Sabine

ABSTRACT In this study, we tested five compounds belonging to a novel series of piperazine arylideneimidazolones for the ability to inhibit the AcrAB-TolC efflux pump. The biphenylmethylene derivative (BM-19) and the fluorenylmethylene derivative (BM-38) were found to possess the strongest efflux pump inhibitor (EPI) activities in the AcrAB-TolC-overproducing Escherichia coli strain 3-AG100, whereas BM-9, BM-27, and BM-36 had no activity at concentrations of up to 50 μM in a Nile red efflux assay. MIC microdilution assays demonstrated that BM-19 at 1/4 MIC (intrinsic MIC, 200 μM) was able to reduce the MICs of levofloxacin, oxacillin, linezolid, and clarithromycin 8-fold. BM-38 at 1/4 MIC (intrinsic MIC, 100 μM) was able to reduce only the MICs of oxacillin and linezolid (2-fold). Both compounds markedly reduced the MIC of rifampin (BM-19, 32-fold; and BM-38, 4-fold), which is suggestive of permeabilization of the outer membrane as an additional mechanism of action. Nitrocefin hydrolysis assays demonstrated that in addition to their EPI activity, both compounds were in fact weak permeabilizers of the outer membrane. Moreover, it was found that BM-19, BM-27, BM-36, and BM-38 acted as near-infrared-emitting fluorescent membrane probes, which allowed for their use in a combined influx and efflux assay and thus for tracking of the transport of an EPI across the outer membrane by an efflux pump in real time. The EPIs BM-38 and BM-19 displayed the most rapid influx of all compounds, whereas BM-27, which did not act as an EPI, showed the slowest influx.

01 Aug 1999·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Evidence for a Neuroprotective Effect of Pyrid-3-yl-sulphonylurea in Photochemically Induced Focal Ischaemia in Rats: Magnetic Resonance Imaging Evaluation

Q3 · MEDICINE

Article

Author: Frois, Ana ; Masereel, Bernard ; Goudemant, Jean-François ; Ritter, Christian ; Demeure, Roger ; Gallez, Bernard ; Baudelet, Christine

AbstractA neuroprotective effect can be obtained with N-[(4-cycloheptylaminopyrid-3-yl)sulphonyl]N′-cycloheptyl urea (BM27), a pyrid-3-yl-sulphonylurea structurally related to torasemide, a loop diuretic. We have investigated the neuroprotective effect of BM27 by magnetic resonance imaging and use of the photothrombotic model of cerebral infarction in the rat. This method enables non-invasive quantification of the extent of the cerebral oedema from T2-weighted spin-echo images.This article reports the evolution of the extent of oedema with time (0.5, 1, 2, 4, 6, 24 and 48 h, 7 and 15 days and 1 month after induction of the lesion) in rats pretreated with 5mg kg−1 BM27 or an appropriate control. At all times, the rats treated with BM27 had, on average, smaller lesions than control rats (30% decrease between 2 h and 6 h).These results strongly suggest a significant (P < 0.01) but modest neuroprotective effect of BM27 in ischaemic cerebral stroke. Further investigations should be performed to determine if BM27 or its analogues are of clinical interest.

01 Mar 1997·EpilepsiaQ1 · MEDICINE

Anticonvulsant Activity of Pyrid‐3‐yl‐Sulfonyl Ureas and Thioureas

Q1 · MEDICINE

Article

Author: J. M. Dogné ; J. Delarge ; B. Masereel ; D. M. Lambert ; J. H. Poupaert

Summary: The N‐[(4‐cycloheptylaminopyrid‐3–yl)sulfonyl]‐N′‐cycloheptyl urea, a neuroprotective agent, and 10 chemically related sulfonyl(thio)ureas were evaluated in the maximal electroshock seizure test in mice. This sulfonylurea, BM 27, and two stucturally related sulfonylthioureas, BM 11 and BM 34, emerged with a 50% effective dose (ED50) of 2.87, 1.72, and 1.19 mg/kg, respectively. Their anticonvulsant profiles were found to be similar to that of phenytoin: active in the maximal electroshock seizure (MES) test and inactive in chemically induced seizures (pentetrazole, strychnine, bicuculline, picrotoxine, N‐methyl‐D,L‐aspartic acid). These compounds exhibited a higher protective index and potency than those of phenytoin. Additional work remains necessary, however, to determine whether BM 27 is of clinical interest.

100 Deals associated with BM-27

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Indication	Highest Phase	Country/Location	Organization	Date
Brain Injuries	Discovery	BE	University of Liege	-
Stroke	Discovery	BE	University of Liege	-

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