Matricaria chamomilla is one of the most ancient and renowned medicinal plant from Asteraceae family. Chamomile is a well-heeled plant of natural stuff having pharmacognostic properties. This plant is natural source of blue oil, prepared by various methods such as hydro-distillation, chromatography techniques, etc. Earlier studies on plant compounds classified have nutritional values and more than one biological activity. Chamomile is thus used in cosmetics, perfumery, in food industry and aromatherapy since thousands of years. It has been suggested as alleviate for numerous diseases. This article briefly reviews the details on chemical constituents of essential oil and plant parts as well as their pharmacological properties, accomplished by QSAR and pharmacophore studies which is an in silico approach that increases the activity of plant by modifying its functional groups. This is an attempt to compile and document information on various aspects of chamomile plant and emphasize its need for research and development.
Keywords: Matricaria chamomilla, chemical constituents, pharmacognostic, QSAR
The relationship of plant life and human well-being has been renowned for thousands of years.1,2 Herbs have been vital to both traditional and non-traditional forms of medication dated back to at least 5000 years.3-5The enduring popularity of herbal remedies may be enlightened by the propensity of herbs to graft gradually, typically with minimal toxic side effects. Plants are imperative sources of medication since time immemorial. Studies on natural-products are meant to establish therapeutic values of plants by exploration of existing precise scientific knowledge, conventional uses, and invention of potential chemotherapeutic agents.6 The history of herbal medicine is as old as human civilization. With the promising global concern in adopting and studying customary system of medicine and exploring their potential based on different Medicare systems, the estimation of rich heritage of medicinally active plants is primarily carried out on the basis of morphological, phytochemical, pharmacological and different techniques such as chromatography, distillation, etc.7 One of the most common herbal plant used for curative purposes is chamomile whose homogeneous tea and herbal mines are primed from dried flowers ofMatricariaspecies.8
Kingdom: Plantae, Division: Magnoliophyta (Flowering plant), Class: Magnoliopsida (Dicotyledons), Family: Asteraceae, Genus: Matricaria L., Species: Matricaria chamomilla (German chamomile).9
Morphology of plant
Matricaria chamomilla commonly known as German chamomile is one of the most ancient annual herbaceous plant of composite family Asteraceae.10 This composite flower is largely favoured aromatic plant having multi-therapeutic values. Chamomile is highly imperative medicinal herb native to southern and eastern Europe. It is most ancient medicinal plant used in herbal remedies for thousands of years known to mankind. Matricaria Chamomilla is a natural resource of blue oil.
Various sections of plant such as aerial parts, root and shoot system contains essential oil that has been recommended for variety of healing ailments and diseases.11 Chamomile is a rich source of natural products. There is an immense demand for chamomile plant world-wide because of its influential medicinal values and pharmacological properties. Chamomile plant has a sweet, verdant, and faintly fruity scent. Its florae are daisy-like flowers, with yellow cores and white petals.12 The color of the Blue oil is due to the terpenoid chamazulene, which has been reported for its anti-inflammatory, anti-allergic, and antispasmodic properties.13 Chamazulene is biosynthesized from sesquiterpene Matricine, which is reported to have solid antioxidant activity and antimicrobial pharmacological actions.14,15
Chamomile being a constituent of various traditional, unani, and homeopathic medicinal provisions, it has been used greatly in flatulence, colic, hysteria, and intermittent fever as a drug.16-18 Many scientists have quoted from writings of several doctors of ancient times that chamomile was also used in cardiac diseases and in functioning of liver.19-22 The diverse range of essential oil isolation techniques and analytical procedures have been smeared for studying the volatile components of chamomile by several groups.23 Numerous essential oils are currently in use as aromatherapy agents to ease anxiety, pressure, and depression. Standard anxiolytic oils include lavender oil, rose oil, orange oil, bergamot oil, lemon oil, sandalwood oil, rose-scented geranium oil and chamomile (German and Roman).24 This aromatherapy is the use of concentrated essential oils extracted from herbs, flowers, and other plant parts to heal several diseases. Aromatherapy is becoming increasingly more popular; however there are only a few apparent indications for its use.25 Aromatherapy massage exerts optimistic effects on anxiety, self-esteem and also highly reduces stress and stress responses in adolescents by taking aroma treatments.26, 27 The international demand for chamomile oil has been steadily growing. Chamomile is internally used as tisane for stomach pain, slow digestion, diarrhoea and nausea; more rarely and very efficiently for inflammation of the urinary tract and for aching menstruation. Chamomile is used chiefly as an anti-inflammatory and antiseptic, also as antispasmodic and mildly sudorific.28 The chamomile extracts was found to have the most effective anti-leishmanial activity.29 The other uses of Matricaria chamomilla are in cosmetics, perfumes, food additives, while the external use includes the powder form of drug that can be applied for healing, skin eruptions, and infections.10,30 A number of chemical constituents have been identified in chamomile as secondary metabolites, including terpenoids, flavonoids, phenyl propanoids and many other additional compounds with potential pharmacological action.
Phytochemistry and Pharmacology of Compounds
Plants engender primary and secondary metabolites which encompass a wide range of functions. Plants can produce many different types of secondary metabolites that comprise of compounds having multivariate function, exposed by humans for their beneficial role in a varied array of applications.31
Phytochemicals have been the single most fruitful source of leads for the expansion of new drug entities from the dawn of drug discovery. They cover up a wide array of therapeutic indications with a huge assortment of chemical structures.32
The Phytochemicals isolated from Matricaria chamomilla have been classified into different classes of compounds (see table no. 1). The detailed information for each class of compounds can be accessible from supplementary table no. S1-S10.
Alkanes are acyclic branched or unbranched hydrocarbons having the general formula CnH2n+2 , and therefore comprises completely of hydrogen atoms and saturated carbon atoms.33 Drugs are increasingly being developed from natural products and several alkane compounds such as hexane have already been reported, offering a very promising approach to identify novel anti-angiogenic and anti-cancer agents.34 A considerable number of alkanes derived from chamomile have been identified mostly as antimicrobial and anti-inflammatory agents. A list of alkanes along with its structure and biological activity has been documented in a table (see supplementary table no. S1).
Flavonoids are low molecular weight bioactive compounds of enormous biological importance. Flavonoids are secondary metabolites outlined by flavan nucleus and its carbon framework refers to C6-C8-C6.35 These compounds can be classified as polyphenols or phenolics. Flavonoids can be further grouped into subclasses such as flavones, flavonols, flavanones, chalcones, aurones, isoflavones, anthocyanins, and proanthocyanidins. Flavonoid displays several biological properties like antioxidant, anti-inflammatory, anticancer, antiobesity, cardio protective, and neuroprotective activities.36 A huge number of flavonoid compounds such as rutin, quercetin hesperidin and many others have been reported as drugs that tend to possess anticancer, antioxidant and even senescence effects.37,38 A list of flavonoids along with its structure and biological activity has been listed in a table (see supplementary table no. S2).
Terpenoids, encompasses the most abundant and morphologically diverse group of plant secondary metabolites. Terpenoids are more frequently present in plants and around 23,000 compounds have been isolated in all. Terpenoids being a rich reservoir of candidate compounds have been characterized as monoterpenes, diterpenes, hemiterpenes and sesquiterpenes.39 Terpenoid production from plants has various defensive and protective functions that holds potential therapeutic properties such as anticancer (mostly leukemic), analgesic, antioxidant, antimicrobial and others. The terpenoid, eucalyptol which is a fragrant chemical has been propagated as nutraceutical having analgesic, anticancer and anti-inflammatory properties.40,41 A list of terpenoids along with its structure and biological activity has been revealed in a table (see supplementary table no. S3).
Coumarin, which was isolated in 1820 for the first time is classified as an element of benzopyrone family of compounds.42 Coumarins are the well-known phytochemicals that are comprehensively used as a natural active compound. The synthesis of coumarins and their derivatives have noteworthy significance from organic and medicinal chemists for several years. They have been generally used in food, perfumes, cosmetics, pharmaceuticals and as optical brighteners.43 Several coumarins and their derivatives have been reported for its antimicrobial and anticancer effects, some of which act as drugs. Dicumarol, cyclocoumarol, coumarin and its derivatives are used as an anticoagulants.44 A list of coumarins along with its structure and biological activity has been listed out in a table (see supplementary table no. S4).
Phenyl propanoids are the varied family of organic compounds synthesized from amino acid phenyl alanine.45 Phenyl propanoids are the plant polyketides that tend to possess multiple biological functions such as anti-inflammatory, antioxidant, anti-depressant and anticancer.46 Phenyl alanine which is an essential amino acid is sold as nutritional supplement for its reputed analgesic and antidepressant effects.47,48 Phenyl alanine first gets converted to cinnamic acid by deamination which is than followed by hydroxylation and frequent methylation to produce coumaric acid and others with phenyl propane.49 A list of phenyl propanoids along with its structure and biological activity has been recorded in a table (see supplementary table no. S5).
Spiroether isomers isolated from chamomile showed antispasmodic and anti-inflammatory activities.50 A list of spiroethers along with its structure and biological activity has been mentioned in a table (see supplementary table no. S6).
Fatty acids are carboxylic acids with a long aliphatic hydrocarbon tail produced by hydrolysis of triglycerides. These are either saturated or unsaturated naturally occurring fatty acids. 51 More interestingly, isoamly acetate released from honey bee’s sting act as pheromone.52 Isoamyl acetate is also found to be isolated from wine.53 Fatty acids possesses anticancer, antioxidant and other pharmacological actions which has been depicted in a table (see supplementary table no. S7).
Fatty acid esters
Fatty acid esters can be obtained by esterification of fatty acids. They are the product of combination of fatty acid with an alcohol.54 Fatty acids acts against microbes, as an analgesic and also as melanogenesis inhibitor. A list of fatty acid esters along with its structure and above mentioned biological activity with its references has been reported in a table(see supplementary table no. S8).
Phthalic acid is an aromatic dicarboxylic acid which is formed by catalytic oxidation of naphthalene directly to phthalic anhydride.55 The significant pharmacological properties of phthalic acid involves anti-androgenic, antimutagenic and anti-leukemic activity. Phthalic acid along with its structure and biological activity has been depicted in a table (see supplementary table no. S9).
Fatty alcohols are the aliphatic alcohols which are naturally found as waxes produced by plants, bacteria and animals having various biological properties.56 The metabolism of fatty alcohol compounds in fibroblasts is impaired in several inherited humanperoxisomaldisorders, includingadrenoleukodystrophyandSjogren-Larsson syndrome.57 Fatty alcohol along with its structure and biological activity has been documented in a table (see supplementary table no. S10).
Catalogue of Bioinformatics and Cheminformatics repositories
The large amount of Chamomile phytochemical information is highly discrete and can be easily procurable by a number of web-accessible bioinformatics and cheminformatics databases like PubChem,58,59 Chemspider,60 Human Metabolome Database(HMDB),61 ChemBank,62 NAPRALERT,63 SuperNatural database,64 NPACT65 and many more.
PubChem is an open repository for chemical structures and their biological activities, maintained by NCBI, a division of NLM under NIH. PubChem is becoming a valued reserve for drug development fascinating noteworthy interest from researchers in academe and diligence.66 PubChem includes substance information, compound structures, and BioActivity information from three principal databases, Pcsubstance, Pccompound, and PCBioAssay, respectively. Pcsubstance contains descriptions of small molecules, PcBioassay contains biological screening results of substances provided by depositors and Pccompound database contains the unique chemical structures. The aim of PubChem is to make this information easily available.67 Pcsubstance contains about 93 million records, Pccompound contains nearly 33 million unique structures and PCBioAssay contains more than 621,000 BioAssays.68
ChemSpider is a free chemical structure database providing rapid text search and structure search access to more than 28 million structures from hundreds of data sources.69 ChemSpider is a very valued web-based database that facilitates access to various chemical structures, nomenclature, chemical properties and other systematic information. ChemSpider is integrated with RSC (Royal Society of Chemistry).60
The Human Metabolome Database is an opulently annotated resource that is devoted to provide researchers with most recent and comprehensive coverage of human metabolome.70 The latest version of HMDB release is HMDB 3.0 that contains 40278 metabolite entries. The database is intended to contain three kinds of entries: chemical data, clinical data and molecular biology/biochemistry data.61
ChemBank is a public web-based database cheminformatics database established by Broad Institute’s Chemical Biology Programand funded by National Cancer Institute’s (NCI) Initiative for Chemical Genetics (ICG). ChemBank, a unique among small molecule database houses all the chemical molecular information such as names and identifier of the compounds, their calculated molecular descriptors as well as human curated biological information.62
NAPRALERT (NAtural PRoduct ALERT), an largest ethnobotanical database on pharmacology, pharmacokinetics, toxicology and phytochemistry of plants. NAPRALERT, a relational database was initiated in 1975 by Norman Fransworth and is housed within the Program for Collaborative Research at College of Pharmacy, UIC. It includes biochemical information of extracts of organism, in vivo, in situ, in vitro in humans and clinical studies.63
SuperNatural database is the first public database containing 3D structures, their conformers, derivatives and analogues. It consists of ~ 50,000 natural compounds from different sources. Natural products compounds are classified based on different classes of compounds.64
NPACT is Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database. It presently comprises of 1574 compound entries with detailed information on the structure, and activity of compound. This database gathers experimentally validated plant derived natural compounds exhibiting anti-cancerous property, both in vitro and in vivo. It also provides inhibitory values of compounds (IC50, ED50, EC50, GI50), their molecular targets and drug-likeliness.65
Chamomile is extensively in use in world market because of its wide and varied appliance in medical science. Moreover, natural substances are preferred more, rather than synthesized one due to its minimal side effects and easy extraction of its compounds. Chamomile is a natural source for plenty of bioactive substances that cure numerous diseases. Cheminformatics, an in silico approach is a way out for ample of problems in field of medicinal chemistry. This avenue can be used in drug discovery processes. In silico has gained a considerable thrust over last few years. Due to increased availability of computational power, in silico simulations have reward over in vitro methods. In silico methods are time and cost effective, tumbling lots of biological confirmations and offers the possibility of replacing some animal tests with suitable insilicomodels. QSAR and Pharmacophore studies can be carried out at primary level to increase the activity of the compounds which further leads to drug discovery processes.