Synthesis and anti-Helicobacter pylori properties of NO-donor/metronidazole hybrids and related compounds

Two series (A, B) of 2-(2-methyl-5-nitro-1H-imidazolyl)ethyl derivatives (6-9, 18-23) conjugated through an oxygen or an aminomethyl bridge with either a furoxan NO-donor moiety or a furazan substructure, devoid of NO-donor properties, were synthesised. A third group (C) of 2-(2-methyl-5-nitro-1H-imidazolyl)ethyl derivatives conjugated with nitrooxy and dinitrooxy NO-donor functions (35, 38) as well as the corresponding analogue without these functions (40) were prepared. All the compounds were evaluated in vitro for their activity against a number of Helicobacter pylori strains. Metronidazole (1) and its amino analogue (11) were taken as reference compounds. All the synthesised hybrids and their analogues exhibited good anti-H. pylori activity with MIC50 in the range less than 0.0039-1, resulting in compounds more active than metronidazole. Derivatives 6-9 displayed good potency also against metronidazole-resistant strains. Compounds lacking the 5-nitroimidazole moiety (24-29, 30-33) proved to be inactive against H. pylori with the exception of 33. The lack of significant differences in the antibacterial potency between furoxan and furazan hybrids in both series (A, 13) suggest that the role of the N-oxide moiety of the furoxan system either as an inductor of oxidative stress or as a promoter of NO-donor properties is marginal. The substitution of the furoxan substructures with nitrooxy moieties (35, 38) afforded active compounds. In view of their NO-donor properties, NO-metronidazole hybrids could represent potential therapeutic tools both in the treatment of gastric ulcer and in a number of extragastrointestinal disorders such as ischaemic heart diseases and atherosclerosis-related to some H. pylori strains. (C) 2003 Wiley-Liss, Inc.