PRENYLATED BENZOIC ACID DERIVATIVES FROM PIPER SPECIES AS SOURCE OF ANTI-INFECTIVE AGENTS

PRENYLATED BENZOIC ACID DERIVATIVES FROM PIPER SPECIES AS SOURCE OF ANTI-INFECTIVE AGENTS

Ibrahim Malami

Department of Pharmacognosy and Ethnopharmacy, Usmanu Danfodiyo University, Sokoto, P.M.B 2346, Sokoto-Nigeria

ABSTRACT

A number of prenylated benzoic acids derivatives with interesting biological activities have been previously isolated and characterized from different species of piperaceae family. Several Piper species contained structurally similar compounds with diverse biological activities such as anti-bacterial, anti-fungal, insecticidal as well as anti-parasitic all of which produces compounds that can be classified as prenylated benzoic acid derivatives. Piper sp has proven to serve as a source of potential anti-infective agents by developing a biosynthetic route to the synthesis of prenylated benzoic acids derivative natural products as their chemical defense system. Despite the frequent isolation of these interesting compounds with strong biological activity, yet none have been taking into consideration for development into therapeutic agents.

Antibacterial activity

INTRODUCTION:Medicinal plants are important sources of natural compounds with novel potential therapeutic agents ^{1, 2}. Plants are rich in a wide variety of secondary metabolites such as tannins, terpenoids, alkaloids and flavonoids ³ and they have limitless ability to synthesis aromatics most of which are phenols.

Medicinal plants are used for centuries as remedies for human diseases and offer the richest biosources of drugs or traditional medical system, modern medicines, neutraceuticals, food supplements, folk medicines, pharmaceuticals, intermediate and chemical entities for synthetic drugs ⁴. Among the estimated 250,000-500,000 plant species ⁵, Piper species are estimated to contained 4000 species ⁶ widely distributed in the world. About 25 to 50% of current pharmaceuticals are derived from plants ³; none of the Piper species are yet to be developed into therapeutic agent.

Piper is one of the species found in ancient Ayurvedic medicine not only used as spices but also as folk medicine ⁶. Piperaceae family is a basal angiosperm family, estimated to contained more than 4000 species widely distributed in the tropical and subtropical region of the world, its species are chemically very rich and contained major classes of compounds ^{7, 8}, of which among them includes benzoic acid derivatives.

This review paper tend to highlight some of the recent bio-activity guided isolation and characterization of prenylated benzoic acid derivatives that have been previously reported from different Piper species with different interesting biological activities.

Prenylated benzoic acid derivatives from P. species: Several phytochemical investigation on piper family has been investigated to contain several interesting prenylated benzoic acid with interesting biological activities and also have been described to contained structurally similar compounds ⁹ exhibiting diverse biological activities such as antibacterial ^{10, 11, 12}, antifungal ^{13, 14, 15, 16}, insecticidal ¹⁷ and antiparasitic ^{10, 18, 19} all of which produces compounds that can be classified as prenylated benzoic acid derivatives, and more related compounds are continuously to be isolated with potent biological activities.

Phytochemical investigations carries out on deferent Piper species ¹⁴ has revealed the isolation of several related prenylated benzoic acid derivatives. 3-[(2E, 6E, 10E)-11-carboxy-3, 7, 15-trimethyl-2, 6, 10, 14-hexadeca-tetraenyl)-4, 5-dihydroxybenzoic acid 7,3-[(2E, 6E, 10E)-11-carboxy-13-hydroxy-3, 7, 15-trimethyl-2, 6, 10, 14-hexadecatetraenyl]-4, 5-dihydr oxybenzoic acid 8 and 3-[(2E, 6E, 10E)-11-carboxy-14-hydroxy-3, 7, 15-tri-methyl-2, 6, 10, 15-hexadeca tetraenyl]-4, 5-dihydroxy benzoic acid 9 are acyclic diterpene dihydroxybenzoic acids recently reported to be isolated from Piper heterophyllum and P. aduncum along with 4, 5- dihydroxy-3-(E, E, E-11-formyl-3, 7, 15-trimethyl-hexadeca-2, 6, 10, 14-tetraenyl) benzoic acid (arieianal) 3, 3, 4-dihydroxy-5-(E, E, E-3, 7, 11, 15-tetramethyl-hexadeca-2, 6, 10, 14-tetraenyl)benzoic acid 4, 3-(E, E, E-3, 7, 11, 15-tetramethyl-hexadeca-2, 6, 10, 14-tetraenyl)benzoic  acid 10, 3-(3, 7-dimethyl-2, 6-octadienyl)-4-methoxy-benzoic  acid 11, 4-hydroxy-3-(3, 7-dimethyl-2,6-octadienyl)benzoic acid 19 and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid 30 with antiparasitic activity. Compound 4, 10 and 11 are acyclic diterpene dihydroxybenzoic acids, 3 and 19 are geranylated p-hydroxybenzoic acids and geranylated p-methoxybenzoic acid respectively, while compound 30 is a di-prenylated p-methoxybenzoic acid.

The leaves of Piper aduncum are traditionally used for the treatment of inflammation and as antiseptic ¹⁰. These compounds shown to have potent antiparasitic against Leishmania braziliensis, Trypanosoma cruzi and Plasmodium falciparum with 19 having potent selective activity against L. brazilianses at IC₅₀ 6.5 μg/ml while 11 and 7 exhibit moderate antiplasmodial and trypanocidal activities at IC₅₀ 3.2 μg/ml and IC₅₀ 16.5 μg/ml respectively ¹⁹.

4-hydroxy-(3',7'-dimethyl-1'-oxo-octa-E-2'-6'-dienyl) benzoic  acid  1, 3 and 4-hydroxy-(3',7'-dimethyl-1'-oxo-octa-2'-Z-6'-dienyl)  benzoic  acid 2 are geranylated p-hydroxybenzoic acids and acyclic diterpene dihydroxybenzoic acids first reported to be isolated from Piper murrayanum (fig. 2).

The P. murrayanum is ethnomedicinally used by Jamaican for the treatment of fever, pain, wounds, toothache, colds, asthma, stomach ache and insect repellant ^{20, 21} while 10 and 11 were reported from Piper saltuum ²².

FIGURE 3

Compound 4, piperoic acid 5 and 19 were reported from Piper arieianum and Piper aduncum used locally as ant-repellant and for both treatment of stomach ache and as an insect repellant, respectively ^{11, 21}.

Bio-activity guided fractionation on different P.species has revealed the isolation of antiparasitic prenylated benzoic acid derivatives lanceaefolic acid methyl ester [methyl ester of 4, 5- dihydroxy-3-(3-methyl-2-butenoyl)benzoic acid] 12, 4, 5- dihydroxy-3-(3-methyl-2-butenoyl)benzoic acid 13, methyl  4-hydroxy-3-(methyl-2- butenyl)benzoate 17, methyl  4-hydroxy-3-(20 -hydroperoxy-30 -methyl-30 -butenyl)benzoate 18, and 3, 4-dihydroxy-5-(2-hydroxy-3-methyl-3-butenyl) benzoate 20, 4-hydroxy-3-(2-hydroxy-3-methyl-3-butenyl)benzoate 21, methyl 3, 4-dihydroxy-5-(3-methyl-2-butenyl)benzoate 22, 4-hydroxy-3, 5-bis(3-methyl-2-butenyl)benzoic acid 23, 4-methoxy-3,5-bis(3-methyl-2-butenyl)benzoic acid 24, 4-hydroxy-3-(2-hydroxy-3-methyl-3-butenyl)-5-(3-methyl-2-butenyl) benzoic acid 25, 3-(2-hydroxy-3-methyl-3-butenyl)-4-methoxy-5-(3-methyl-2-butenyl)benzoic acid 26, 3-[(1E)-3-hydroxy-3-methyl-1-butenyl)-4-methoxy-5-(3-methyl-2- butenyl)benzoic acid 27, 4-hydroxy-3,5-bis(2-hydroxy-3-methyl-3- butenyl)benzoic acid 28, 4-Hydroxy-3-(3 -methyl-2-butenyl)benzoic acid 29 are di-prenylated p-methoxybenzoic acid, mono-prenylated dihydroxybenzoate esters, mono-prenylated dihydroxy benzoic acids, mono-prenylated p-hydroxybenzoate esters and mono-prenylated p-hydroxybenzoic acids, respectively has also being reported to be isolated and  characterized from Piper lanceaefolium ¹³, P. aduncum ^{15, 16}, P. hostmannianum ^{15, 16}, P. glabratum and P. acutifolium ¹⁸ (fig. 4).

Compound 12 was reported to exhibit antifungal properties showing inhibition (MIC 100μg/ml) against Candida albicans ¹³ while 18 was recently shown to displayed antifungal activity (MIC 5.0 μg) against both Cladosporium cladosporioides and C. sphacrospermum ¹⁶.

FIGURE 4

FIGURE 5

The antiparasitic 22 exhibit both leishmanicicidal activity (IC₅₀ 18.2, 13.8 and 18.5μg/ml) against Leishmania amazonensis, L. brazilliensis and L. donovani, respectively. The trypanocidal activity of 22 also reported to have activity (18.5μg/ml) against T. cruzi. 20 and 21 has significant trypanocidal activity at IC₅₀ 16.4 and 15.5μg/ml while 17; 24-28 has shown poor or no effective against parasite ¹⁸. Piper. Guanacastensis has also been reported to contained compound 17 and 29 while compound 17 is biologically active (LC₅₀ 20.5 μg/ml) against mosquito larvae, Aedes atropalpus ¹⁷.

A series of bio-activity guided fractionations leads to the isolation of fungitoxic compounds 4-hy-droxy-3-(3,7-dimethyl-3-hydroxy-1-oxo-6-octenyl)benzoic acid 14, 4-hydroxy-3-(2, 3-dihydroxy-3-methylbutyl) benzoate 15 and 4-hydroxy-3-(2,3 -dihydroxy-3-methylbutyl)benzoate 16 from Piper crassinervium, P. aduncum and P. hostmannianum, respectively. These compounds (14, 15 and 16) have potent activity against both Cladosporium cladosporioides and C. sphaerospermum at MIC 0.5, 5.0 and 0.5 μg, respectively ¹⁵ (fig. 5).

Further literature survey on biologically active benzoic acid derivative compounds from P. species revealed the isolation and characterization of antibacterial and mulluscidal compounds 17, 19, 30, 31, 32, 1-(1-methylethyl)-4-methyl-3-cyclohexenyl 3,5-bis(3-methyl -2-butenyl)-4-hydroxybenzoate 33 (fig. 6) from Piper aduncum traditionally used by the villagers from the coastal areas of the Morobe Province of Papua New Guinea (P.N.G.) for the treatment of wounds. Compound 17, 30, 31 and 32 were shown to display both mulluscidal and antibacterial activities with 30 (13 ppm), 31 (10 ppm) and 32 (15 ppm) having activity against Biomphalaria glabrata. Compound 17, 30, 31 and 32 exhibit antibacterial activity against both Bacillus subtilis and Micricoccus luleus at MIC 2.8, 0.9, 1.25 and 2.0 nmol respectively ¹⁰.

FIGURE 6

3-Farnesyl-2-hydroxybenzoic acid (34)is an anti-bacterial compound isolated and characterized by Rugg, (2006) from the leaves of Piper multiplinervium. The plant is traditionallyused by the local Kuna Indians of Panama for the treatment of stomach ache. Compound 34 was found to have broad spectrum of activity against both Gram positive and Gram negative bacteria including Escherichia coli, Staphylococcus aureus and Helicobacter pylori. 34 has antimicrobial activity at MICs between 2.5 and 5 μg/ml against S. aureus, E. coli, Klebsiella pneumoniae, Mycobacterium smegmatis, Pseudomonas aeruginosa as well as Candida albicans and showed anti-Helicobacter pylori activity at MIC 37.5 μg/ml.

Phytochemical investigation recently reported by Puhl, et al (2011), revealed the isolation and characterization of antimicrobial agents 1 and 2 of which belongs to the family of prenylated benzoic acid derivatives from P. gaudichaudianum. Compound 1 and 2 shown activity against both S. aureus and B. subtilis using bioautographic analysis ²³.

CONCLUSION: Phytochemical investigations previously carried out on different Piper species revealed to contain several interesting prenylated benzoic acid with interesting biological activities and has also being described to contain structurally similar compounds^{9, 14}. Despite the frequent isolation of these interesting compounds with strong biological activity, yet none have been taking into consideration for development into therapeutic agents.

Piper sp has proven to serve as a source of potential anti-infective agents by developing a biosynthetic route to the synthesis of natural products as their chemical defense system. These natural products posses broad spectrum of activities against most infections among them includes prenylated benzoic acid derivatives.

REFERENCE:

1. Silva D. R., Endo E. H, Filho B. P. D., Nakamura C. V., Svidzinski T. I. E., De Souza A. C., Young M. C. M., Nakamura T. U: Chemical Composition and Antimicrobial Properties of Piper ovatum Vahl. Molecules 2009; 14: 1171 – 1182.
2. Silva M. L. A., Combra H. S., Pereira A. C., Almeida V. A., Lima T. C., Costa E. S., Vinholis A. H. C., Royo V. A., Silva R., Filho A. A. S., Cunha W. R., Furtado N. A. J. C., Martins C. H. G., Carvalho T. C., Bastos J. K: Evaluation of Piper cubeba Extract, (-)-Cubebin and its Semi-synthetic Derivatives against Oral Pathogens. Phytother. Res. 2007; 21: 420 – 422.
3. Cowan M. M: Plants Products as Antimicrobial Agents. Clin. Microbiol. Rev. 1999; 12 (4): 564 – 582.
4. Das K, Tiwari R. K .S., Shrivastava D. K: Techniques for Evaluation of Medicinal Plant Products as Antimicrobial Agents: Current Methods and Future Trends. J. Med. Plant. Res. 2010; 4 (2): 104 – 111.
5. Mahesh B, Satish S: Antimicrobial Activity of Some Important Medicinal Plant Against Plant and Human Pathogens. World J. agric. Sci. 2008; 4: 839 – 843.
6. Nakatani N, Inatani R, Ohta H, Nishioka A: Chemical Constituents of Peppers (Piper spp.) and Application to Food Preservation: Naturally Occurring Antioxidation Compounds. Environmental Health Perspectives 1986; 67: 135 – 142.
7. Lopez S. N, Lopes A. A, Batista Jr J. M, Flausino Jr O, Bolzani V. S, Kato M. J, Furlan, M: Geranylation of Benzoic Acid Derivatives by Enzymatic Extracts from Piper crassinervium (Piperaceae). Bioresource Technology 2010; 101: 4251 – 4260.
8. Stohr J. R, Xiao P, Bauer R: Constituents of Chinese Piper species and their Inhibitory activity on Prostaglandin and Leukotriene Biosynthesis in vitro.     Journal of Ethnopharmacology 2001; 75: 133 – 139.
9. Yamaguchi L. F, Lago J. H. G, Tanizaki M. T, Mascio P. D, Kato M. J: Antioxidant Activity of Prenylated Hydroquinone and Benzoic Acid Derivatives from Piper crassinervium Kunth. Phytochemistry 2006; 67: 1838 – 1843.
10. Orjala J, Erdelmeier C. A. J, Wright A. D, Rali T, Sticher O: Five New Prenylated p-Hydroxybenzoic Acid Derivatives with Antimicrobial and Molluscidal Activity from Piper aduncum Leaves. Planta Med. 1993; 59: 546 – 551.
11. Baldoqui D. C, Kato M. J, Cavalheiro A. J, Bolzani V. S, Young M. C. M, Furlan M: A Chromene and Prenylated Benzoic Acid from Piper aduncum. Phytochemistry 1999; 51: 899 – 902.
12. Ruegg T, Calderon A. I, Queiroz E. F, Solis P. N, Marston A, Rivas F, Ortega-Barria E, Hostettmann K, Gupta M. P: 3-Farnesyl-2-hydroxybenzoic acid is a New Anti-Helicobacter pylori Compound from Piper multiplinervium. Journal of Ethnopharmacology 2006; 103: 461 – 467.
13. Lopez A, Ming D. S, Towers G. H. N: Antifungal Activity of Benzoic Acid Derivatives from Piper lanceaefolium. J. Nat. Prod. 2002; 65: 62 – 64.
14. Danelutte A. P, Lago J. H. G, Young M. C. M, Kato M. J: Antifungal Flavanones and Prenylated Hydroquinones from Piper crassinervium Kunth. Phytochemistry 2003; 64: 555 – 559.
15. Lago J. H. G, Ramos C. S, Casanova D. C. C, Morandim A. A, Bergamo D. C. B, Cavalheiro A. J, Bolzani V. S, Furlan M, Guimaraes E. F, Young M. C. M, Kato M. J: Benzoic Acid Derivatives from Piper Species and Their Fungitoxic Activity against Cladosporium clasdosporioides and C. sphaerospermum. J. Nat. Prod. 2004; 67: 1783 – 1788.
16. Lago J. H. G, Chen A, Young M. C. M, Guimaraes E. F, Oliveira A, Kato M. J: Prenylated Benzoic Acid derivatives from Piper aduncum L. and P. hostmannianum C. DC (Piperaceae). Phytochemistry letters 2009; 2: 96 – 98.
17. Miranda R. P: Methyl 4-Hydroxy-3-(3’-methyl-2’-butenyl) benzoate, Major Insecticidal Principle from Piper guanacastensis. J. Nat. Prod. 1997; 60: 282 – 284.
18. Flores N, Jinenez I. A, Gimenez A, Ruiz G, Gutierrez D, Bourdy G, Bazzocchi I. L: Benzoic Acid Derivatives from Piper Species and Their Antiparasitic Activity. J. Nat. Prod. 2008; 71: 1538 – 1543.
19. Flores N, Jinenez I. A, Gimenez A, Ruiz G, Gutierrez D, Bourdy G, Bazzocchi I. L: Antiparasitic Activity of Prenylated Benzoic Acid Derivatives from Piper Species. Phytochemistry 2009; 70: 621 – 627.
20. Seeram N. P, Jacobs H, McLean S, Reynolds, W: Prenylated Hydroxybenzoic Acid Derivatives from Piper murranyanum. Phytochemistry 1996; 43(4): 863 – 865.
21. Green T. P, Treadwell E. M, Wiemer D. F: Arieianal, a Prenylated Benzoic Acid from Piper arieianum. J. Nat. Prod. 1999; 62: 367 – 368.
22. Maxwell A, Rampersad  D: Novel Prenylated Hydroxybenzoic acid Derivatives from Piper Saltuum. J. Nat. Prod. 1989; 52(3): 614 – 618.
23. Puhl M. C. M. N, Cortez D. A. G, Nakamura T. U, Nakamura C. V, Filho B. P. D: Antimicrobial Activity of Piper gaudichaudianum Kuntze and Its Synergism with Different Antibiotics. Molecules 2011; 16: 9925-9938.
    

    ---