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Abstract

The therapeutic potential of urease inhibition of Helicobacter pylori has been studied by examining the effect of the potent urease inhibitor, fluorofamide (N-(diaminophosphinyl)-4-fluorobenzenamide), on urease activity and bacterial survival in vivo and in vitro. In culture, acid protection in H. pylori was shown to be due to changes in the pH of the medium brought about by the release of ammonia. Both the acid protection and the ammonia release were completely blocked by fluorofamide at low doses (ED50 = approximately 100 nM). However, fluorofamide was unstable under acidic conditions (T1/2 = 5.7 min at pH 2). Despite this, fluorofamide was the best available compound to test in vivo. In ferrets naturally infected with H. mustelae, a single dose (50 mg/kg, per os) of fluorofamide completely inhibited bacterial urease. In repeat dosing studies, fluorofamide (50 mg/kg per os, three times a day) was compared with the Helicobacter triple therapy regime (amoxycillin, metronidazole, and bismuth subcitrate). Fluorofamide failed to eradicate the H. mustelae infection, compared to 80% eradication with triple therapy. However, histological samples showed a profound reduction in bacterial numbers following fluorofamide treatment. A combination of fluorofamide and amoxycillin was dosed to ferrets (seven days of treatment with 50 mg/kg fluorofamide plus 10 mg/kg amoxycillin per os twice a day); however, this failed to eradicate the infection, despite there being a reduction in bacterial numbers in 3/5 ferrets after 21 days after dosing stopped. It was concluded that urease inhibitors (either alone or in combination with antibiotics) are unlikely to have therapeutic potential for Helicobacter pylori infections. This is probably because, in vivo, some bacteria (perhaps dormant forms) are not entirely dependent upon urease for survival. However, given the acid instability of fluorofamide, the possibility that more stable urease inhibitors might have therapeutic potential, cannot be excluded.

Metronidazole–Flavonoid Derivatives as Anti‐Helicobacter pylori Agents with Potent Inhibitory Activity against HPE‐Induced Interleukin‐8 Production by AGS Cells

“…[5,6] H. pylori strains susceptible to amoxicillin, clarithromycin, or metronidazole are generally easily eradicated, whereas those resistant to clarithromycin or metronidazole are much more difficult to clear. Consequently, these findings are indeed major drivers for developing novel anti-H. pylori agents.…”

“…The most serious among these side effects would be the drug resistance of H. pylori strains, which has badly affected the treatment outcome of triple H. pylori eradication therapy. [5,6] Metronidazole used to be one of the most effective agents against H. pylori, but now it is unlikely to have great therapeutic potential for this bacterium in the clinic because of the increasingly serious resistance of most H. pylori strains. Hence, there are unmet medical needs for novel, efficacious, and selective eradication therapies that minimize resistance problems in both H. pylori and also other bacteria, that lack the common gastrointestinal side effects that often associated with antibacterials.…”

“…Among these compounds, high anti-H. pylori activities were observed in isoflavones derivatives [4][5][6][7]19, and 20 but exhibited no inhibitory activity against other sorts of bacteria and fungi, for example, Streptococcus pneumoniae, Bacillus subtilis, Escherichia coli, Pseudomonas fluorescence, and Aspergillus niger.…”

Three component Kabachnik-Fields condensation leading to substituted aminomethane-P-hydroxymethylphosphonic acids as a tool for screening of bacterial urease inhibitors

“…The highest activities were exhibited by compounds which were mono Nsubstituted analogues 2, 4, 7, 9 and 11. Within this group N-cyclohexyl-aminomethane-Phydroxymethylphosphinic acid (11) was the most potent with K i = 92 µM. With the exception of structure 3, N,N-disubstituted compounds were found to be inactive.…”

“…Amides of phosphoric acid, being classical transition state analogs, represent the group with the highest activity, but unfortunately their utility is strongly limited by low hydrolytic stability (the reported half-life of N-(diaminophosphinyl)-4-fluorobenzamide, flurofamide at pH 2 is around 5 min.). 11 Interestingly, a moderately active urease inhibitor -acetohydroxamic acid was approved by FDA in 1983 for urinary tract infections treatment (trademarks Lithostat, Uronefrex), although it exhibits severe side effects including teratogenicity, psychoneurologic and musculo-integumentary symptoms. 12,13 In this paper we apply a multi-component reaction strategy for screening urease's phosphinate inhibitors.…”