Open Access Short Communication

The Potential of Pyrogallol as a Possible Antimalarial Drug Candidate

Alfaqih, H. and Abu-Bakar, N*

School of Health Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Corresponding Author

Received Date: August 18, 2020;  Published Date: October 05, 2020

Abstract

Pyrogallol is a phenolic compound naturally found in oak, hardwood plants and many fruits such as apricot, avocado and gall. This compound possesses antibacterial, antipsoriatic and antifungal properties. However, the oxidative properties of pyrogallol have been encouraging numerous researches into the potential health hazards of its consumption. Nevertheless, the oxidising agent could be used for the treatment of some diseases such as malaria. According to previous studies, some antimalarial drugs such as primaquine, chloroquine and derivatives of artemisinin have the capability to kill the parasites through the generation of oxidative stress by the free radicals they generate. In this review, the potential of pyrogallol as an antimalarial drug candidate will be discussed, focusing on the biological activities as well as the toxicological effects it has on human health.

Keywords:Pyrogallol, antimalarial drugs, oxidizing agents.

Abbreviations: G6PD: Glucose-6-phosphate dehydrogenase; P. falciparum: Plasmodium falciparum; ACTs: Artemisinin-based combination therapy; O2: Oxygen; ONOO: Peroxide Nitrite; H2O2: Hydrogen peroxide; OH: Hydroxyradical; ROS: Reactive oxygen species; Cu2+: Cupric ion; Fe3+: Ferric iron or iron (III); Mn2+: Manganese; Co2: Carbon dioxide; Fe2: Ferrous or iron (II); NPs: Nanoparticles

Introduction

Malaria is an infectious disease caused by parasites of the genus Plasmodium. The infection is transmitted to humans via female mosquitoes of the genus Anopheles. The disease has long been identified as one of the leading causes of mortality and morbidity around the world [1]. This has led to the discovery of many antimalarial drugs over decades of years; however, drugrelated problems have been existed in parallel with these drugs. Plasmoquine, the first 8 aminoquinoline was introduced as an antimalarial drug in 1926 [2]. However, the consumption of this drug led to the occurrence of haemolytic toxicity in patients with glucose-6-phosphate dehydrogenase (G6PD) deficient [3]. Due to this problem, a new class of antimalarial drugs known as chloroquine was introduced in early 1940s [4]. This drug was safer, inexpensive, less toxic and highly efficacious as compared with plasmoquine [5]. However, the chloroquineresistant strains of P. falciparum emerged in Asia specially in Cambodia [6]. Consequently, a number of antimalarial drugs have been introduced as alternatives for chloroquine such as antibiotics, atovaquone and antifolates. Likewise, the resistance of malaria parasites had occurred to these drugs. As a result, the combination therapy has been utilised to improve the treatment of uncomplicated malaria [7]. For instance, artemisinin-based combination therapy (ACTs) has widely been used to fight against malaria and demonstrated positive impacts in malaria treatment as compared to other combination therapies; unfortunately, the emergence of ACTs resistance has recently been reported in Cambodia [8].

Due to the problem of drug resistance, numerous researches have been conducted on the field of herbal medicine to discover new effective antimalarial drugs [9]. Nowadays, a number of plant species have proved invaluable in the fight against malaria such as Quercus infectoria Olivier, Clerodendrum viscosum Vent, Duranta repens L, Nyctanthes arbor-tristis L, Lantana camara L, Cinnamosma fragrans H, Dracaena reflexa Lamk, Desmodium mauritianum DC, Ficus megapoda Bak and Andropogon schoenanthus L [10, 11]. Q. infectoria is a medicinal herb, which belongs to the family Fagaceae [12]. The parts of this plant that have been utilised for medicinal uses are particularly root, stem, seed, leaf, bark and gall [13]. Previous studies reported that Q. infectoria possesses antimalarial properties However, the exact phytochemical constituents of this plant leading to the treatment of malaria remain searchable. A study on Q. infectoria reported that pyrogallol was found among the phytochemicals of the plant [14, 15]. Pyrogallol has a capability of generating free radicals [16], which may cause the inhibition of parasite growth. However, the pyrogallol-related toxicity remains a large gap that needs further studies.

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Pyrogallol also known as pyrogallic acid or 1,2,3-trihydroxybenzene, an organic phenol compound that exists naturally in many plants such as oak, eucalyptus, Terminalia chebula and Myriophyllum spicatum (Figure 1) [17-19]. People are naturally exposed to pyrogallol through several ways including consumption of tea, use of hair colouring creams, inhaling smoke produced during cooking mutton, fish and so on [17, 20]. Pyrogallol was found for the first time in the natural extract of the seeds of Abrus precatorius [21]. It is also found as a contaminant in anthocyanins, alkaloids, flavones and tannins and produced during its disposal, industrial use and isolation [17]. Resorcinol, its metabolite, is produced as a thermal breakdown material in effluents of wastewater during the process of converting coal. Nowadays, pyrogallol is obtained commercially via decarboxylation of gallic acid under high pressure and temperature [22]. It is utilised by various industries and consumer products [17].

Pyrogallol possesses antibacterial, antipsoriatic, antifungal and oxidative properties [18, 23-25]. It is autoxidised rapidly in solutions ranging from pH 3.5 to 4.5 [26] and generates free radicals such as molecular oxygen (O2), peroxide nitrite (ONOO−), hydrogen peroxide (H2O2), and hydroxyradical (OH-) by the Haber- Weiss reaction Inui et al. [16, 26]. The auto-oxidation of pyrogallol is extremely influenced via metallic ions as Cu2+, Fe3+ and Mn2+ increase while Co2+ reduces the rate of auto-oxidation [17]. These free radicals may enable the inhibition of parasite growth. Previous studies reported that the antimalarial drugs such as primaquine, chloroquine and derivatives of artemisinin consist of free radicals, which are a source of oxidation that may cause parasite death [27]. For instance, reactive oxygen species (ROS) are produced by artemisinin in the digestive vacuole through the activation of endoperoxide bridge and free Fe+2 can increase the production of ROS by Fenton process; hence, it has been suggested that artemisinin-activated ROS may induce parasite death via reducing the capability of the parasite’s antioxidant defence system to eliminate free radicals [28]. As mentioned above, pyrogallol is autooxidised in the pH ranging from 3.5 to 4.5, thus, this compound can function within the parasite’s digestive vacuole as this organelle also has the pH ranging from 3.7-6.5 [29]. This indicates that pyrogallol has a great potential to be a future antimalarial drug candidate.

Research studies reported several toxic end points occurred after exposure to pyrogallol [30,31]. The exposure to pyrogallol could cause many toxic side effects such as carcinogenesis, mutagenesis and hepatotoxicity [17, 20, 32-34] through the induction of the oxidative stress, which in turn leads to the destruction of different types of human cells. It could impair immune response through the inhibition of phagocytosis as well as suppressing the proliferation of lymphocytes due to its strong potential for generating free radicals [35]. As a result, Nanoparticles (NPs) is suggested to be used for reducing the toxicity of the drug molecules. Numerous studies reported that the conjugation of antimalarial drugs with some types of nanoparticles enables the direct action of the drugs on the parasite’s digestive vacuole, thus achieving high efficacy and low toxicity [36].

Conclusion

To sum up, the present review provides a better understanding of how pyrogallol can be the potential drug candidate against the malaria parasite through the production of free radicals. It has also discussed the treatment-related toxicity and offers a possible solution in a very brief way.

Acknowledgement

This review was supported by the Fundamental Research Grant Scheme (FRGS) (203/PPSK/6171225).

Conflict of Interest

No conflict of interest.

References

  • Talapko J, Škrlec I, Alebić T, Jukić M, Včev A (2019) Malaria: The past and the present. Microorganisms 7(6):
  • Van Der Hoogte AR, Pieters T (2016) Quinine, Malaria, and the Cinchona Bureau: Marketing Practices and Knowledge Circulation in a Dutch Transoceanic Cinchona-Quinine Enterprise (1920s–30s). Journal of the history of medicine and allied sciences, 71(2): 197-225.
  • Chu CS, White NJ (2016) Management of relapsing Plasmodium vivax Expert review of anti-infective therapy 14(10): 885-900.
  • Bogaczewicz A, Sobów T (2017) Psychiatric adverse effects of chloroquine. Psychiatria i Psychologia Kliniczna 17(2): 111-114.
  • Hu TY, Frieman M, Wolfr am J (2020) Insights from nanomedicine into chloroquine efficacy against COVID-19. Nature Nanotechnology 15(4): 247-249.
  • Thu AM, Phyo AP, Landier J, Parker DM, Nosten FH (2017) Combating multidrug‐resistant Plasmodium falciparum The FEBS journal 284(16): 2569-2578.
  • Ouji M, Augereau JM, Paloque L, Benoit-Vical F (2018) Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination. Parasite 25:
  • Conrad MD, Rosenthal PJ (2019) Antimalarial drug resistance in Africa: the calm before the storm? The Lancet Infectious Diseases 19(10): e338-e351.‏
  • Shen B (2015) A new golden age of natural products drug discovery. Cell 163(6): 1297-1300.
  • Nik Nor Imam Nik Mat Zin, Wan Nur Addiena Wan Mohd Rahimi, Bakar NA (2019) A Review of Quercus infectoria (Olivier) Galls as a Resource for Anti-parasitic Agents: In Vitro and In Vivo Studies. The Malaysian Journal of Medical Sciences: MJMS 26(6): 19-34.
  • Noronha M, Pawar V, Prajapati A, Subramanian R (2020) A literature review on traditional herbal medicines for malaria. South African Journal of Botany 128: 292-303.
  • Karimi A, Moradi MT (2015) Total phenolic compounds and in vitro antioxidant potential of crude methanol extract and the correspond fractions of Quercus brantii L. acorn. Journal of Herb Med Pharmacology 4(1): 35-39.
  • Hamad HO, Alma MH, Gulcin İ, Yılmaz MA, Karaoğul E (2017) Evaluation of phenolic contents and bioactivity of root and nutgall extracts from Iraqian Quercus infectoria Records of Natural Products 11(2): 205-210.
  • Baharuddin NS, Abdullah H, Wan Nor Amilah Wan Abdul Wahab (2015) Anti-Candida activity of Quercus infectoria gall extracts against Candida species. Journal of pharmacy & bioallied sciences 7(1): 15-20.
  • Tayel AA, El-Sedfy MA, Ibrahim AI, Moussa SH (2018) Application of Quercus infectoria extract as a natural antimicrobial agent for chicken egg decontamination. Revista Argentina de microbiologia 50(4): 391-397.
  • Torii Y, Saito H, Matsuki N (1994) Induction of emesis in Suncusmurinus by pyrogallol, a generator of free radicals. British journal of pharmacology 111(2): 431-434.‏
  • Upadhyay G, Gupta SP, Prakash O, Singh MP (2010) Pyrogallol-mediated toxicity and natural antioxidants: triumphs and pitfalls of preclinical findings and their translational limitations. Chemico-biological interactions 183(3): 333-340.‏
  • Singh G, Kumar P (2013) Extraction, gas chromatography–mass spectrometry analysis and screening of fruits of Terminalia chebula For its antimicrobial potential. Pharmacognosy research 5(3): 162-168.‏
  • Shao J, Wu Z, Yu G, Peng X, Li R (2009) Allelopathic mechanism of pyrogallol to Microcystis aeruginosa PCC7806 (Cyanobacteria): from views of gene expression and antioxidant system. Chemosphere 75(7): 924-928.‏
  • Upadhyay G, Kumar A, Singh MP (2007) Effect of silymarin on pyrogallol-and rifampicin-induced hepatotoxicity in mouse. European journal of pharmacology 565(1-3): 190-201.‏
  • Selvaraj S, Rajkumar P, Thirunavukkarasu K, Gunasekaran S, Kumaresan S (2018) Vibrational (FT-IR and FT-Raman), electronic (UV–vis) and quantum chemical investigations on pyrogallol: A study on benzenetriol dimers. Vibrational Spectroscopy 95: 16-22.
  • Wang H, Kang H, Zhang L, Cheng S, Liu H et al. (2015) Composition of ethyl acetate extracts from three plant materials (shaddock peel, pomegranate peel, pomegranate seed) and their algicidal activities. Polish Journal of Environmental Studies 24(4): 1803-1807.
  • Shahzad M, Millhouse E, Culshaw S, Edwards CA, Ramage G et al. (2015) Selected dietary (poly) phenols inhibit periodontal pathogen growth and biofilm formation. Food & function 6(3): 719-729.
  • Panzella L, Napolitano A (2017) Natural phenol polymers: Recent advances in food and health applications. Antioxidants 6(2):
  • Bianco MA, Handaji A, Savolainen H (1998) Quantitative analysis of ellagic acid in hardwood samples. Science of the total environment 222(1-2): 123-126.‏
  • Inui T, Nakahara K, Uchida M, Miki W, Unoura K et al. (2004) Oxidation of ethanol induced by simple polyphenols: Prooxidant property of polyphenols. Bulletin of the Chemical Society of Japan 77(6): 1201-1207.‏
  • Percário S, Moreira DR, Gomes BA, Ferreira ME, Gonçalves ACM et al. (2012) Oxidative stress in malaria. International journal of molecular sciences 13(12): 16346-16372.‏
  • Ismail HM, Barton V, Phanchana M, Charoensutthivarakul S, Wong MHL et al. (2016) Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum Proceedings of the National Academy of Sciences 113(8): 2080-2085.
  • Hayward R, Saliba KJ, Kirk K (2006) The pH of the digestive vacuole of Plasmodium falciparum is not associated with chloroquine resistance. Journal of cell science 119(Pt 6): 1016-1025.‏
  • Aptula AO, Roberts DW, Cronin MT, Schultz TW (2005) Chemistry-toxicity relationships for the effects of di-and trihydroxybenzenes to Tetrahymena pyriformis. Chemical research in toxicology 18(5): 844-854.‏
  • Schultz TW, Sinks GD, Cronin MTD (1997) Identification of mechanisms of toxic action of phenols to Tetrahymena pyriformis from molecular descriptors. Environmental Sciences 7: 24-28.‏
  • Gupta YK, Sharma M, Chaudhary G (2002) Pyrogallol-induced hepatotoxicity in rats: a model to evaluate antioxidant hepato-protective agents. Methods and findings in experimental and clinical pharmacology 24(8): 497-500.‏
  • Upadhyay G, Singh AK, Kumar A, Prakash O, Singh MP (2008) Resveratrol modulates pyrogallol-induced changes in hepatic toxicity markers, xenobiotic metabolizing enzymes and oxidative stress. European journal of pharmacology 596(1-3): 146-152.‏
  • Gupta YK, Sharma M, Chaudhary G, Katiyar CK (2004) Hepatoprotective effect of New Livfit®, a polyherbal formulation, is mediated through its free radical scavenging activity. Phytotherapy Research 18(5): 362-364.‏
  • Joharapurkar AA, Wanjari MM, Dixit PV, Zambad SP, Umathe SN (2004) Pyrogallol: A novel tool for screening immunomodulators. Indian journal of pharmacology 36(6):‏
  • Rahman K, Khan SU, Fahad S, Chang MX, Abbas A et al. (2019) Nano-biotechnology: a new approach to treat and prevent malaria. International journal of nanomedicine 14: 1401-1410.‏
  • Wang J, Shen X, Yuan Q, Yan Y (2018) Microbial synthesis of pyrogallol using genetically engineered Escherichia coli. Metabolic engineering 45: 134-141.‏
  • Alavi Rafiee S, Farhoosh R, Sharif A (2018) Antioxidant activity of gallic acid as affected by an extra carboxyl group than pyrogallol in various oxidative environments. European Journal of Lipid Science and Technology 120(11):‏
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