2870 Chem. Commun., 2013, 49, 2870--2872 This journal is c The Royal Society of Chemistry 2013 Cite this: Chem. Commun., 2013, 49, 2870 Making Bispirin: synthesis, structure and activity against Helicobacter pylori of bismuth(III) acetylsalicylate† Philip C. Andrews,* a Victoria L. Blair, a Richard L. Ferrero, b Peter C. Junk c and Ish Kumar a Reaction of Bi(O t Bu) 3 with aspirin (acetylsalicylic acid = aspH) in dry toluene results in the bismuth(III) complex, [Bi(O 2 C(C 6 H 4 )OAc) 3 ] N 1 (O 2 C(C 6 H 4 )OAc = asp), minimum inhibitory concentration (MIC) against Helicobacter pylori Z 6.25 lg mL À1 , while the inclusion of a stoichiometric equivalent of KO t Bu leads to crystals of the bismuthate salt [KBi(O 2 C(C 6 H 4 )OAc) 4 ] N 2. Acetylsalicylic acid (or Aspirin) is one of the worlds most widely used drugs, providing anti-inflammatory, anti-pyretic and analgesic action. 1,2 In contrast to other common non-steroidal anti-inflam- matory drugs (NSAIDs) it acts irreversibly by deactivating both COX- 1 and COX-2 enzymes. In low doses (o300 mg per day) it functions as an anti-platelet agent, preventing heart attack and blood-clotting and thus lowering the risk of adverse cardiovascular and brain- bleeding events. 3,4 It has also been demonstrated to reduce and delay incidences of various types of cancer when taken on a regular basis. 3–6 As with other NSAIDs, the major drawback in the con- sistent ingestion of aspirin is a greater risk of upper-gastrointestinal bleeding, affecting 1–2% of patients, though this can be higher is some populations. 7,8 The associated risk factors include; old age, a history of peptic ulcer disease, co-administration of other NSAIDs, antithrombotic drugs, and infection by Helicobacter pylori. 7 While there have been contradictory reports dealing with the relationship of NSAIDs, H. pylori and peptic ulcer disease, 7 it is now generally accepted that H. pylori infection should be treated to minimise the possibility of NSAID induced gastrointestinal injury, ulceration and prolonged bleeding. 9,10 Attempts to minimise aspirin related gastro- intestinal injury have primarily focused on dose lowering and modified release formulations. This appears to have little effect. 8 Bismuth compounds; bismuth subsalicylate and potassium bismuth citrate, are commonly used in triple and quadruple therapies in the treatment and eradication of H. pylori infec- tion. 11–13 They also have a positive effect on reducing bleeding and in healing stomach ulcers. It is feasible that a single drug; bismuth(III) acetylsalicylate [Bi(O 2 C(C 6 H 4 )OAc) 3 ], could provide simultaneously the desirable therapeutic and preventative effects of aspirin while providing the gastrointestinal protection of chemotherapeutic bismuth(III) carboxylates. Metal complexes of aspirinate (acetylsalicylate) and its derivatives can show improved anti-inflammatory action when compared with the parent acids. 14–16 They have also been shown to have potential in a wider range of biological and therapeutic activities; for example, the organometallic cobalt(II) complex [(m 4 - Z 2 )-(prop-2-ynyl)-2-acetoxy- benzoate] dicobalthexacarbonyl is cytotoxic towards tumorous cells, 17 and bis-substituted [Zn(asp) 2 ] complexes are described as promising candidates for treating type-2 diabetes and metabolic disorders. 18 Other examples for which crystal structures of the ‘active compounds’ are known are: [Cu 2 (asp) 4 (DMF) 2 ] 19 and [Zn(asp)(H 2 O) 2 ] 20 as anticonvulsants; [Cu 2 (asp) 4 (DMSO) 2 ] as an antioxidant; 21 and [Ag(asp)(PPh 3 ) 3 ] ÁDMF as an anti-tumour agent. 22 In this vein, we recently described the synthesis, character- isation and activity against H. pylori of bismuth(III) carboxylates derived from a series of common NSAIDs, 23 as well as the polynuclear oxido-cluster structure of bismuth subsalicylate. 24 However, the aspirin derivative remained elusive due to facile deacetylation during deprotonation and complexation, a com- mon problem since bases frequently increase the rate of hydrolysis and/or deacetylation. The only previous report in this arena coming from a solution study on the 2 : 1 complex formed between acetylsalicylic acid and bismuth nitrate. 25 Having explored various synthetic routes and reaction con- ditions for the formation of bismuth aspirinate complexes, we can now describe the formation, stability, solubility and crystal structures of [Bi(asp) 3 ] N 1 and [KBi(asp) 4 ] N 2, and the bacteri- cidal activity of 1 against three strains of H. pylori. The protolysis reaction of aspirin with BiPh 3 (3 : 1) under both solvent-mediated and solvent-free conditions, our typical routes into bismuth carboxylates, proved problematic providing a mixture a School of Chemistry, Monash University, Clayton, Melbourne, VIC 3800, Australia. E-mail: phil.andrews@monash.edu b Monash Institute of Medical Research, Centre for Innate Immunity and Infectious Diseases Monash University, Clayton, Melbourne, VIC 3168, Australia c School of Pharmacy and Molecular Sciences, James Cook University, Townsville, QLD 4811, Australia † Electronic supplementary information (ESI) available: Full experimental and analytical details, including crystallographic data and tables. CCDC 920801 and 920802. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc40645h Received 25th January 2013, Accepted 21st February 2013 DOI: 10.1039/c3cc40645h www.rsc.org/chemcomm ChemComm COMMUNICATION Published on 22 February 2013. Downloaded by Rice University on 25/12/2013 02:37:15. View Article Online View Journal | View Issue