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

Abstract

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 MIC 50 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, B) 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. Drug Dev. Res. 60:225-239, 2003.

Synthesis and biological activity of novel amidrazones incorporating 5-nitroimidazole, ciprofloxacin, and 7-chloro-4-piperazinylquinoline

“…Metronidazole, a 5-nitroimidazole antibiotic medication, is used particularly for anaerobic bacteria and protozoa (Bertinaria et al, 2003;Martino et al, 2005;Hay et al, 2003;Günay et al, 1999). Easy availability and overuse of metronidazole can lead to emergence of metronidazole drug resistance at a significant level.…”

Synthesis of new compounds derived from metronidazole and amino acids and their esters as antiparasitic agents

“…Mertonidazole, 2-(2-methyl-5-nitro-1H-imidazol-1-yl)-ethanol (1) and its derivatives have a wide range of biological activity (Bertinaria et al, 2003;Martino et al, 2005;Hay et al, 2003;Günay et al, 1999). They are highly effective against trichomoniasis, various forms of amoebiasis, and infection with anaerobic bacteria and protozoa (Goldman and Wuest, 1981); it can kill or inhibit the majority of anaerobic bacteria when the metronidazole concentration in serum is in the range from 2 to 8 lg per ml (Salimi et al, 1997).…”

An exploration of the mechanisms for the formation of 3,4-bis(4-aminofurazan-3-yl)-furoxan by density functional theory

“…In this study, the dimerization mechanism of 4-aminofurazan-3-carbonitrile N-oxide, 8, has been investigated. The PES for the dimerization of 4-amino-furazan-3-carbonitrile N-oxide (8) to form the tricyclic furoxan species, 3,4-bis(4-aminofurazan-3-yl)-furoxan (11), is shown in Fig. 3, together with the optimized structures for the reactant, intermediates, TSs and product.…”

“…In some cases, molecular mechanisms of their action have been proposed. Particular attention has been focused on furoxans as sources of NO in biological studies and biological markers [8][9][10][11]. Because of their high nitrogen contents, the furoxan derivatives have also found applications as sources of high-density energetic materials (HDEM) of use as fuels, explosives, pyrotechnic compounds and propellants [12,13].…”