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Biotransformation of monoterpenoids and their antimicrobial activities.

ABSTRACT

Biotransformation is an economically and ecologically viable technology which has been used extensively to modify the structures of many classes of biologically active products. The discovery of novel antimicrobial metabolites from biotransformation is an important alternative to overcome the increasing levels of drug resistance by plant and human pathogens. Monoterpenes, the main constituents of essential oils, are known for their antimicrobial activities. In 2004, Farooq, Atta-Ur-Rahman and Choudhary published a review on fungal transformation of monoterpenes which covers papers published up to 2002. The present review not only updates the previous one but also discusses the antimicrobial activities (antibacterial, antifungal and antiviral) of biotransformed compounds.

Keywords:

Biotransformation

Monoterpenes

Antibacterial

Antifungal

Antiviral
Contents

Introduction
Fungal transformation of monoterpenes
  Transformation by Aspergillus species (Aspergillus niger,
    Aspergillus ochraceus and Aspergillus cellulosae)
  Transformation by Diplodia gossypina
  Transformation by Botrytis species (Botrytis cinerea and
    Botrytis allii)
  Transformation by Clomerella cingulata
  Transformation by Mucor species (Mucor piriformis, Mucor
    circinelloides, Mucor Mucedo and Mucor parasiticus)
  Transformation by Armillaria mellea
  Transformation by Streptomyces species (Streptomyces bottropensis,
    Streptomyces ikutamanesnsis, Streptomyces acidoresistans)
  Transformation by Corynespora cassicola
  Transformation by Rhizoctonia solani and Fusarium species (Fusarium
    solani, Fusariam oxysporium and Fusarium lini)
  Transformation by Cephalosporium aphidicola
  Transformation by Rhizopus species (Rhizopus solani and Rhizopus
    arrhizus and Rhizopus stolonifer)
  Transformation by Absidia glauca
  Transformation by Penicillium species (Penicillium italicum,
    Penicillium granulatum)
  Transformation by Cibberella cyanea
  Transformation by Curvularia lunata
  Transformation by M. isabellina, Botryosphaeria rhodina
  Transformation with Spirodela oligorrhiza
  Transformation with Flypocrea Sp
  Biological activities of monoterpenes
      Antimicrobial activities of monoterpenes
      Antibacterial activities of monoterpenes
      Antifungal activities of monoterpenes
      Antiviral activities of monoterpenes
      Antioxidant activities of monoterpenes
      Anxiolytic activities of monoterpenes
    Conflicts of interest
    References


Introduction

Monoterpenes, the main constituents of essential oils, are known for their several biological activities (Martino et al. 2010). Many monoterpenes have been described as potent inhibitors of seed germination and growth of several plant species (Abrahim et al. 2000). The monoterpene: ([+ or -])-[beta]-citronellol, ([+ or -])-citronellal, (-)-[alpha]-pinene, (-)-[beta]-pinene, [alpha]-terpinene, [gamma]-terpinene, [alpha]-terpineol, 1,8-cineole, citral, thymol, carvacrol, [alpha]+[beta]-thujone, camphene, ([+ or -])-camphor, (-)-borneol, p-cymene, myrcene, menthone, ([+ or -])menthol, geraniol, geranyl acetate, linalool, linalyl acetate, (R)-(-)-[alpha]-phellandrene, estragole, (R)-(-)-carvon, limonene showed potent phytotoxic activity and these compounds could be used both as potential bio-herbicides and lead structures for the development of new, potentially safe and ecocompatible pesticides (Martino et al. 2010).

The monoterpenes have been reported as potent antimicrobial agent. The three monoterpenes viz. linalyl acetate, (+) menthol, and thymol, have shown antimicrobial efficacy against the gram-positive bacterium Staphylococcus aureus and the gram-negative bacterium Escherichia coli (Trombetta et al. 2005). While the carvacrol, (+)-carvone, thymol, and trans-cinnamaldehyde were reported for their inhibitory activity against Escherichia coli and Salmonella typhimurium (Helander et al. 1998). The halogenated monoterpenes have been reported for their potent cytotoxic activity (de Ines et al. 2004) and antialgal (Kdnig et al. 1999) as well as antimalarial activity (Sun et al. 2008). The monoterpenes have a good acaricides against Psoroptes cuniculi (Perrucci et al. 1995). The monocyclic monoterpenes have been reported as good insecticidal agent (Prates et al. 1998) along with low toxicity to mammals (Karr and Coats 1988). The monoterpenes are also used as an ingredient of soaps, perfumes, and food additives (Prates et al. 1998). The monoterpenes have been reported as antiviral agent (Armaka et al. 1999) and antifungal agent as well (Kurita et al. 1979). The thymol, a monoterpene has promising antileishmanial potential (Hammer et al. 2003) and widely used in medicine for its antimicrobial, antiseptic, disinfectant, and wound-healing properties (Aeschbach et al. 1994; Cenas et al. 2006; Didry et al. 1994; Kulevanova et al. 1999; Ogaard et al. 1996; Shapiro and Guggenheim 1995). Moreover, the monoterpenes have also been reported as potent antioxidant (Ruberto and Baratta 2000).

Biotransformation is considered to be an economically and ecologically viable technology and has recently been used to modify the structures of some biologically active products and study the metabolism of natural products (De Carvalho and da Fonseca 2006). Many of steroidal drugs having potential biological activities were synthesized by microbial transformation (Choudhary et al. 2007). Microorganisms have also been used to convert the bioactive natural products to derivatives with enhanced activities and/or decreased toxicities (Davis 1987).

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Fungal transformation of monoterpenes

This section describes the biotransformation of cyclic (monocyclic, bicyclic) and acyclic monoterpenes by different fungi.

Transformation by Aspergillus species (Aspergillus niger,

Aspergillus ochraceus and Aspergillus cellulosae)

YaMazaki et al. (1988) reported the transformation of fi-myrcene (1) by A. niger (JTS191) to yield three diols known as 2-methyl-6-methylene-7-octene-2,3-diol (2), 6-methyl-2-ethenyl-5-heptene-1,2-diol (3) and 7-methyl-3-methylene-6-octene-1,2-diol (4) (Scheme 1).

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The biotransformation of camphor (5) and [beta]-pinene (5a) was studied by Rozenbaum et al. (2006) with A. niger IOC-3913. For camphor (5), three main products were detected in all the tests done. The proposed structures of these products, based on an analysis of the ions formed by fragmentation in mass spectrometer, are of two isomers of keto acid derivative (6a and 6b) and (7), and one lactone (8) (Scheme 2). [beta]-Pinene (5b) yielded only [alpha]-terpineol (9) (Scheme 3).

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Citronellyl acetate (7) was transformed to citronellol (8) and 8I hydroxycitronellol (9) by fermentation of A. niger (Madyastha and Murthy 1988) (Scheme 4).

Miyazawa et al. (1990) transformed (+)-fenchone (10) to (+)I 6-endo-hydroxy-fenchone (11) and (+)-5-endo-hydroxyfenchone (12) by A niger (Scheme 5).

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Terpinolene (13) afforded 1,7-dihydroxy-p-menth-3-ene-2-one (14) by transformation with fungus A. niger (Asakawa et al. 1991) (Scheme 6).

A. niger transformed 1,4-cineole (15) regiospecifically to 2[alpha]-hydroxy-1,4-cineole (16) and (+)-3endo-hydroxy-1,4-cineole (17) along with formation of 9-hydroxy-1,4-cineole (18) and p-menthan-1,4-diol (19) (Miyazawa et al. 1991). These metabolic pathways are shown in Scheme 7.

(-)-Carvotanacetone (20) was fermented with A. niger to afford p-menthan-2,9-diol (21) (Asakawa et al. 1991) as reported in Scheme 8.

3R and 3S-isomers of citronellol-N-phenylcarbamate, (22) and (25) were efficiently hydroxylated by A. niger at different pH values (Zhang et al. 1992). 3f?-Citronellol-N-phenylcarbamate (22) was transformed to (3R,6S)-6,7-dihydroxy citronellol-3,7-dimethyl-octan-1-yl phenyl carbamate (23) and (3R,6R)-6,7-dihydroxy citronellol-3,7-dimethyl-octan-1-yl-phenyl carbamate (24) by fermentation with A. niger at pH 2 and 6, respectively (Scheme 9). Fermentation of 3S-citronellol-N-phenylcarbamate (25) with A. niger yielded (3S,6S)-6,7-dihydroxy citronellol-3,7-dimethyl-octan-1-yl phenylcarbamate (26) and (3S,6R)-6,7-dihydroxy citronellol-3,7-dimethyl-octan-1-yl-phenyl carbamate (27) at pH 2 and 6, respectively (Scheme 10).

Fungal transformations of (4S,8R)-limonene-8,9-epoxide (28) and (41?,8S)-limonene-8,9-epoxide (30) have been reported by Chen et al. (1993). (4S,8R)-Limonene-8,9-epoxide (28) was hydroxylated to (4S,81?)-p-menth-1-en-8,9-diol (29), whereas, (4R,8S)-limonene-8,9-epoxide (30) afforded (4R,8S)-p-menth-1-en-8,9-diol (31) by fermentation with A. niger as described in Scheme 11.

Biotransformation of (+)-isomenthol (32) and (-)-neomenthol (35) by A. niger have been reported by Takahashi et al. (1994). Compound (32) was smoothly transformed to 1[alpha]- (33) and 6[beta]-hydroxy-(+)-isomenthol (34) (Scheme 12). Compound (35) was nonspecifically transformed to 2[beta]- (36), 6[beta]- (37), 7- (38), 8- (39) and (8R and 8S)-9-hydroxy-(-)-neomenthol (40a and 40b) and 1[beta],8-dihydroxy-(-)-neomenthol (41). These transformations are represented in Scheme 13.

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Karahanaenone (42) was fermented with A niger (Miyazawa et al. 1995d) to yield (S) karahanaenol (43) as shown in Scheme 14.

(-)-Camphorquinone (44) was transformed to (+)-(2R)-endohydroxy camphor (45) by A niger as described in Scheme 15. Miyazawa et al. (1995b) also reported the metabolism of (+)-Camphorquinone (46). Compound (46) was metabolized to (+)-(2R)-exo-hydroxy-epicamphor (47) by A niger as shown in Scheme 16.

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Geranyl-N-Phenylcarbamate (48) was transformed to (6S)-6.7-dihydroxy geranyl-N-phenylcarbamate (49) and (6R) 6,7-dihydroxy geranyl-N-phenylcarbamate (50) by fermentation with A niger (Fourneron et al. 1989) as shown Scheme 17.

A niger transformed ([+ or -]) cis nerodilol (51) into (Z)-3,7-11-trimethyl-1,6 dodecadien-3,10,11-triol (52) and (6Z, 10E)-3,7,11-trimethyl-1,6,10-dodecatrien-3,12 diol (53) (Scheme 18).

Fermentation of (2E, 6E) farnesol (54) by A niger (Madyastha and Gururaja 1993) produced two oxidized metabolites, i.e. (2E, 6E) 3.7.11-trimethyl-2,6-dodecadien-1,10,11-triol (55) and (2E, 6E)-3.7.11-trimethyl-2,6,10 dodecatrien-1,13-diol (56) shown in the Scheme 19.

1,8-Cineole (57) was hydroxylated by A niger (Nishimura et al. 1982) to yield 2-exohydroxy-1,8-cineole (58) and 3-exo-hydroxy 1,8-cineole (59) (Scheme 20).

[beta]-Thujone (60) was transformed to 6-hydroxy-[alpha]-thujone (61) by Aspergillus ochraceus (Ilidrissi et al. 1990) (Scheme 21). (-)-(1R,2R,S)-[alpha]-Thujone (62) yielded (1S,2S,5S)-2-hydroxythujone (63) after metabolism by Aspergillus niger (Alaoui et al. 1994) (Scheme 22).

Noma et al. (1992) reported the biotransformation of ([+ or -])-(4R)-limonene (64) and (-)-(4S)-limonene (67). ([+ or -])-(4R)-Limonene (64) afforded (1S,2S,4R)-p-menth-8-en-1,2-diol (65) and isopiperitenone (66) when fermented with Aspergillus cellulosae (Scheme 23). Whereas (-)-(4S)-limonene (67), yielded (1R,2R, 4S)-p-menth-8-en-1,2-diol (68) and (-)-perillyl alcohol (69) with the same fungus. The fungal metabolites of (-)-(4S)-limonene (67) are shown in Scheme 24.

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(+)-Menthol (70) after fermentation with A. niger yielded p-menthan-3,7 diol (71) (Scheme 25), while (-)-menthol (72) afforded p-menthan-3,9-diol (73) (Asakawa et al. 1991) (Scheme 26).

The biotransformation of nerol (74) and geraniol (77) (Demyttenaere et al. 2000) by A. niger was studied (Scheme 27). Linalool (75) and a-terpineol (76) were the main products obtained from nerol by sporulated surface cultures along with some minor products, where as geraniol (77) was converted predominantly to linalool (75) also resulting in higher yields (Scheme 28).

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Transformation by Diplodia gossypina

YaMazaki et al. (1988) reported the transformation of [beta]-myrcene (1) by Diplodia gossypina to yield three diols known as 2-methyl-6-methylene-7-octene-2,3-diol (2), 6-methyl-2-ethenyl-5-heptene-1,2-diol (3) and 7 methyl-3-methylene-6-octene-1,2-diol (4) (Scheme 1a).

(3S)-citronellene (78) and (3R)-citronellene (80) afforded (3S,6S)-7,6 dihydroxycitronellene (79) and (3R,6R)-7,6 dihydroxycitronellene (81) by fermentation with fungus Diplodia gossypina (Abraham and Stumpf 1987) (Scheme 29).

D. gossypina (Abraham and Stumpf 1987) transformed neryl acetone (82) into (Z)-9,10 dihydroxy-6,10-dimethyl-5-undecen-2-one (83) and (Z)-6,10-dimethyl-5-undecean-2,9,10 triol (84) (Scheme 30).

([+ or -])-(4R)-Limonene (64) yielded (lS,2S,4R)-p-menth-8-ene-1,2, diol (69) when fermented with the fungus Diplodia gossypina (Scheme 31) while (-)-(4S)-limonene (67) afforded (1R,2R, 4S)-p-menth-8-ene-l ,2-diol (72) by fermentation with D. gossypina (Abraham et al. 1986) (Scheme 32).

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Terpinolene (13) transformed into (1R,2R)-p-menth-4 (8)-ene, 1,2-diol (85) with fungus D. gossypina (Asakawa et al. 1991) (Scheme 33).

Transformation by Botrytis species (Botrytis cinerea and Botrytis allii)

Brunerie et al. (1987) converted Citronellal (85) into 8-hydroxycitronellal (86) and 2,6-dimethyl-octane-1,8-ol (87) along with seven minor metabolites, i.e. 2,6-dimethyl-2,8 octandiol (88), p-menthan-2,8-diol (89), (Z)-2,6-dimethyl-2-octen-1,8-diol (90), isopulegol (91), 2 methyl-hepten-6-one-ol (92) and 2-methyl-8-butyrolactone (93) by four strains of B. cinerea. When grape must was added to the medium products, compounds 86,88 and 89 were absent while three new products 2-methyl-2-hepten-6-one (94), 2-methyl-2-hepten-6-ol (95) and citronellic acid (96) were formed (Scheme 34).

Geraniol (77) was transformed to Z-2-methyl-2-hepten 6-one-1-ol (97), E-2-methyl-2-hepten-6-one-1-ol (98), E-2-methylhepten-6-one-1-ol (99), 7-hydroxy-6-methyl-2-heptanone (100), 3,7-dimethyl-2,6 octadiene-1,8-diol (101), E-3,7-dimethyl-2-octen-1,8-diol (102), p-menth-1-ene-9-ol (103), 2E, 6E, 8 hydroxy-2,6-dimethyl-2,6-octadienol (104), geranial (105), citronellol (8), 2-methyl 2-hepten-6-one (106), 2-methyl-2-hepten-6-ol (107), 2,6 dimethyl-2,7-octadien-1,6 diol (108), 6-hydroxyl-2,6 dimethyl-2,7 octadienol (109), 2,6 dimethyl-octandiol (110), (2Z, 6E)-3,7-dimethyl-2,6-octadien-1,8-diol (111), (Z)-3,7-dimethyl-2-octen-1,8-diol (112) and nerol (74) by using B. cinerea (Bock et al. 1988) (Scheme 35).

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(-)-[alpha]-Pinene (113) was biotransformed by the plant pathogenic fungus, B. cinerea (Bocket al. 1988) to afford four metabolites characterized as Verbenone (114), 3[beta]-hydroxy-(-)-[beta]-pinene (115), 9-hydroxy-(-)-[alpha]-pinene (116) and .4[beta]-hydroxy-(-)-[alpha]-pinen-6-one (117) (Scheme 36).

The transformation of (-)-[beta]-pinene (118) by B. cinerea presented in Scheme 36 was reported by Dracksynzka et al. (Farooq et al. 2002) to yield 6a-hydroxy-(-)-[beta]-pinene (119) 4[beta],5[beta]-dihydroxy-(-)-[beta]-pinene (120), 2,3-dihydroxy-2[beta], 3[beta]-dihydroxy-(-)-[beta]-pinene (121), 4-[beta]-(-)-hydroxy-(-)-[beta]-pinene-6-one (122) (Scheme 37).

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Nerol (74) was transformed to metabolite 123-140 (Scheme 38) by incubation with B. cinerea (Bock et al. 1988).

Linalool (75) yielded 8-hydroxylinalool (141) when incubated with fungus B. cinerea (Fourneron et al. 1989) (Scheme 39).

Citral (142) was transformed to nerol (74) and geraniol (77) (Draczynska et al. 1985) by fermentation with B. cinerea as shown in Scheme 40.

Bock et al. (1986a, b) studied of the biotransformation of linalool (143) in grape must three different strains of B. cinerea. Linalool (143) was converted into (E)-2,6-dimethylocta-2,7-diene-1,6-diol (144). Other products of the metabolization of linalool (143), amounting to less than 10% of those identified, were the corresponding (Z)-isomer (145), 2-vinyl-2-methyltetrahydrofuran-5-one (146), the four (E) and (Z) linalool oxides in their furanoid (147, 148) and pyranoid (149, 150) forms, the (E) and (Z) acetates of pyranoid linalool oxides (151,152), as well as 3,9-epoxy-p-menth-1-ene (153) (Scheme 41).

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Schwab et al. studied the stereo selective formation of metabolites from 2-methylhept-2-en-6-one (154) by B. cinerea (Schwab et al. 1991). The compound obtained as the major biotransformation product was (S)-(+)-2-methylhept-2-en-6-ol (155) (Scheme 42).

(+)-R-Pulegonne (156) on fermentation with Botrytis allii (Miyazawa et al. 1991a) yielded (-)-(1R)-7-hydroxy-p-menth-4-en-3-one (157) and piperitenone (158) (Scheme 43).

Transformation by Glomerella cingulata

Miyazawa et al. (1997a) reported the metabolism of (-)-cis-myrtanol (159) (-)-4-oxo-cis-myrtanol (160) 5-hydroxy-cis-myrtanol (161) (-)-(4R)-4-hydroxy-cis-myrtanol (162) (-)-(3S)-3-hydroxy-cis-myrtanol (163) by Glomerella cingulata (Scheme 44). The same authors further reported the fermentation of (-) transmyrtanol (164) yielded four compounds 165-168 by the same fungus as presented is Scheme 45.

Nopol (169) transformed into (-)-(4R)-4-hydroxynopol (170), 4-oxonopol (171) and 5-hydroxynopol (172) with G. cingulata as reported by Miyazawa et al. (1995c) (Scheme 46).

(+)-Isopinocampheol (173) yielded (1S,2S,3S,5R,7R)-pinane-3,6-diol (174) (1S,2S,3S,5R)-pinane-3,9-diol (175) and (lS,2S,3S,5S)-pinane-3,5-diol (176) after metabolism by G. cingulata (Schwab et al. 1991) (Scheme 47). (-)-lsopinocampheol (177) was also transformed to (1R,2R,3S,4S,5R)-3,4 pinane diol (178). (1R,2R,3R,5R)-pinan-3,5-diol (179) (lS,2S,3R,5S)-pinan-2,3-diol (180) by C. Cingulata (Scheme 48).

(+)-Camphorquinone (46) was metabolized by G. cingulata yielded (+)-(1S,2R,3S)-comphane-2,3-diol (181) (Scheme 49). While (-)-Camphorquinone (44) was metabolized by Glomerella dngulata (Archelas et al. 1986) to yield (+)-(1R,2R,3R)-Camphane-2,3-diol (182) and 3S-endo-hydroxycamohor (183) (Scheme 50).

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Miyazawa et al. (1995a) used plant pathogenic fungus C. dngulata to transform neryl acetone (82) into (Z)-9,10-dihydroxy 6.10- dimethyl-5-undecen-2-one (184) as the major product along with three minor products. These products were identified as (Z)-6,10-dimethyl-5,9-undecadien-2-ol (185), (Z)-10-hydroxy-6,10-dimethyl-5-undecen-2-one (186) and (Z)-6,10-dimethyl-5undecen-2,9,10-triol (187) (Scheme 51).

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([+ or -])-Citronellol (188) was transformed to 6,7-dihydroxycitronellol (189) by fermentation with a plant pathogenic fungus, Glomerella dngulata (Miyazawa et al. 1996b) (Scheme 52).

Nankai et al. (1996) fermented ([+ or -])-citronellal (190) with Glomerella dngulata. The biotransformation afforded citronellol (8) and 3,7-dimethyl-1,6,7-octantriol (191) as shown in Scheme 53.

([+ or -])-Lavandulol (192) was fermented with Glomerella cingulata (Nankai et al. 1998) to produce the metabolite (-)-(2S,4S) 1,5-epoxy-5-methyl-2-(l-methylethenyl)-4-hexanol (193) and cis and trans-1,4 epoxy-5-methyl-2-(1-methylethenyl)-5-hexanols (194) and (195) (Scheme 54), while ([+ or -])-tetrahydrolavandulol (196) was transformed to 5-hydroxy tetrahydrolavandulol (197) by Clomerella cingulata (Nankai et al. 1997), as shown in Scheme 55.

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Karahanaenone (42) was fermented with Glomerella cingulata, to yield (-)-(S)-karahanaenol (43) (Miyazawa et al. 1995d). The fungal transformation of karahanaenone (42) is shown in Scheme 56.

Miyazawa et al. (1997b) reported the biotransformation of lime-oxide-T (2-(1-methylethenyl)-5-ethenyl-5-methenyl-tetrahydrofuran), a cyclic monoterpene (198) by Glomerella cingulata. It was observed that acetic acid adds to the double bond of isopropenyl group to form 5-ethenyltetrahydro-[alpha],[alpha], 5-trimethyl-2-furanmethanyl acetate (199) as described in Scheme 57.

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The fungal transformation of (-)-cis-myrtanol (159) was investigated by Miyazawa et al. (1997b) using Glomerella cingulata. Compound (159) afforded (-)-4-oxo-ris-myrtanol (200), 5-hydroxy-cis-myrtanol (201), (-)-(4R)-4-hydroxy-cis-myrtanol (162) and (-)-(3S)-3-hydroxy-ris-myrtanol (202). These metabolites are shown in Scheme 58.

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Tetrahydrogeraniol (203) was transformed to hydroxy citronellol (204) by fermentation with G. cingulata (Scheme 59).

Miyazawa et al. (1995a) ([+ or -]) cis-nerodilol (51) described the hydroxylation of (51) by plant pathogenic fungus G. cingulata to yield (Z)-3,7,ll-tri methyl-1,6-dodecadien-3,10,11-triol (52) (Scheme 60).

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Oxidation of (2E, 6E)-farnesol (54) proceeded by plant pathogenic fungus, G. cingulata (Miyazawa et al. 1996a) yielded (2E, 6E)-3,7,ll-trimethyl-2,6 dodecadien 1,11 -triol (205) and (2E, 6E) 3,7,11-trimethyl-2,6-dodecadien-l,ll-diol (206) in the first step. In the second step, the hydroxylation of (2E, 6E)-3,7,11-trimethyl-2,6-dodecadien 1,11-diol (206) at C-5 position yielded (2E, 6E)-3,7,11-trimethyl-2,6 dodecadien-1,5,11 triol (207) which was transformed to (2Z, 6E)-3,7,ll-trimethyl-2,6-dodecadien 1,5,11-triol (208) through isomerization (Scheme 61).

1,8-Cineole (57) was hydroxylated by G. cingulata (Miyazawa et al. 1991c) to yield (+)-(1S,2S,4R)-2-endo-hydroxy-1,8-cineole (209) (Scheme 62).

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Transformation by Mucor species (Mucor piriformis, Mucor circinelloides, Mucor Mucedo and Mucor parasiticus)

Stumpf and Kieslich (1991) carried out the biotransformation of geraniol (77) with Mucor circinelloides to yield (2S,3R)-5,9-dimethyl-deca-4E-8E-dien-2,3-diol(210).The biotransformation is represented in Scheme 63.

Biotransformation of Citral (142) by Mucor circinelloides (CBS 27749) afforded a mixture of nerol (74) and geraniol (77) as major product (31.5%) along with (2S,3R)-3,6-dimethyl-deca-4E, 8E-dien 2,3-diol (211) (7.7%) 3,7-dimethyl-6E-octen-l,3-diol (212) (2.9%) and 3-oxo-l-menthen-7-ol (213) (0.2%) (Scheme 64).

Mucor circinelloides transformed neryl acetone (82) into (Z)-9,10 epoxy 6,10-dimethyl-5-undecen-2-one (214) and (Z)-11-hydroxy-6, 10-dimethyl-5-undecen-2-ene (215) (Scheme 65).

Biotransformation of a monoterpenes ketone, (R)-(+)-pulegone (156), a potent hepatotoxin, was also studied by Madyastha and Thulasiram (1999) using a fungal strain, Mucor piriformis. Eight metabolites, namely, 5-hydroxypulegone (216), piperitenone (158), 6-hydroxypulegone (217), 3-hydroxypulegone (218), 5-methyl-2-(1-hydroxy-1-menthyethyl)-2-cyclohexen-l-one (219), 3-hydroxyisopulegone (220), 7-hydroxypiperitenone (221) and 7hydroxypulegone (222) were obtained (Scheme 66).

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(-)-Camphorquinone (44) was metabolized by Mucor mucedo (Archelas et al. 1986) to yield (+)-(lR,2R,3R)-Camphane-2,3-diol (223) and 3S-endo-hydroxycamohor (183) (Scheme 67). Miyazawa et al. (1995b) also reported the metabolism of (+)-Camphorquinone (46). Compound 46 was metabolized to (-)-(3S)-exo-hydroxycamphor (224) by Mucor Mucedo (Scheme 68).

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([+ or -])-Piperitone oxide (225) by fermentation with M. parasiticus yielded (-)-4-hydroxypiperitone (226) (Nishimura et al. 1982) as presented in Scheme 69.

Transformation by Armillaria mellea

Fermentation of (-)-trans-sobrerol (227) with Armillaria mellea afforded (4R)-7-hydroxy-p-menthan-1-en-6-one (228) and (4R)-7-hydroxy-p-menthan-6-one (229) (Draczynska Lusiak and Siewinski 1991), as described in Scheme 70.

Draczynska Lusiak (1987) have described the use of A mella to transform (-)-(4-R)-1-p-menthene (230) to p-menthene-1,2-diol (231) (Scheme 71).

([+ or -])-(4R)-Limonene (64) yielded (1S,2S,4R)-p-menth-8-ene-1,2, diol (69) when fermented with the A mella (Noma and Nishimura 1987) (Scheme 72). (-)-(4S)-Limonene (67) afforded (1R,2R,4S)-p-menth-8-ene-1,2-diol (72) by fermentation with A mella (Draczynska Lusiak and Siewinski 1991) (Scheme 73).

Draczynska Lusiak and Siewinski (1991) reported the hydroxylation and hydrolysis of ([+ or -])-menthyl acetate (232), 8-hydroxy menthyl acetate (233) and p-menthane-3,8 diol (234) by A mella (Scheme 74).

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Draczynska et al. (1985) transformed (+)-a-pinene (235) and (-)-[alpha]-pinene (113) to (+)-trans sobrerol (236) and (-)trans sobrerol (237) by fermentation with Armillaria mella (Schemes 75 and 76).

Verbenole (238) was metabolized to Verbenone (114) by Armillaria mella (Noma and Nishimura 1987) as described in Scheme 77.

The transformation of (-)-[beta]-Pinene (118) by A mellea presented in Scheme 78 was reported by Draczynska et al. (1985) to yield trans-pinocarveole (239).

[alpha]-Terpineol (240) yielded (+)-(1R,2R,4R)-p-menthan, 2,7,11-triol (241) along with (-) trans sorberol (237)by incubation with A mellea (llidrissi et al. 1990) (Scheme 79).

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Transformation by Streptomyces species (Streptomyces bottropensis, Streptomyces ikutamanesnsis, Streptomyces acidoresistans)

C/s-(+)-(2S,4S)-carveol (242) yielded (+)-(2S,4S,8R)-2,8-oxidomenth-6-en-9-ol (243) by Streptomyces ikutamanesnsis as reported by Draczynska and Siewinski. While ris-(-)-(2R,4R)-carveol (244) yielded metabolite (245) by fermentation with streptomyces bottropensis or S. ikutamanesnsis (Draczynska Lusiak and Siewinski 1991; Pawlowicz et al. 1988) (Scheme 80).

Biotransformation of tetramethyl-limonene (246) with Streptomyces acidoresistans gave only metabolite 8,9-epoxy-6-hydroxy-3,3,5,5 tetramethyl limonene (247), (Scheme 81) (Abraham et al. 1986).

Transformation by Corynespora cassicola

Abraham et al. reported the transformation of [alpha]-phellandrene (248) catalyzed by the fungus Corynespora casiicola to yield a metabolite (IS,2S,4R)-p-menth-5-ene-l,2-diol (249) (Stumpf et al. 1990) (Scheme 82).

Abraham et al. (1990) reported the biotransformation of neryl acetone (82) by Coryneospora cassicola into 10-hydroxy-5, 6-epoxynerylacetone (250) and 9S-hydroxyl-5,6-epoxnerylacetone (251) (Scheme 83).

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[alpha]-Terpinene (252) and [gamma]-Terpinene (253) afforded (1R,2R)-p-menth-3-ene-1,2-diol (254) and (1R,2R)-p-menth-4-ene-1,2-diol (255) after fermentation with Corynospora cassicola (Stumpf et al. 1990) (Scheme 84).

Transformation by Rhizoctonia solani and Fusarium species (Fusarium solani, Fusariam oxysporium and Fusarium lini)

(+)-R-Pulegonne (156) yielded (-)-(1R)-7-hydroxy-p-menth-4-en-3-one (157), along with (-)-p-mentha-4,8-dien-3-one (256) was obtained by incubation with R. solani (Miyazawa et al. 1992a) (Scheme 85).

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([+ or -])-Piperitone (257) was hydroxylated by plant pathogenic fungus, Rhizoctonia solani (Miyazawa et al. 1993, 1992b) to (4R)10-hydroxypiperitone (258), (4S,6R)-trans-6-hydroxypiperitone (259), (4R,6R)-ris-6-hydroxypiperitone (260), (4S)-10-hydroxypiperitone (261), (4S,6S)-cis-6-hydroxypiperitone (262) and (4R,6S)-trans-6-hydroxypiperitone (263). This biotransformation is shown in Scheme 86.

Karahanaenone (42) was fermented with Rhizoctonia solani to yield (-)-(S)-karahanaenol (43), while fermentation with Fusarium solani afforded (-MR)-karahanaenol (264) (Miyazawa et al. 1995d). The fungal transformation of karahanaenone (42) is shown in Scheme 87.

(-)-Camphorquinone (44) was transformed to (+)-(3R)-exohydroxycamphor (265) by Rhizoctonia solani and Fusarium solani (Miyazawa et al. 1995b) as described in Scheme 88.

Miyazawa et al. (1995b) also reported the metabolism of (+)-camphorquinone (46). Compound 46 was metabolized to (-)-(3S)-exo-hydroxycamphor (224) by Fusarium solani and (+)-(3R)-endo-hydroxycamphor (266) by Rhizoctonia solani as described in biotransformation (Scheme 89). L-Menthol (267) was transformed to (-)-(1S,3R,4S,6S)-6-hydroxymenthol (268), (-)-(1S,3R,4S)-1-hydroxymenthol (269) and (+)-(1S,3R,4R,6S)-6, 8-dihydroxymenthol (270) with Rhizoctonia solani (Miyazawa et al. 2003) as described in Scheme 90.

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Piperitenone (158) on fermentation with Rhizoctonia solani (Miyazawa et al. 1992a) yielded 10-hydroxypiperitenone (271), (+)-8-hydroxypiperitenone (272) and (-)-(5S)-5-hydroxypiperitenone (273) (Scheme 91).

(+)-Isopiperitenone (274) was fermented by using Rhizoctonia solani to (-)-(4R)-hydroxyisopiperitnane (275), (4R,5R)-5-hydroxyisopiperitenone (276), (+)-7-hydroxyisopiperitenone (277) (Miyazawa et al. 1992a) (Scheme 92).

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Microbial transformation of (+)-isomenthol (32) (Scheme 93) by various strains of fungi was investigated. Fusarium lini has successfully converted compound (32) into a new metabolite, 5[alpha]-hydroxy isomenthol (278), and a known metabolite, 1[alpha]-hydroxyisomenthol (279) (Miyazawa et al. 1993).

Biotransformation of (2E, 6E)-farnesol (6E) farnesol (54) to (2E)-3,7,11 -trimethyl-2,6,10-dodcadien 1,7 diol (280) (Scheme 94) by f. oxysporium (Miyazawa et al. 1991a).

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Transformation by Cephalosporium aphidicola

Biotransformation of (-)-menthol (72) has also been reported by Atta-ur-Rahman et al. (1998). (-)-Menthol (72) yielded (-)10-acetoxymenthol (281), (-)-7-hydroxymenthol (282), (-)-6[alpha] hydroxy menthol (283), (-)-5[alpha]-hydroxymenthol (284), (-)-9-hydroxymenthol (285), and (-)-10-hydroxy menthol (286) by fermentation with Cephalosporium aphidicola (Scheme 95).

Myrtenol (287) on incubation with Cephalosporium aphidicola afforded 4[beta], 10-dihydroxy-pin-2-ene (288) as reported by Farooq and Hanson (1995) (Scheme 96).

Farooq and Hanson (1995) also reported the metabolism of verbenole (238) and nopinol (289) by Cephalosporium aphidicola. Verbenole (238) was metabolized to Verbenone (114) while nopinol (289) was oxidized to nopinone (290) as described in Scheme 97.

Nopol (169) transformed with C. aphidicola yielded (-)-(4R)-4[beta]-methoxynepol (291), 4[beta]-hydroxynopol (292) (Scheme 98) (Farooq and Hanson 1995).

(-)-Isopinocampheol (174) was metabolized to (1R,3S,4S,5R)-3,4-pinandiol (293) by C. aphidicola (Farooq and Hanson 1995) as shown in Scheme 99.

Transformation by Rhizopus species (Rhizopus solani and Rhizopus arrhizus and Rhizopus stolonifer)

(+)-Isopinocampheol (173) was metabolized to (1S,2S,3S,5R,7R)-pinane-3,6-diol (174) by Rhizopus solani, Rhizopus arrhizus (Abraham 1994) as shown in Scheme 100.

(+)-R-pulegonne (156) on fermentation with Rhizopus arrhizus (ismaili-Alaoui et al. 1992), 1-hydroxy (294) was obtained as presented in Scheme 101. (+)-R-Pulegonne (156) yielded (-)-(1R)-7-hydroxy-p-menth-4-en-3-one (157) along with (-)-p-mentha-4,8-dien-3-one (256) was obtained by incubation with R. solani (Miyazawa et al. 1992a).

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(+)-Isomentho! (32) incubation with Rhizopus stolonifer only yielded a-hydroxyisomenthol (295) (Scheme 102) (Miyazawa et al. 1993).

Biotransformation of an irregular monoterpene alcohol, ([+ or -])lavandulol [([+ or -])-5-methyl-2-(1-methylethenyl)-4-hexen-1-ol] (296) was studied using a soil isolated fungal strain Rhizopus oryzae. Five metabolites,2-((3,3-dimethyloxiran-2-yl)methyl)-3methylbut-3-en-l-ol (297), 2-methyl-5-(prop-1-en-2-yl)hex-2ene-1,6-diol (298), 2-methyl-5-(prop-1-en-2-yl)hexane-l,6-diol (299), 2-(3-methylbut-2-enyl)-3-methylenebutane-l,4-diol (300), 5-methyl-2-(2-methyloxiran-2-yl)hex-4-en-l-ol (301) have been isolated from the fermentation medium and characterized with lavandulol as a substrate (Miyazawa et al. 1993) (Scheme 103).

Transformation by Absidia glauca

(-)-Carvone (302), a cyclic monoterpene ketone was metabolized by the plant pathogenic fungus Absidia glauca (Demirci et al. 2004) to afford (+)-trans-dihydrocarvone (303), (+)-neodihydrocarvone (304) and (+)-neodihydrocarveol (305) as shown in Scheme 104.

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Transformation by Penicillium species (Penicillium italicum, Penicillium granulatum)

The Prolonged fragmentation of geranial (105) by sporulated surface cultures of Penicillium italicum (Demyttenaere and De Pooter 1996) resulted in the degradation of geraniol to 6-methyl-5-hepten-2-one (306) (Scheme 105).

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([+ or -])-Piperitone oxide (225) by fermentation with Penicillium granulatum yielded (-)-4-hydroxypiperitone (226) and (4S)-(+)- piperitnione (307) (llidrissi et al. 1990), as presented in Scheme 106.

Biotransformation of menthol (72) by sporulated surface culture of Penicillium sp. (Esmaeili et al. 2009) was studied. The main products obtained by surface Penicillium sp. were [gamma]-terpinene (253), limonene (64), and p-cymene (308) using sporulated surface culture (Scheme 107).

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Transformation by Cibberella cyanea

Gibberella cyanea has transformed 3,3,5,5-tetramethyllimonene (309) into 6-hydroxy-3,3,5,5-tetra methyl-limonene (310) and 8,9-epoxy-6-hydroxy-3,3,5,5 tetramethyl limonene (311) (Scheme 108) (Miyazawa et al. 1991b).

[alpha]-Terpineol (9) yielded (+)-(lR,2R,4R)-p-menthan,2,7,ll-triol (312) by incubation with G. cyanea (Abraham et al. 1990) shown in Scheme 109.

[alpha]-Terpinene-4-ol (313) yielded an oxidized metabolite (+)- (lS,2S,4S)-p-menthan-l,2,4-triol (314) when fermented with fungus Gibrellea cyanea (Abraham et al. 1990) (Scheme 110).

Transformation by Curvularia lunata

Miyazawa et al. in 1991 published an article (Miyazawa et al. 1991b) by using piperitenone (158), a compound characterized by its penetrating aroma of mint. While Fermentation with Curvularia lunata (Miyazawa et al. 1991b) afforded peperitenone (315) as described in Scheme 111.

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Transformation by M. isabellina, Botryosphaeria rhodina

(+)-Isopinocampheol (173) was also transformed to the metabolite (1S,2S,3S,5R,7R)-pinan-3,6-diol (174) by Botryosphaeria rhodina (Abraham 1994) and M. isabellina (Scheme 112). While (-)-Isopinocampheol (177) was also transformed to the metabolite (1R,2R,3R,5R)-pinan-3,5-diol (179) by Botryosphaeria rhodina, and to (1S,2S,3R,5R)-Pinan-3,5-diol (316) (Abraham 1994) by M. isabellina (Scheme 113).

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Transformation with Spirodela oligorrhiza

Pawlowicz et al. (1988) used Spirodela oligorrhiza to hydrolyse ([+ or -])-menthyl acetate (232) to (-)-menthol (72) (Scheme 114).

Transformation with Hypocrea Sp.

Geraniol (77) (Scheme 115) is the biogenetic precursor of a number of monoterpenes. During studying various marine-derived microorganisms to determine their ability to biotransform 77. Only Hypocrea sp. was capable of transforming 77 into its oxidized derivative, l,7-dihydroxy-3,7-dimethyl-(E)-oct-2-ene (317) (Yu et al. 2010).

Biological activities of monoterpenes

Antimicrobial activities of monoterpenes

Biotransformed products having antibiotic activity can be defined as low-molecular-weight organic natural substances made by microorganisms that are active at low concentrations against other microorganisms (Guo et al. 2008; Noma et al. 1982). The discovery of novel antimicrobial metabolites from biotransformation is an important alternative to overcome the increasing levels of drug resistance by plant and human pathogens (Yu et al. 2010; Song 2008). The antimicrobial compounds can be used not only as drugs by humankind but also as food preservatives in the control of food spoilage and food-borne diseases, a serious concern in the world food chain (Liu et al. 2008).

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Antibacterial activities of monoterpenes

The antibacterial activities of twenty one monoterpenes (borneol, d-3-carene, carvacrol, carvacrol methyl ester, cis/trans citral, eugenol, geraniol, Geranyl acetate, cis-hex-3-en-1-ol, R(+)-limonene, (2)-linalool, menthone, nerol, [alpha]-pinene, [beta]-pinene, (+)-sabinene, [alpha]-terpinene, terpinen-4-ol, [alpha]-terpineole, (-)-thujone, thymol) against twenty five strains of bacteria were reported previously (Liu et al. 2008). These activities based on previously reported studies on the monterpenes (Charai et al. 1996; Dorman and Deans 2000; Kim et al. 1995; Lattaoui and Tantaoui-Elaraki 1994; Mahmoud 1994; Meena and Sethi 1994; Moleyarand Narasimham 1986; Nadal et al. 1973; Naigre et al. 1996; Pelczar et al. 1988; Shapiro et al. 1994; Suresh et al., 1992).

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The monoterpenes with phenolic structures, such as carvacrol, eugenol and thymol, were highly active against the test microorganisms. Members of this class are known to be either bactericidal or bacteriostatic agents, depending upon the concentration used (Dorman and Deans 2000).

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The importance of the hydroxyl group in the phenolic structure was confirmed in terms of activity when carvacrol was compared to its methyl ether. Furthermore, the relative position of the hydroxyl group exerted an influence upon the components effectiveness as seen in the difference in activity between carvacrol and thymol against Gram-negative and Gram-positive bacteria, respectively. Furthermore, the significance of the phenolic ring was demonstrated by the lack of activity of the monoterpene cyclic hydrocarbon p-cymene. The high activity of the phenolic components may be further explained in terms of the alkyl substitution into the phenol nucleus, which is known to enhance the antimicrobial activity of phenols (Dorman and Deans 2000). The presence of an acetate moiety in the structure appeared to increase the activity of the parent compound. In the case of geraniol, the geranyl acetate demonstrated an increase in activity against the test microorganisms. Alcoholic monoterpenes are known to possess bactericidal rather than bacteriostatic activity against vegetative cells.

The monoterpenes with aldehydes, notably formaldehyde and glutaraldehyde, are known to possess powerful antimicrobial activity. It has been proposed that an aldehyde group conjugated to a carbon carbon double bond is a highly electronegative arrangement, which may explain their activity (Moleyar and Narasimham 1986) suggesting an increase in electronegativity increases the antibacterial activity (Kurita et al. 1979).

The aldehydes cis + trans citral displayed moderate activity against the test microorganisms while citronellal was only active against B. subtilis, Cl. sporogenes, Fl. suaveolens, M. luteus and Pseudomonas aeruginosa. The monterpenes ketone was also reported as antibacterial agent.

The presence of an oxygen function in the framework increases the antimicrobial properties of monoterpenes (Moleyar and Narasimham 1986). Menthone was shown to have modest activity. An alkenyl substituent (1-methylethenyl) resulted in increased antibacterial activity, as seen in limonene [1-methyl-4-(1-methylethenyl)-cydohexene], compared to an alkyl (1-methylethyl) substituent as in p-cymene [l-methyl-4-(1-methylethyl)-benzene]. The inclusion of a double bond increased the activity of limonene relative to p-cymene. These data suggest that an allylic side chain seems to enhance the inhibitory effects of monterpenes and chiefly against Gram-negative organisms.

Furthermore, the stereochemistry had an influence on bioactivity. It was observed that [alpha]-isomers are inactive relative to [beta]-isomers, e.g. [alpha]-pinene; cis-isomers are inactive contrary to transisomers, e.g. geraniol and nerol; compounds with methyl-isopropyl cyclohexane rings are the most active; or unsaturation of the cyclohexane ring further increases the antibacterial activity, e.g. terpinolene, terpineol and terpineolene (Naigre et al. 1996).

Antifungal activities of monoterpenes

Minimum fungicidal concentration (MFC) is defined as the lowest concentration of monoterpnes resulting in the death of 99.9% of the inoculum (Kurita et al. 1981). The antifungal activities of thirteen monterpenes ((+)-terpinen-4-ol, [gamma]-terpinene [alpha]-terpinene terpinolene [alpha]-pinene 1,8-cineole [rho]-cymene (+)-limonene [beta]-myrcene (+)-/l-pinene ([+ or -])-linalool [alpha]-phellandrene, [alpha]-terpinoel) against fourteen fungal strain was reported (Kurita et al. 1979). These activities based on previously reported studies on the monterpenes (Adegoke et al. 2000; Burt 2004; Carson and Riley 1995; Cox et al. 2000; Griffin et al. 1999). Thymol, carvacrol, and carvone showed high antifungal activity and camphor showed very low antifungal activities (Flimejima et al. 1992; Inouye et al. 2001). High antifungal activity for carvacrol and thymol against food storage (Jeon et al. 2001) and phytopathogenic fungi (Dorman and Deans 2000) was also reported.

The monoterpene alcohols terpinen-4-ol, [alpha]-terpineol, 1,8-cineole and linalool had relatively good antifungal activity. Although linalool differs slightly from the other monoterpene alcohols because it is acyclic, this monoterpene still showed significant antifungal activity. This suggests that the presence of the alcohol moiety is a greater determinant of antifungal activity than whether the component has a cyclic or acyclic structure. The monocyclic terpenes [gamma]-terpinene, [alpha]-terpinene, terpinolene, [rho]-cymene, limonene and [alpha]-phellandrene showed activity ranging from negligible (Burt 2004; Mueller-Riebau et al. 1995) to moderate or good (Adegoke et al. 2000; Burt 2004; Carson and Riley 1995; Cox et al. 2000; Griffin et al. 1999; Himejima et al. 1992; Inouye et al. 2001; Jeon et al. 2001; Kurita et al. 1979), While not as active as the monoterpene alcohols. Myrcene, an acyclic monoterpene, showed no antifungal activities (Smid et al. 1995). The lack of activity observed for this acyclic monoterpene suggests that the cyclic structure of the cyclic monoterpenes may be contributing significantly to their activity. The bridged bicydic monoterpenes [alpha]- and [beta]-pinene showed considerable antifungal activity, with [beta]-pinene showing the most.

Antiviral activities of monoterpenes

The antiviral activities of nine monoterpenes ([alpha]-terpinene, [gamma]-terpinene, [alpha]-pinene, [rho]-cymene, terpinen-4-ol, [alpha]-terpineol, thymol, citral and 1,8-cineole) against herpes simplex virus type 1 (HSV-1) were reported (Thompson 1989). Among the analyzed compounds, monoterpene hydrocarbons were slightly superior to monoterpene alcohols in their antiviral activity. Thymol and carvacrol were also reported as effective agents against Tobacco mosaic virus (TMV) and Cucumber mosaic virus (CMV) (Astani et al. 2010). In addition to these, other monoterpenes such as borneol, bornyl acetate, and isoborneol, 1,8-cineole, thujone, and camphor exhibited considerable antiviral activities against HSV-1 (Dunkic et al. 2010; Sivropoulou et al. 1997). Linalool showed strongest activity against AVD-I1 (Chiang et al. 2005).

Antioxidant activities of monoterpenes

The antioxidant molecule inhibits the oxidation reaction of other molecules. In oxidation reactions the free radicals produced that start chain reactions in the cell. These harmful radicals cause damage to the cell. Antioxidants removed these radicals, and inhibit the oxidation reactions as well (Sies 1997). One of the well known class of antioxidants are monoterpenes. In literatures, there are a lot numbers of essential oils are reported for antioxidants properties, which due to their monoterpenes constitution, but limited antioxidant studies on pure monoterpenes (Bayala et al. 2014; Darriet et al. 2014; Delgado et al. 2014; Dorman et al. 2000; Hoferl et al. 2014; Martins et al. 2014; Mimica-Dukic et al. 2004; Ricci et al. 2005; Ruberto and Baratia 2000; Singh et al. 2009b, 2010). Ojeda-Sana et al. reported the antioxidant activities of pure a-pinene, myrcene and thymol by testing them against DPPH assay (Ojeda-Sana et al. 2013). The Ojeda-Sana et al. reported significant antioxidant activity of a-pinene, myrcene and thymol with [IC.sub.50] values 18 [+ or -] 0.5, 4.5 [+ or -] 0.9 and 0.4 [+ or -] 0.03 [micro]g/mL, respectively.

Literatures studies also demonstrated that both [alpha]-pinene and [beta]-pinene have antioxidant properties by 2,2-diphenyl-1-picrylhydrazyl, hydroxyl (OH) radical, superoxide anion ([O.sup.2-]), malonaldehyde/gas chromatography, aldehyde/carboxylic acid, and [beta]-carotene bleaching methods (Ho and Su 2012; Singh et al. 2009a; Wang et al. 2008). Limonene is a monoterpene present in citrus fruit and is used as flavoring agents of foods. It was shown that monoterpenes possess antioxidant activity. Roberto et al. reported the antioxidant activity of limonene and was found it significantly active against catalase, peroxidase and superoxide dismutase activities and DPPH scavenging activity (Roberto et al. 2010). Chen et al. reported the antioxidant activity of [beta]-pinene, p-cymene, [gamma]-terpinene by testing against the scavenging activities of alkylperoxyl radical generated in the [beta]-carotene-linoleic acid system and the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH). According to results of Chen et al. (2014), the [gamma]-terpinene exhibited the strongest response in both [beta]-carotene bleaching assay and DPPH scavenging test as compared to [beta]-pinene and p-cymene. Rather et al. reported the DPPH radicals scavenging activity of [beta]-pinene and his results demonstrated that [beta]-pinene showed dose-dependent antioxidant activity with [IC.sub.50] values of 78.1 [micro]g/mL.

Anxiolytic activities of monoterpenes

Anxiolytics are a type of medications that used to reduce the anxiety. It has been reported that essential oils containing monotepenes have anxiolytic, sedative and anticonvulsant effects (Ambavade et al. 2006; Blanco et al. 2009; Buchbauer et al. 1993; Carvalho-Freitas et al. 2002; Emamghoreishi et al. 2005; Rabbani et al. 2003; Sayyah et al. 2004, 2002; Setzer 2009). The linalool, a major component of essential oils, which has well studied for many in vivo and/or in vitro anxiolytic, sedative and anticonvulsant effects (Brum et al. 2001; Elisabetsky et al. 1995,1999; Kuroda et al. 2005; Linck et al. 2009, 2010). Tankam and Ito reported that R-(-)-linalool played a major role in the inhalative sedative effect (Tankam and Ito 2013). Souto-Maior et al. (2011) investigated the effect of linalool oxide in mice, being administered by inhalation at concentrations of 0.65%, 1.25%, 2.5% and 5.0%. Results show that the anxiolytic drug profile of this monoterpene is similar to that of linalool in mice when a 3% concentration is inhaled.

The citral is also a major monoterpenes of essential oils, which have anxiolytic, sedative and anticonvulsant effects. Vale et al. reported the sedative and muscles relaxant effects of the three main monoterpenes (citral, myrcene and limonene) of essential oils by using open-field test and rota rod test in mice. The sedative effect was observed only at the dose (200 mg/kg body wt.) with all compounds. They also caused a potentiation of the pentobarbital-induced sleeping time in mice that was more intense in the presence of citral (Gurgel do Vale et al. 2002). Quintans-Junior et al. evaluated citral for antinociceptive and anti-inflammatory activities in rodents by using acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of citral had significant protection (p< 0.001) against acetic acid, morphine (0.8%) induced nociceptive behavior, while formalin induced nociception was significantly protected (p<0.05) only at higher dose (200 mg/kg). The pretreatment with citral (100 and 200 mg/kg) significantly reduced the paw edema induced by carrageenan (Quintans-Junior et al. 2011). Quintans-Junior et al. investigated the anticonvulsant effect of carvacrol, (-)-borneol and citral in two animal models of epilepsy, pentylenetetrazole (PTZ) and maximal electroshock (MES) tests and his results suggest that carvacrol, (-)-borneol and citral possess anticonvulsant activity effect against PTZ-induced convulsions and MES (Quintans-Junior et al. 2010). Almeida et al. reported nxiolytic-like effects of a mixture of cis and trans of (+)-limonene epoxide in animal models of anxiety. In open field test, (+)-limonene epoxide at doses of 25, 50 and 75 mg/kg, after intraperitoneal administration, significantly decreased the number of crossings, grooming and rearing. In the elevated-plus-maze test, (+)-limonene epoxide increased the time of permanence and the number of entrances in the open arms. In addition, (+)-limonene epoxide (75 mg/kg) also produced a significant inhibition of the motor coordination. All these effects were reversed by flumazenil (de Almeida et al. 2012). de Sousa et al. evaluated the anticonvulsant effect of citronellol on pentylenetetrazol- and picrotoxin-induced convulsions and maximal electroshock-induced seizures in mice (de Sousa et al. 2006). Melo et al. evaluated the antinociceptive effect of citronellal through behavioral experimental models. In pentobarbital-induced hypnosis, (citronellal) at 50, 100, and 200 mg/kg (i.p.) significantly increased sleeping time (88.0 [+ or -] 11.4, 100.2 [+ or -] 16.4, and 119.5 [+ or -] 20.9 min) when compared to vehicle solution injections (43.0[+ or -]6.1) (Melo et al. 2010). All together these results suggest that monoterpenes might represent important tool for treatment of painful conditions.

http://dx.doi.org/10.1016/j.phymed.2014.05.011

Conflicts of interest

The authors declare that they have no conflicts of interest.

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ARTICLE INFO

Article history:

Received 31 December 2013

Received in revised form 14 April 2014

Accepted 11 May 2014

Haq Nawaz Bhatti (a), * (1), Saleha Suleman Khan (b), Ajmal Khan (b), Mubeen Rani (b), Viqar Uddin Ahmad (b), **, (1), Muhammad Iqbal Choudhary (b)

(a) Department of Chemistry, University of Agriculture, Faisalabad, Pakistan

(b) H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan

* Corresponding author. Tel.: +92 41 9200161-69/3309/3319; fax: +92 41 9200764.

** Corresponding author. Tel.: +92 21 34819020; fax: +92 21 34819018-19.

E-mail addresses: hnbhatti2005@yahoo.com (H.N. Bhattl), profviqar@gmall.com (V.U. Ahmad).

(1) Both authors contributed equally.
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Author:Bhatti, Haq Nawaz; Khan, Saleha Suleman; Khan, Ajmal; Rani, Mubeen; Ahmad, Viqar Uddin; Choudhary, M
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Oct 15, 2014
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