In vitro inhibitory activity of boropinic acid against Helicobacter pylori Francesco Epifano, a, * Luigi Menghini, a Rita Pagiotti, b Paola Angelini, b Salvatore Genovese c and Massimo Curini c a Dipartimento di Scienze del Farmaco, Via dei Vestini 31, 66013 Chieti Scalo (CH), Italy b Dipartimento di Biologia Vegetale e Biotecnologie Agroambientali, Borgo XX Giugno, 74, 06126 Perugia, Italy c Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Via del Liceo, 06123 Perugia, Italy Received 10 July 2006; revised 5 August 2006; accepted 8 August 2006 Available online 30 August 2006 Abstract—In this study, we assessed in vitro minimum inhibitory concentration (MIC) values of some natural geranyloxycoumarins, geranyloxy- and isopentenyloxy acids against growth of Helicobacter pylori. Boropinic acid, active principle isolated from Boronia pinnata (Fam. Rutaceae), was seen to be the most effective compound with a MIC value of 1.62 lg/mL. Ó 2006 Elsevier Ltd. All rights reserved. Helicobacter pylori is a highly motile, gram-negative microaerophilic bacterium thought to be an infective agent of more than 50% of the world population and can be considered the most common chronic infection for humans. 1 Moreover, H. pylori is now well known to be the main causal factor in the etiogenesis of chronic active or type B gastritis, peptic and duodenal ulcer, gas- tric carcinoma, and mucosa-associated lymphoid tu- mors. 2 Pharmacological treatment of H. pylori infections includes administration of a proton pump inhibitor and a combination of two or more antibiotics, among which the most active ones are amoxicillin, clar- ithromycin, metronidazole, and tetracyclines. 3 However, bacterial resistance to these antibiotics is a growing problem: for example, metronidazole is no longer effec- tive in 10–50% of H. pylori-positive subjects and also amoxicillin and clarithromycin resistance have increased in the last few years. 4 For these reasons, the search for alternative therapeutic remedies for H. pylori infections is a field of current interest. Secondary metabolites of phenylpropanoid biosynthetic origin containing a sesquiterpenyl, monoterpenyl, and isopentenyl chains attached to a phenol group represent quite a rare group of natural products. Among these, coumarins, cinnamic, and benzoic acids have been recently shown to exert valuable biological properties. 5,6 In continuation of our research studies aimed to evalu- ate pharmacological properties of this novel class of nat- ural compounds, we wish to report here the activity of some prenyloxy-phenylpropanoids, namely, 3-(4 0 -gera- nyloxyphenyl)-2-trans propenoic acid 1, 3-(4 0 -geranyl- oxy-3 0 -methoxyphenyl)-2-trans propenoic acid 2, both isolated from Acronychia baueri Schott (Fam. Ruta- ceae), 7 boropinic acid 3, isolated from Boronia pinnata Sm. (Fam. Rutaceae), 8 valencic acid 4, isolated from Citrus sinensis L. and Aegle marmelos (Fam. Rutaceae), 9 4-isopentenyloxy-3-methoxy benzoic acid 5, 4-geranyl- oxy-3-methoxy benzoic acid 6, both isolated as methyl esters from the liverwort Trichocolea lanata (Ehrh.) Dumm. (Fam. Trichocolaceae), 10 and finally auraptene, 7, the most common geranyloxycoumarin extracted from plants belonging to genus Citrus, 6 as inhibitors of growth of H. pylori in vitro. The synthesis of compounds 1, 3, 4, 5, and 6 was accom- plished following an environment friendly route similar to that we already reported for the synthesis of com- pound 2. 5 Compound 1 was obtained in 97% overall yield starting from commercially available p-coumaric acid that was first converted into its methyl ester by reaction in refluxing MeOH catalyzed by concd. H 2 SO 4 , then alkylated with geranyl bromide and hydro- lyzed in a basic medium (Scheme 1). 0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2006.08.043 Keywords: Boropinic acid; Helicobacter pylori; Prenyloxy- phenylpropanoids. * Corresponding author. Tel.: +390 8713555321; fax: +390 8713555315; e-mail: fepifano@unich.it Bioorganic & Medicinal Chemistry Letters 16 (2006) 5523–5525