Medicinal Properties of Cinchona Alkaloids - A Brief Review
Anubhav Dubey*, Yatendra Singh
Assistant Professor, Department of Pharmacology, Maharana Pratap College of Pharmacy, Kanpur (U.P.) - India.
*Corresponding Author E-mail: anubhavdwivedi803@gmail.com
ABSTRACT:
Cinchona which belongs to family Rubiaceae, got its importance from the centuries because of its anti- malarial activity. Alkaloids present in this herb, Quinine, Chichonine, Quinidine and Cinchonidine are the main, but percentage may vary in species to species. Since the early 17th century, these alkaloid are frequently used in Indian ayurvedic, sidha and traditional folk medicine to treating fever and Still now in modern medicine cinchona alkaloids are used for the treatment of malaria as well as for other diseases and became the well-known drug after the treatment of malaria caused by Plasmodium Sp. Literature study revealed that along with the antimalarial activity the cinchona alkaloids has other potentiality like anti-obesity, anti-cancer, anti-oxidant, anti-inflammatory, anti-microbial activity. These article reviews the biological activities of cinchona alkaloids along with its toxic effect.
KEYWORDS: Cinchonidine, Ayurvedic, Sidha, Rubiaceae, Quinine, Toxic effect.
INTRODUCTION:
Cinchona, regularly known as Peruvian bark, has a place with the family Rubiaceae, is local to South America explicitly from the Andes mountain range. It can likewise be found in India, Java, Cameroon, and Vietnam and in some other Asian and African nations. In India it is essentially found in sloping zones because of estate or development. Indonesia turns into the biggest maker of cinchona all through the world. Cinchona is a 10 to 20m tall trees with straight trunk around 30cm in width, It has a thick and unpredictable globular crown, dimly green, oval formed leaf with a thick focal nerve with full edge, the shade of blossom is white or pinkish with white hairs found in panicles and the organic product is dim earthy colored 2-4cm long with 3-4 seeds.
The fundamental piece of the plant which is principally utilized for therapeutic and other intention is the bark that can be upto 30cm long and 2-6cm thick. The earthy colored bark of cinchona is resembled a cylinder which is angled or bended during maturing. Bark are normally obvious in trunk or branches and after quick assortment, the outside has an earthy colored grayish tone while within has a ruddy earthy colored. Cinchona calisaya d Cinchona ledgeneria, ordinarily referred to across the globe as the yellow cinchona and Cinchona succirubra prominently referred to as in exchange as Red cinchona.
In excess of 20 alkaloids containing 15% sum, especially as quinine, quinidine, cinchonidine and cinchonine are found in the bark of cinchona joined with rule dynamic mixes, for example, tannins (3-10%)1. Alongside these fixings the bark likewise contains acids, basics oils and minerals, for example, triterpine (quinovic acid), natural (quinic acids), phenolic (caffeic acid), flavonoids (psoanthycyanidine), phytosterols2. These alkaloids are all in all known as quinoline alkaloids fundamentally got from tryphan by the alteration of terpenoids indole3. What's more, the terpenoid indole alkaloids are exceptionally normal in the class cinchona. In various species under class cinchona, in excess of twenty sorts of alkaloids have been confined. Nonetheless, it has been uncovered that a normal business yield of the cinchona alkaloids from the dry bark materials plant are as per the following: quinine (5.7%); quinidine (0.1-0.3%); cinchonine and cinchonidine (0.2-0.4%)4. Among these, the most mainstream quinoline alkaloids known as are quinine, cinchonine, quinidine and cinchonidine.
Quinine (C20H24N2O2):
The most important and characteristic alkaloids of cinchona contain 16%3 of quinine (Figure 1) in the bark but the percentage varies (6-10%) according to the species variety. The cinchona representative sample of dried cinchona or cinchona bark is found to be containing 0.4-4%3. It is frequently used as anti-malarial agent along with some other uses as a flavor in carbonated beverages4, skeletal muscle relaxant, treats hemorrhoids and varies vein and also used as oxytoxic agent[3]. Quinine is supposed to be prophylactic for flu3. Quinine got its antimalarial5 properties with interference in the synthesis of DNA in the merozoite phase of protozoa of the genus Plasmodium6 Quinine generally known as “a general protoplasmic poison”7 affects variety of biological systems. Its curare like action on skeletal muscle and toxic effects on bacteria and unicellular organisms such as plasmodium are the basis for its therapeutic use in man for muscle cramps and malaria, respectively7.
Quinine has a poisonous impact due to the excess. The sensory system including optic and hear-able nerve were the essential site of harm by quinine harmfulness and auxiliary to both vascular and neural injury7. Quinine causes fever, daze and expanded ventilator rate by an underlying summed up incitement of the focal sensory system, which is trailed by unconsciousness and respiratory discouragement. Quinine likewise causes myocardial despondency, fringe vasodilatation, and electro physiologic impacts remembering an Increase for activity possible length and viable stubborn period and a lessening in film responsiveness and automaticity. Moreover, renal disappointment, hemolytic frailty, hypo-prothrombinemia, and gastrointestinal side effects of both focal and nearby cause are accounted for7. Literature study uncovered that, papillary dialation is a reliable component of quinine harmfulness which happens due to the draw out utilization of the alkaloid to treat serious intestinal sickness once in a while makes respective visual impairment8. Furthermore, lethal heart failure9 has been depicted in which the intravenous medication (heroin) is adjusted with quinine.
Fig 1: Chemical formula/structure of Quinine
Cinchonine (C19H22N2O):
The next important alkaloid present within cinchona after quinine is cinchonine (Figure 2) which is also used as an anti-malarial agent10 and has a lower toxicity than quinine and having a higher activity compared to that of other quinine related compounds11. But the exact percentage of the cinchonine present in cinchona is controversial to the researcher. It is mainly used as antimicrobial agent and broadly used for schizonticide, amoebiasis, flu, dysentery and fever. It acts as mild stimulant of gastric mucosa3.
Fig 2: Chemical formula of Cinchonine
Quinidine:
The another important alkaloid is quinidine (Figure 3) mainly present in cinchona bark ranging from 0.25%-3.0%4. It is a dextrorotatory stereoisomer of quinine. The main function is it act as anti-malarial agent but it is also used as good anti-arrhythmic agent12, when the anti- arrhythmic metabolism is accomplished through membrane stabilization. It helps to treat atrial flutter, AV junction and ventricular constructions, atrial and ventricular tachycardia and atrial fibrillation and premature atrial condition3. The anti—arrhythmic property of quinidine is due to the direct interference with the electrophysiological properties of cardiac cells, which causes rapid sodium influx and decrease of the atrial and intraventricular condition velocity6.
Fig 3: Chemical formula of Quinidine.
Cinchonine (C19H22N2O):
The next important alkaloid
Cinchonidine (C19H22N2O):
Cinchonidine (Figure 4) is obtained in most of the varieties of cinchona bark especially in the bark of C. pusescensval and C. pitayensis and it is mostly used as an anti-malarial agent. It is a stereoisomer and pseudo-enantiomer of cinchonine and used chiefly as a substitute of quinine. Epicinchonidine is mostly used as an antimalarial agent4.
Fig 4: Chemical formula of Cinchonidine
Anti-obesity Property:
Hyperlipidemia is described by raised serum levels of total cholesterol (TC), low- density lipoprotein (LDL), Very low -density lipoprotein (VLDL), and diminished serum level of high density- lipoprotein (HDL). According to American heart incorporation, a high level of fats known as hyperlipidemia. These fats consist of cholesterol and triglyceride. Lipids and fatty substances in the blood and is a greater risk factor in the growth of atherosclerosis and heart diseases13. Cinchonine, the potent alkaloids in cinchona bark, is widely used for anti-malarial activity. But, it could be a potential agent that can solve the concerns related to obesity. According to Jung et al. 2012 cinchonine effects dramatically than other phyto-chemicals that have been known to exert anti-obesity effects13. Even the supplemented dose was higher than or same, cinchonine showed higher rate of final body weight reductions compared to EGCG (epigallocatechin gallate) and curcumin14 where 0.32% EGCG supplementation showed 9.4% decrease in final body weight in high fat died fed mice15 and 0.05% curcumin supplementation is also known to lower the body weight by 11% in the same model16. Along with cinchonine’s effect on body weight reduction, cinchonine decreases the plasma level of lipid in mice fed on the HFD (High fat diet). Cinchonine effectively ameliorated hyperlipidemia and hyperglycemia induced by the HFD; cholesterol, LDL+VLDL cholesterol, HDL cholesterol, TG, and the plasma glucose levels. Cinchonine affect the HFD-mediated hyperlipidemia and hyperglycemia that are early symptoms of the metabolic syndrome and associated disorders. So, finally cinchonine has a dramatic suppressive effect on adipogenesis through the down-regulation of WNT and galanin-mediated adipo genesis signaling pathway, and it also attenuates inflammation by repressing TLR2- and TLR4-mediated pro-inflammatory signaling pathways in the adipose tissue13. In several literature studies, it was demonstrated that cinchonine is a useful dietary phyto-chemical for the prevention of not only obesity, but also adipose inflammation.
According to Krishnavedi and Suresh,2015, quinine is more potent to inhibit the cell proliferation and induce apoptotic cell death in cancer cell line in a dose and time dependent manner17, the IC50 values obtained after 24hr treatment of different concentrations of quinine (125.23 μM/mL for 24 hr). ROS (Reactive oxygen species) is critical for the metabolic and signal transduction pathways associated with cell growth and apoptosis18. Several anticancer agents, including anthracyclines, cisplatin, bleomycin, and irradiation currently used for cancer treatment have been shown to cause increased intracellular ROS generation. The results of this study showed that the intracellular ROS levels were significantly increased in cancer cell line treated with quinine at time and dose dependent manner. Induction of cell death through indirect activation of the mitochondria dependent pathway is the conventional anticancer treatment but sometimes it is altered in drug resistant cancer cells. Effect of quinine induce typical morphological change as the signal of apoptosis like cell shrinkage, membrane blebbing, chromatid condensation, nuclear fragmentation, apoptotic bodies and loss of adhesion19. So quinine may be a strong anticancer agent in future due to its huge apoptotic activities in cancer.
As described by Ravishankara et.al cinchona exhibit efficient antioxidant properties due to presence of phenolic compounds20. The biological properties of phenolics include like anti- tumor, anti-viral, anti HIV and also inhibition of lipid peroxidation21,22. The study was mainly concentrated on three major radicals – superoxide hydroxyl and nitric oxide radicals as these are the main radicals responsible for the oxidative damage of cellular components of the human body23,24,25,26. Methonalic and water extract showed a concentration dependent antiradical activity by inhibiting DPPH, with the EC50 value of 8.08µg/ml and 64.19µg/ml respectively. And also the extract of cinchona shows the inhibition of erythrocytes hemolysis induced by phenyl hydrazine which was done in dose dependent manner and as a result Methanolic extract showed a better protection than α- tocopherol which revels the ability of the cinchona extract to scavenge the free radical.
According to Pankaj et.al cinchona alkaloids showed the antibacterial activity against the Staphylococcus aureus with the inhibition zone ranged from 8-18mm done by the disc diffusion method27. It has been studied that antimicrobial activity increases according to the concentration of the cinchona alkaloids. Extraction of cinchona alkaloids is found effective against amebiasis. Dried bark is used to treat disease caused by a pathogenic strain like P.falciparum and herpes28. Rojas J.J et al. confirmed that cinchona was active against the several microorganisms which are harmful to the human body29.
In this modern world of medicine still the protozoan parasites causes the infectious disease and remain as major health problem. Among the disease, leishmaniasis, malaria and trypanosomiasis are the major health problem caused by the leishmaniasp, Plasmodium sp. and Trypanosome sp.
Moreover the main major problem in the treatment of these diseases is due to the increase of resistant strains to the medicine and the toxic effects and relative efficacy of some of the drugs used for treatment nowadays. Among the drug used for the treatment of malaria is quinine, the major alkaloid of cinchona and still remain the drug of choice. According to Aurelie Leverrier et al., compound possessing a quinolone nucleus display a variety of biological properties and can be used as anti-parasitic such as for malaria, leishmania and trypanosomiasis30. By the means of a Barton-Zard decarboxylation reaction a series of Cinchona alkaloids and bile acids was prepared. The alkaloids of cinchona i.e., quinine, quinidine, cinchonine, cinchonidine were functionalized at C-2 of the quinoline nucleus by radical attack of norcholane substituent. The hybrid compounds showed promising trypanocidal activity with IC50 values in the same range as the suramin(a commercial anti trypanosomal drug). As well as the hybrid showed antiplasmodial activity (IC50≤6µg/ml), particularly those containing a nor-chenodeoxycholate moiety with IC50 values comparable to those of the natural alkaloids and selectively indices in the range of 5.6 – 15.7.
Apart from treating malaria, quinine is also used to treat nocturnal leg cramps and arthritis, and there have been attempts (with limited success) to treat prion diseases. It is also use as ingredient of tonic drinks for its bitter taste. Infusions of the bark of the Peruvian cinchona tree have been used for centuries for medicinal purposes and were observed to have both antimalarial and anti-inflammatory properties. The active agents, quinine and cinchonine were isolated and used as early as 1894 to treat lupus31. As slow acting, low toxicity drugs they are useful in combination therapy, especially for SLE (systemic lupus erythematous), since their mode of action is quite different to other anti-inflammatory drugs. They act by inhibiting lysosomal and endosomal function, thus limiting the release of secreted proteins, including cytokines. Antigen processing and presentation, and thus T cell activation are also inhibited 31.
Nature provides huge medicinal agents for thousands of years and a significant number of human drugs are developed from herbal sources. From ancient periods cinchona bark was traditionally used as anti-malarial drug to cure several health problems associated with malaria. The most important property of cinchona is due to the presence of several types of alkaloids. Researcher shows that the combinatorial effects of more than twenty alkaloids are the key source of its medicinal property rather than one of them. Among these twenty alkaloids four are mainly responsible for its anti-malarial property and contain maximum percentage of the alkaloids present. But the other alkaloids found in cinchona have not only an anti-malarial activity but also have other important biological properties and has been vital tool for pharmacologist and molecular biologist. In the present study, extensive literature review revealed that cinchona also have potential property of anti-obesity, anti-cancer, anti-oxidant, anti-microbial, anti-parasitic and anti- inflammatory activity. So, the trace amount of remaining alkaloids could be the major effective molecules for the mentioned characteristic of this wonder herb. But few researcher shows that the use of cinchona have mild to moderate side effects in a dose dependent manner. Cardiotoxicity and neurotoxicity are the major problem discouraging the medical use of this vital drug. However, a closer look in data of cinchona alkaloids clearly indicates that the toxicity is dose dependent. Thus, a well- controlled use of it can help to reduce its toxicity. Furthermore, a new drug with greater potency and significantly reduced toxicity can be designed from cinchona alkaloids. Without doubt a modification in alkaloids in a proper way may likely produce a lead drug in treatment of more diseases. So, there is an urgent need to developed new drug with better bioactive potential and without or less side effects.
CONFLICT OF INTEREST:
None.
CONTRIBUTION:
All Author Participated Equally.
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Received on 30.01.2021 Modified on 11.02.2021
Accepted on 18.02.2021 ©Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 2021; 11(3):224-228.
DOI: 10.52711/2231-5659.2021.00036