Seventeen mono-, di- and trifunctionalized 1,8-cineole derivatives carrying OH, OAc, keto and lactone functions at C-5, C-8 and C-9 were synthesized from 1,8-cineole with fair to excellent yields. The antibacterial activity of these synthetic compounds against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus using the agar dilution method was examined. Lactones 1,3-dimethyl-2-oxabicyclo[2.2.2]octan-8-endo-acetyloxy-5→9-olide (15) and 1,3-dimethyl-2-oxabicyclo[2.2.2]octan-8-endo-ol-5→9-olide (16) showed the highest antibacterial activity against all the three Gram negative bacteria assayed. A structure-activity relationship (SAR) study on the oxygenated 1,8-cineole derivatives has allowed a model to be proposed for the recognition of the minimal structural requirements for the antimicrobial effect.
GuentherE. (1949) The Essential Oils. Van Nostrand Reinhold Co.New York, vol. II, 708.
3.
CarmanRM, FletcherMT. (1983) Halogenated terpenoids. XX. The seven monochlorocineoles. Australian Journal of Chemistry, 36, 1483–1493.
4.
MacRaeIC, AlbertsV, CarmanRM, ShawIM. (1979) Products of 1,8-cineole oxidation by a Pseudomonas. Australian Journal of Chemistry, 32, 917–922;
5.
CarmanRM, MacRaeIC, PerkinsMV. (1986) The oxidation of 1,8-cineole by Pseudomonas flava. Australian Journal of Chemistry, 39, 1739–1746;
6.
WeiGL, RosazzaJPN. (1990) Stereospecific hydroxylation of 1,8-cineole using a microbial biocatalyst. Tetrahedron Letters, 31, 2833–2836;
7.
TrudgillPW. (1990) Microbial metabolism of monoterpenes-recent developments. Biodegradation, 1, 93–105;
8.
RasmussenJAM, HendersonKA, StraffonMJ, DumsdayGJ, CoultonJ, ZachariouM. (2005) Two new biocatalysts for improved biological oxidation of 1,8-cineole. Australian Journal of Chemistry, 58, 912–916.
9.
SouthwellIA. (1975) Essential oil metabolism in the koala. III Novel urinary monoterpenoid lactones. Tetrahedron Letters, 24, 1885–1888;
10.
BoyleR, McLeanS, FoleyW, DaviesNW, PeacockEJ, MooreB. (2001) Metabolites of dietary 1,8-cineole in the male koala (Phascolarctos cinereus). Comparative Biochemistry and Physiology Part C, 129, 385–395;
11.
BoyleR, McLeanS, DaviesNW. (2000) Biotransformation of 1,8-cineole in the brushtail possum (Trichosurus vulpecula). Xenobiotica, 30, 915–932;
12.
FlynnTM, SouthwellIA. (1979) 1,3-Dimethyl-2-oxabicyclo[2.2.2]octane-3-methanol and 1,3-dimethyl-2-oxabicyclo[2.2.2]octane-3-carboxylic acid, urinary metabolites of 1,8-cineole. Australian Journal of Chemistry, 32, 2093–2095;
13.
MiyazawaM, KameokaH, MorinagaK, NegoroK, MuraN. (1989) Hydroxycineole: Four new metabolites of 1,8-cineole in rabbits. Journal of Agricultural and Food Chemistry, 37, 222–226.
14.
LaudeEA, MoriceAH, GrattanTJ. (1994) The antitussive effects of menthol, camphor and cineole in conscious guinea-pigs. Pulmonary Pharmacology, 7, 179–184;
15.
TzakouO, PitarokiliD, ChinouIB, HarvalaC. (2001) Composition and antimicrobial activity of the essential oil of Salvia ringens. Planta Medica, 67, 81–83;
16.
CoppenJW. (2002) Production, trade and markets for eucalyptus oils. In Eucalyptus: The genus Eucalyptus, Medicinal and Aromatic Plants-Industrial Profiles, vol. 22, CoppenJW (Ed). Taylor & Francis, London;
17.
MiyazawaM, ShindoM, ShimadaT. (2001) Oxidation of 1,8-cineole, the monoterpene cyclic ether originated from Eucalyptus polybractea, by cytochrome P450 3A enzymes in rat and human liver microsomes. Drug Metabolism and Disposition, 29, 200–205.
18.
MartindaleW. (1993) The Extra Pharmacopoeia. Pharmaceutical Press, London
19.
LeeB-H, AnnisPC, TumaaliiF, ChoiW-S. (2004) Fumigant toxicity of essential oils from the Myrtaceae family and 1,8-cineole against 3 major stored-grain insects. Journal of Stored Products Research, 40, 553–564;
20.
KordaliS, KesdekM, CakirA. (2007) Toxicity of monoterpenes against larvae and adults of Colorado potato beetle, Leptinotarsa decemlineata Say (coleoptera: Chrysomelidae). Industrial Crops and Products, 26, 278–297.
21.
LeeB-H, ChoiW-S, LeeS-E, ParkB-S. (2001) Fumigant toxicity of essential oils and their constituent compounds towards the rice weevil, Sitophilus oryzae (L.). Crop Protection, 20, 317–320.
22.
MiyazawaM, HashimotoY. (2002) Antimicrobial and bactericidal activities of esters of 2-endo-hydroxy-1,8-cineole as new aroma chemicals. Journal of Agricultural and Food Chemistry, 50, 3522–3526.
23.
SilvestreAJD, CavaleiroJAS, FeioSS, RoseiroJC, DelmondB, FilliatreC. (1999) Synthesis of some new benzylic ethers from 1,8-cineole with antimicrobial activity. Monatshefte für Chemie, 130, 589–595.
24.
SimonsenJL. (1953) The Terpenes. Cambridge University Press, Vol 1, 423–432.
25.
de BoggiattoMV, HeluaniCS, FenikIJS, CatalánCAN. (1987) Regiospecific functionalization of the monoterpene ether 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane (1,8-cineole). Synthesis of the useful bridged γ-lactone 1,3-dimethyl-2-oxabicyclo[2.2.2]octan-3→5-olide. Journal of Organic Chemistry, 52, 1505–1511;
26.
De MartinezMV, De VendittiFG, De FenikIJS, CatalanCAN. (1982) Oxidation of 1,8-cineole with chromyl acetate. Some new oxygenated derivatives of 1,8-epoxy-p-menthane. Anales de la Asociacion Quimica Argentina, 70, 137–48.
27.
SilvestreAJD, CavaleiroJAS. (1996) 1,8-Cineole: applications, metabolism and chemical transformations. Revista Farmaceutica, 138, 49–57.
28.
VilleccoMB, MuroAC, CatalánJV, CatalánCAN. (2005) Capitulo IX. Síntesis de derivados de 1,8-cineol, cariofileno y cariolan-1-ol con utilidad en perfumería y farmacología. In Plantas Iberoamericanas como fuente de terpenoides Útiles en química fina. FernándezBarrero A. (Ed). Programa CYTED, Granada, Spain, 189–211.
29.
BitteurSM, BaumesRL, BayonoveCL, VersiniG, MartinCA, Dalla SerraA. (1990) 2-exo-Hydroxy-1,8-cineole: A new component from grape var. Sauvignon. Journal of Agricultural and Food Chemistry, 38, 1210–1213.
30.
SouthwellIA, RusselMF, MaddoxCDA, WheelerGS. (2003) Differential metabolism of 1,8-cineole in insects. Journal of Chemical Ecology, 29, 83–94.
31.
CarruthersW. (1978) Some Modern Methods of Organic Synthesis. 2nd ed. Cambridge University Press, Cambridge, 240–260 and references cited therein.
32.
SrebrenikS, WeinsteinH, PaunczR. (1973) Analytical calculation of atomic and molecular electrostatic potentials from the Poisson equation. Chemical Physics Letters, 20, 419–423.
33.
PolitzerP, TruhlarDG. (1981) Chemical Applications of Atomic and Molecular Electrostatic Potentials.Plenum Press, New York.
34.
CarruptPA, El TayarN, KarlénA, TestaB. (1991) Molecular electrostatic potentials for characterizing drug-biosystem interactions. Methods in Enzymology, 203, 638–677.
35.
GreelingP, LangenaekerW, De ProftF, BaetenA. (1996) Molecular Electrostatic Potentials: Concepts and Applications. Theoretical and Computational Chemistry, vol. 3, MurrayJS, SenK (editors). Elsevier Science, Amsterdam, 587–617.
36.
YangY, ZhangW, PeiS, ShaoJ, HuangW, GaoX. (2005) Blue-shifted and red-shifted hydrogen bonds: Theoretical study of the CH3CHO…NH3 complexes. Journal of Molecular Structure (Theochem), 732, 33–37.
37.
United States Pharmacopeial Convention (1975) Biological tests and assays. Antibiotic-microbial assays. In United States Pharmacopeia XIX.Rockville Mack Publishing Co., MO, 595
SantagataLN, SuvireFD, EnrizRD, TordayLL, CsizmadiaIG. (1999) A geometrical algorithm to search the conformational space of flexible molecules. Journal of Molecular Structure (Theochem), 465, 33–67.
40.
SantagataLN, SuvireFD, EnrizRD. (2000) An analytic ring closure condition for geometrical algorithm to search the conformational space. Journal of Molecular Structure (Theochem), 507, 89–95.
41.
SantagataL, SuvireFD, EnrizRD. (2001) Partially relaxed ring closure conditions for geometrical algorithm to search the conformational space for minimum energy conformations. Journal of Molecular Structure (Theochem), 536, 173–188.
42.
BeckeAD. (1988) Density-functional exchange-energy approximation with correct asymptotic behavior. Physical Review A, 38, 3098–3100.
43.
BeckeAD. (1993) Density-functional thermochemistry. III. The role of exact exchange. Journal of Chemical Physics, 98, 5648–5652.
44.
LeeC, YangW, ParrRG. (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Physical Review B, 37, 785–789.
45.
MOLEKEL 4.3, FlükigerP, LüthiHP, PortmannS, WeberJ. (2000) Swiss Center for Scientific Computing, Manno (Switzerland), 2000–2002. Stefan Portmann & Hans Peter Lüthi. MOLEKEL: An Interactive Molecular Graphics Tool. Chimia, 54, 766–770.
