Received: 10 February 2019 Revised: 20 May 2019 Accepted: 4 June 2019 DOI: 10.1002/ptr.6423

REVIEW

Mentha: A genus rich in vital nutra‐pharmaceuticals—A review

Farooq Anwar1 | Ali Abbas1,2 | Tahir Mehmood1,3 | Anwarul‐Hassan Gilani4 | Najeeb‐ur Rehman5

1 Department of Chemistry, University of Sargodha, Sargodha, Pakistan The genus Mentha comprises several aromatic species, which are cultivated world‐ 2 Department of Chemistry, Government Post over due to their distinct aroma and commercial value. In addition to traditional food Graduate Taleem ul Islam College, Chenab Nagar, Pakistan flavoring uses, Mentha are well recognized for their folk medicinal uses, especially to 3 Institute of Biochemistry and Biotechnology, treat cold, fever, and digestive and cardiovascular disorders. A number of biological University of Veterinary and Animal Sciences, activities such as antioxidant, antimicrobial, biopesticidal, antitumor, anticancer, anti- Lahore, Pakistan viral, antiallergic, antiinflammatory, antihypertensive, and urease inhibitory activity 4 Natural Products Research Division, Department of Biological and Biomedical have been ascribed to Mentha. The traditional pharmacological attributes of Mentha Sciences, The Aga Khan University Medical herbs can be linked to the occurrence of bioactive phytochemicals such as terpenoids, College, Karachi, Pakistan 5 Department of Pharmacology, College of alcohols, rosmarinic acid, and antioxidant phenolics among others. A rich source of Pharmacy, Prince Sattam bin Abdulaziz bioactives, different species of Mentha, can be explored as a promising candidate University, Al‐Kharj, Saudi Arabia for the development of nutra‐pharmaceuticals. This review covers the nutritional, Correspondence phytochemical, and traditional medicinal aspects and multiple biological activities of Professor Dr. Farooq Anwar, Department of Chemistry, University of Sargodha, Sargodha some commonly available species of Mentha so as to explore their potential 40100, Pakistan. applications for nutra‐pharmaceutical and cosmo‐nutraceutical industry. Detailed Email: [email protected] chemical profile and pharmaceutical attributes of various Mentha essential oils are Professor Dr. Anwarul‐Hassan Gilani, Natural Products Research Division; Department of also covered. Moreover, based on computational analysis, quantitative chemical Biological and Biomedical Sciences, The Aga component–antioxidant activity relationship model is reviewed to predict and corre- Khan University Medical College, Karachi 74800, Pakistan. late structure–activity relationship of potential bioactives in selected Mentha essen- Email: [email protected] tial oils leading to discovery and developmenmt of novel natural drugs.

KEYWORDS

genus Mentha, bioactives, medicinal uses, biological activities, functional foods, nutraceuticals

1 | INTRODUCTION obtained from various plants are considered safer (Abbas, Anwar, & Ahmad, 2017; Ahmad & Sher, 2001; Ahmed & Gilani, 2014). In view Historically, plants have been used as a vital source to fullfill shelter, of some reports, currently, a large proportion (approximately 80%) of fuel, and food related needs of human beings. On the other hand, the world's population, especially in the Africa and South Asian plants have always served as a source of folk medicine and modern regions depend on traditional medicine, mainly the plant derived nat- drugs to meet health care needs of mankind (Gilani & Atta‐ur‐Rahman, ural products and phytomedicines for maintenance or improvement 2005; Mishra et al., 2018; Mishra et al., 2018; Saily, Sabu, Mohan, of health (Emiru, Ermias, Wolde, & Degitu, 2011; Muhammad et al., Gupta, & Sondhi, 1994; Sharifi‐Rad et al., 2018). Due to the high cost 2015). Many food and medicinal plants, especially aromatic herbs and safety issues of pharmaceutical medicine, there is renewed inter- and spices, have been evaluated for their nutra‐pharmaceutical poten- est in the utilization of plants/herbs both as a food and medicine tial due to the presence of a wide array of natural bioactive com- (Anwar et al., 2016; Jamshed, Sultan, Iqbal, & Gilani, 2015; Muham- pounds and novel chemical entities (Akhtar et al., 1992; Ali & Qaisar, mad, Hussain, Anwar, Ashraf, & Gilani, 2015). The medicinal products 2009; Descalzo & Sancho, 2008; Dorman & Deans, 2000).

Phytotherapy Research. 2019;1–23. wileyonlinelibrary.com/journal/ptr © 2019 John Wiley & Sons, Ltd. 1 2 ANWAR ET AL.

Likewise, genus Mentha is popular for its medicinally and/or eco- in cross section. Its roots are fibrous, and leaves are 2–6 cm long and nomically important aromatic species with potential bio‐prospects. 1–4 cm broad, and flowers are tiny and pinkish or purple in color. It is The genus Mentha, with more than 30 reported species, grows across commonly called as water mint (Blamey & Grey‐Wilson, 1989; Huxley, the world at almost all agro‐climatic conditions (Gulluce et al., 2007). 1992). Some of the common species of Mentha such as M. aquatica, M. Mentha longifolia is characterized by the length of its plant up to arvensis, M. citrata, M. longifolia, M.piperita, M. pulegium, M. rotuntifolia, 40–120 cm and have oblong elliptical leaves with 5–10 cm long and and M. spicata are commonly grown for the production of essential 1.5–3 cm broad. Its flowers are lilac or white colored and produced oils (EOs) and/or utilized as food flavoring and medicinal agents in in dense cluster. Mentha piperita, commonly known as peppermint, is many countries of Europe, Australia, America, and the Middle East 30–100 cm tall with smooth stem. Leaves of this species are 4–9cm (Gulluce et al., 2007; Nickavar, Alinaghi, & Kamalinejad, 2008; Pandey, long and 1.5–4 cm broad; flowers are purple in color and produced Rai, & Acharya, 2003; Savithri, Priti, Sushil, & Anil, 2002). in the form of whorls (Clark & Menory, 1980). The plant of Mentha Mentha species are widely used as a flavoring agent in raw and spicata usually grows 30–100 cm tall with leaves 5–9 cm long and processed foods such as soups, salads, herbal teas, cheese, and bread 1.5–3 cm broad. Its flowers are produced in slender spikes and have (Kofidis, Bosabalidis, & Kokkini, 2004; Moreno, Bello, Prime‐Yufera, & white or pink color. Esplugues, 2002). Likewise, the EOs and extracts from Mentha plants The herbaceous plants of genus Mentha are widely distributed in are now gaining popularity as natural ingredients in herbal cosmetics temperate and subtemperate regions of the world. Many intermediary and pharmaceutical preparations (Salehi et al., 2018; Yadegarinia forms can be produced by freely crossing of different members of et al., 2006). Mentha EOs and extracts are used in the treatment of dis- these species (Hefendehl & Murray, 1973). Polyploidy is a frequent eases such as fever, cough, and digestive disorders due to their antipy- phenomenon in Mentha genus and has played a significant role in bio- retic, bronchodilator, spasmodic/antispasmodic, and carminative diversity of these species. For example, Mentha piperita is an earliest properties (Gulluce et al., 2007; Moreno et al., 2002). Moreover, the group hybrid resulted by cross between Mentha spicata and Mentha EOs and extracts from Mentha have also been reported to exhibit mul- aquatica. On the other side, Mentha spicata is known to be a hybrid tiple biological activities including antioxidant, antimicrobial, of Mentha longifolia and Mentha rotundifolia (Savithri et al., 2002). antiinflammatory, antihypertensive, antiviral, and antiallergic, which Although Mentha citrata, also named as lemon mint, is accepted to can be linked to the presence of bioactives such as terpenoids and be a hybrid variety of Mentha aquatica and Mentha arvensis (Croteau aromatic substances (aldehydes, alcohols, phenols, and methoxy deriv- & Gershenzon, 1994). atives; Dorman, Kosar, Kahlos, Holm, & Hiltunen, 2003; Gulluce et al., Several, medicinally and domestically important, species of mint 2007; Hosseinimehr, Pourmorad, Shahabimajd, Shahrbandy, & are widely cultivated throughout the world, especially for food Hosseinzadeh, 2007). flavoring and pharmaceutical applications. Typically, peppermint and Widespread functional food and folk medicinal uses along with spearmint oils are mainly produced in the United States (Chambers various pharmaceutical attributes of Mentha species, urged us to com- & Hummer, 1992). Peppermint (Mentha piperita) is mainly cultivated pile a comprehensive article reviewing multiple uses of these herbs. in the states of Oregan, Idaho, Ohio, Indiana, and Michigan; however, This manuscript mainly covers the nutrients profile, traditional medic- spearmint (Mentha spicata) is cultivated in Indiana and Michigan inal uses, and multiple pharmacological properties of some common (Savithri et al., 2002). Mentha spicata is also cultivated in the United species of genus Mentha. Efforts have also been made to focus on Kingdom, France, Italy, Bulgaria, Hungary, Yugoslavia, Russia, Vietnam, the detailed bioactives' profile of these species. Furthermore, extrac- Thailand, and South Africa. Mentha citrata (Bergamot mint) is mainly tion and chemical composition of Mentha EOs have also been cultivated in Taiwan, China, and India, and menthol in China, India, reviewed so as to explore potential applications of these species for Pakistan, Thailand, Taiwan, Japan, and Brazil (Aflatuni, 2005; Patra, nutra‐pharmaceutical industry. Kumar, Shukla, Ram, & Srivastava, 2002).

2 | TAXONOMY AND DISTRIBUTION OF 3 | TRADITIONAL MEDICINAL AND MENTHA FUNCTIONAL FOOD APPLICATIONS OF MENTHA Mentha is a genus of aromatic herbs belonging to the family Lamiaceae. Mentha species not only vary in their characteristic plant Traditionally, Mentha species have long been used as a source of food features depending upon genetic factors rather agro‐climatic condi- and folk medicine. A number of medicinal benefits have been ascribed tions also affect their taxonomic and biochemical traits. Of the various to Mentha, which include the treatment of irritable bowel syndrome Mentha species, Mentha arvensis grows up to 10–60 cm with leaves in (Capanni et al., 2005), diarrhea control (Hiki et al., 2003), breast ten- opposite pairs and has usual length of 2–6 cm and width 1–2 cm. The derness (Sayyah et al., 2007), dyspepsia (Thompson & Ernst, 2002), flowers are pale purple or pink (Blamey & Grey‐Wilson, 1989). headache (Gobel, Fresenius, Heinze, Dworschak, & Soyka, 1996), Another species, Mentha aquatica is a rhizomatous perennial herb abdominal distention (Feng, 1997), abdominal pain (Weydert, Ball, & and grows up to 90 cm tall, with green or purple stem, which is square Davis, 2003), bad breath (Hur, Park, Maddock‐Jennings, Kim, & Lee, ANWAR ET AL. 3

2007), cognitive improvement (in brain injury; Sullivan et al., 1998), 2016). Crushed leaves are useful for dizziness and also can be applied common cold (Hansen et al., 1984), dental plaque (Charles et al., on the forehead and temple to cure headaches (Mimica‐Dukic et al., 2000), and urinary tract infection (Ebbinghaus, 1985). In the following 2003). The leaves of M. arvensis also have antiinflammatory potential section we discussed some important medicinal and food uses of some and are in use for treating the arthritis problems; fresh leaves can be commonly distributed species of genus Mentha. heated on low flame, pound and then applied on the painful joints or muscles (Ramesh & Pramod, 2009; Savithri et al., 2002). The menthol isolated from this plant is used in preparations of balms. 3.1 | Mentha aquatica

Dried leaves of Mentha aquatica are used in South African traditional 3.3 | Mentha longifolia medicine as a remedy against respiratory problems; they are also employed as a stimulant and astringent (Esmaeili, Rustaiyan, Masoudi, Mentha longifolia has been valued for its medicinal potential and has & Nadri, 2006). A number of biological activities such as antiallergic, traditionally been used for the treatment of menstrual disorders, colic, analgesic, antipyretic, antiseptic, antispasmodic, carminative, decon- indigestion, pulmonary infection and congestion, headache, fever, gestant, deodorant, diaphoretic, diuretic, antiemetic, insecticidal, seda- colds, cough, and urinary tract infections (Mikaili, Mojaverrostami, tive, stimulatory, and vermifuge actions have been ascribed to this Moloudizargari, & Aghajanshakeri, 2013). Moreover, it has been used aromatic herb (Gruenwald, Brendler, & Jaenicke, 2000). in heart diseases (Duke, 1997). Additionally, the plant has a reputation The leaves of M. aquatica, with carminative attributes, are often for its medical use in other conditions, such as diarrhea, gut spasm, consumed as raw and/or eaten as cooked with other foods. Moreover, indigestion, flatulence, asthma, and cardiovascular diseases (Shah, due to characteristic peppermint odor, this species is widely employed Bhulani, Khan, Rehman, & Gilani, 2010; Shah, Bukhari, & Gilani, as a flavoring ingredient in several foods such as salads and herbal tea. 2016). A leaf decoction from M. longifolia (known as inembe) is popular The plant leaves also have bio‐pesticidal potential and can be used as as a pregnancy tonic (Mimica‐Dukic et al., 2003). It is also used to insect‐pest and rodent repellant. This supports the potential uses of relieve swelling and treat sores or minor wounds due to its this species as a natural source of green pesticides for pest and insect antiinflammatory and antiarthritis potential (Mikaili et al., 2013). control. Mentha aquatica has a pleasant, fresh scent and can be used The leaves or stem parts of the plant may be added to boiling as a strewing herb. It can be strewn in granaries to repel and keep water and the vapour inhaled to relieve nasal or bronchial congestion. mice and rats off the grain (Maureen, 2006). Moreover, due to anti- The aerial parts of the plant are traditionally used in folk medicine sys- septic and antimicrobial properties, the use of fresh or dried plant is tem for the relief and treatment of cough, cold, asthma, and chest valuable in herbal baths (Maureen, 2006); this advocates the potential infections (Mikaili et al., 2013). Moreover, the plant is also used exter- applications of this species as a natural source of antiseptic agents. nally to treat wounds and swollen glands due to antiinflammatory activity (Evans, 1996; Mimica‐Dukic et al., 2003). Mint leave extracts, due to antioxidant and antimicrobial effects, are commonly used as 3.2 | Mentha arvensis food flavoring agent and preservative (Dorman et al., 2003; Mikaili et al., 2013). Besides, M. longifolia is also valued herbal remedy, espe- Mentha arvensis, commonly named as menthol mint, is a rich source of cially for its antiseptic and carminative (Haris, Elvira, Elma, & Kemal, natural menthol. A number of biological properties including carmina- 2012) as well as blood pressure lowering, antispasmodic, bronchodila- tive, antiulcer, antimicrobial, and antispasmodic have been ascribed to tor, and Ca++ channel blocking (Shah et al., 2010; Shah et al., 2016) M. arvensis. Mentha arvensis is traditionally used as a flavoring agent in properties. many culinary preparations (Thawkar, Jawarkar, Kalamkar, Pawar, & Kale, 2016). The plant has traditionally been employed as a natural remedy to treat different health disorders such as skin diseases, indi- 3.4 | Mentha piperita gestion, cough, and colds (Ramesh & Pramod, 2009). The leaf extracts and EO from this mint species has versatile applications in pharmaceu- Mentha piperita, commonly known as peppermint, has a broad spec- tical and cosmeceutical industry, as these are added as a flavoring trum therapeutic uses and is highly valued in both the Eastern and agent in toothpastes, chewing gums, mouth washes, candies, cos- Western traditional medicine for its potential uses in aromatherapy, metics preparations, deodorants, and colognes. In India and Pakistan, toothpaste, mouthwashes, and topical preparations. Topical prepara- menthol is extensively used in betel‐related industries (Sukhmal, Patra, tions prepared from this species oil are in use to cure inflammation Anwar, & Patra, 2004). The crushed and bruised leaves of menthol and irritation (Boon & Smith, 2004; Herro & Jacob, 2010). mint exhibit antivenomic potential and are used to treating insect bites Peppermint fresh leaves and sprigs can be added to drinks and (Mimica‐Dukic, Bozin, Sokovic, Mihailovic, & Matavulj, 2003). An food dishes as a garnish. They are also used to prepare a refreshing infusion/decoction, prepared from the leaves and stems of this medic- tea. Peppermint can also be used as an excellent flavoring agent for inal herb, provides relief in fever, stomachaches, and diuresis due to ice cream, chocolates, and other deserts. The leaves of this plant, carminative, analgesic, and diuretic properties and is also useful boiled in water, are employed as a natural remedy to treat bronchi- against gastrointestinal and cardiovascular disorders (Thawkar et al., tis, coughs, and inflammation of the throat and oral mucosa (Boon & 4 ANWAR ET AL.

Smith, 2004; Fleming, 1998). The leaf EO with therapeutic potential and nutraceutical potential of some common species of Mentha are is employed as a folk medicine to reduce rheumatism and muscular depicted in Table 1: pains and to relieve menstrual cramps (Fleming, 1998; Tyler, 1992). The most common and traditional use of peppermint is in the treat- ment of digestive disorders due to its carminative properties. More- 4 | BIOLOGICAL ACTIVITIES OF GENUS over, it can also provide relief in digestive problems such as nausea, MENTHA heartburn, flatulence, and cramps (Dalvi, Nadkarni, Pardesi, & Gupta, 1991). Currently, there are serious medical concerns on the rapidly growing Peppermint has a strong refreshing menthol odor and exhibits anti- antimicrobial resistance so called drug resistance, which reveals the ability of a microbe to resist the effects of medication previously used microbial, antioxidant, and insect‐repellant properties, which support to treat them. To cope with the challenges of antimicrobial resistance, its wide scale uses in dental preparations (Herro & Jacob, 2010; Schmidt et al., 2009). Peppermint oil is widely used as a flavoring now there is an increasing attention on the investigation and discov- ery of some novel natural drugs and phytomedicines to be used effec- agent in chewing gum, mouthwash, cigarettes, toothpaste, and drugs. tively against infectious diseases and chronic health disorders (Anwar It is also added as an ingredient in cough and cold preparations. The main constituent of the oil, menthol, is used in many antiitch, antisep- et al., 2016; Edris, 2007; Muhammad et al., 2015; Sahib et al., 2013). In particular, there is greater focus on the search of bioactives with tic, and local anesthetic preparations (Fleming, 1998; Tyler, 1992). potential physiological benefits. In this context, a significant number The peppermint oil is also useful in boosting general energy levels and improving thinking. For example, rubbing peppermint oil on the of traditional food and medicinal plants have been screened for anti- temples is reported to be beneficial towards improving memory and oxidant, anticancer, antimicrobial, antiinflammatory, and antidiabetic agents with potential uses to reduce the incidence of different dis- concentration (Tandan, Anand, & Yadav, 2013). Besides, the traditional uses, the peppermint oil vapors are reported to be useful in cough and eases such as cardiovascular, cancer, and infectious disorders (Edris, to control an asthma attack (Wilkinson & Beck, 1994). Peppermint has 2007; Menichini et al., 2009; Muhammad et al., 2015; Rashid, Rather, Shah, & Bhat, 2013). traditionally been used as a rubefacient (Paula, 2000). Moreover, due EOs and extracts derived from several aromatic plants and herbs are to revitalizing and refreshing properties, the mint oil can be added to personal care and cosmetic products such as shampoo, soap, deodor- valued for their antiinflammatory, antimicrobial, and antioxidant effects (Hussain, Anwar, Sherazi, & Przybylski, 2008; Menichini et al., 2009). ant, lotions, and lip balm (Tandan et al., 2013). Based on its odor and Likewise, the EOs/extracts from different Mentha species have shown traditional medicinal uses and antiseptic properties, peppermint EO can be a promising candidate for development of innovative nutra‐ multiple biological activities (Hussain, Anwar, Ashraf, Przybylski, & Shahid, 2010; Hussain, Anwar, Nigma, Ashraf, & Gilani, 2010). It has pharmaceticals. been investigated that these herbal plants possess antioxidant (Nickavar et al., 2008), antimicrobial (Al‐Bayati, 2009), antitumor (Ohara & Matsuhisa, 2002), antiallergic (Satsu, Matsuda, & Toshimitsu, 2004), 3.5 | Mentha spicata antiviral (Minami et al., 2003), antibacterial (Azuma, Ito, Ippoushi, & Higashio, 2003), and antiinflammatory (Juergens, Stober, & Vetter, The leaves of Mentha spicata, also known as mint, are commonly used for culinary purposes due to having a pleasant and aromatic mint cool 1998) activities. Important biological/pharmaceutical activities of com- monly grown species of Mentha are reviewed and enlisted below: odor. In North Africa and Arab regions, mint leaves are usually added to tea, beverages, syrups, and ice creams as flavoring ingredient. Mint is also popular as ingredient in lamb dishes, especially in the Middle 4.1 | Antioxidant activity Eastern cuisine. Mint is also popular as a traditional medicinal herb to treat chest pains and stomachache (Jirovetz, Buchbauer, Shabi, & Recently, there is increasing interest on utilization of plant‐based nat- Ngassoum, 2002). Powdered mint leaves can be used to whiten teeth. ural antioxidants due to their safer nature and medicinal benefits. In Menthol, a major constituent of Mentha spicata EO, is often added to this regard, extracts and EOs from many medicinal and food herbs several cosmetics and perfumes due to its cool odor. Most impor- have been investigated as promising source of effective antioxidant tantly, mint leave EO and/or extracts are used as a natural ingredient agents (Ceylan et al., 2016; Hussain et al., 2008; Naseer, Sultana, in numerous phytomedicine/natural drugs as well as are very famous Anwar, Mehmood, & Mushtaq, 2014; Nouman et al., 2016; Sultana, for their aromatherapy applications (Lawrence, 2006). Anwar, Hussain, & Mahmood, 2010). The mechanism of antioxidants Moreover, mint is added in cigarettes to counter the bitter taste of against reactive oxygen species and free radicals is elucidated in tobacco and for soothing the throat. It is also commonly believed that Figure 1. due to the sharp flavor and scent, mint can be useful as a mild decon- A range of in vitro antioxidant assays such as DPPH radical scav- gestant for common cold. The leaves of this aromatic herb, due to bio‐ enging (Anwar, Alkharfy, Rehman, Adam, & Gilani, 2017; Lafka, pesticide and insect repellant properties, can be used to repel mosqui- Sinanoglu, & Lazos, 2007; Sanchez‐Moreno, Larrauri, & Saura‐Cailxto, toes and other pests such as hornets, ants, wasps, and cockroaches 1998; Turkmen, Sari, & Velioglu, 2006), inhibition of linoleic acid per- (Znini et al., 2011). The medicinal applications as well as functional oxidation (Dapkevicius, Venskutonis, Van Beek, & Linssen, 1998), ANWAR ET AL. 5

TABLE 1 Some traditional medicinal and food science uses of common Mentha species

Sr. # Mentha species Part used Uses Reference

1 Mentha aquatica Dried leaves Treatment of cold and respiratory problems Esmaeili et al. (2006) Sedative, digestive, and analgesic Gruenwald et al. (2000) Fresh leaves Flavoring in salad and glavoring in cooked food Maureen (2006) Whole plant Flies, mice, and rat repellent and herbal bath 2 Mentha arvensis Essential oil Flavoring agent in toothpastes, mouth wash, Sukhmal et al. (2004) chewing gum, cosmetic preparation, and deodorant Fresh leaves Flavoring food and beverages Ramesh and Pramod (2009) and Savithri et al. (2002) Dried leaves Carminative, antipeptic ulcer agent, treatment of skin diseases rheumatic pain, fever, cough, and cold 3 Mentha longifolia Dried leaves Treatment of menstural disorders and pulmonary Mimica‐Dukic et al. (2003) infectionheadache, nausea, fever, cough and cold, and urinary tract infection Leaf oil To induce labour during third trimester of pregnancy Aerial part Treatment of asthma, chest inflammation, wounds, Evans (1996) and swollen glands Extracts Antiseptic, carminative, and prokinetic Haris et al. (2012) 4 Mentha piperita Essential oil Inhalant for respiratory congestion Fleming (1998) Leaves Treatment of cough, bronchitis, inflammation of oral mucosa, diarrhea, nausea, and vomiting Leaf oil Carminative, used as mouth wash and for treatment Tyler (1992) of toothache, rheumatism, musculr pain, and menstrual cramps 5 Mentha spicata Leaves Flavor enhancer,tea manufacturing, processing Jirovetz et al. (2002) of jellies, candies, and ice cream Whole plant Treatment of stomach ache and chest pain Essential oil Cosmetics, perfumes, and aromatherapy Lawrence (2006) Extracts Mosquito killer, insecticide, and pesticide Znini et al. (2011) 6 Mentha citrata ‐ Cosmetics and juice industry Savithri et al. (2002) and Nickavar et al. (2008) 7 Mentha pulegium Oil Scenting soap and manufacturing of menthol Savithri et al. (2002) and Nickavar et al. (2008) 8 Mentha rotuntifolia ‐ Confectionery and food flavoring Savithri et al. (2002) and Nickavar et al. (2008)

FIGURE 1 General mechanism of antioxidant activity against reactive free radicals [Colour figure can be viewed at wileyonlinelibrary.com]

ABTS+ (Bahman, Azadeh, & Mohammad, 2008), and reducing power examined that extract of naturally dried M. longifolia has higher con- (Oyaizu, 1986) assays have been successfully employed by the tent of phenols (113.8 mg GAE/g) and flavonoids (106.7 mg RTE/g) researchers to examine the antioxidant effects of Mentha plants. than the laboratory oven‐dried samples. Similarly, a higher antioxidant Dzamic et al. (2010) investigated that M. longifolia EO (MLEO) is an activity, in terms of ferric reducing power and DPPH scavenging, was effective DPPH free radical scavenger and exhibits scavenging activity also reported for the naturally dried extracts (2.76 mmol Fe2+/mg and in a dose‐dependent manner (IC50, 0.66 ml/ml of solution). Similarly, EC50 = 0.02 mg/ml) compared with the laboratory oven‐dried samples 2+ Haris et al. (2012) reported that MLEO reduced DPPH radicals into (1.13±0.11 mmol Fe /mg of dry extract and EC50 = 0.03 mg/ml; their neutral DPPH‐H form (IC50, 10.5 μg/ml). Moreover, it has been Dragana et al., 2012). This advocates that processing of Mentha at 6 ANWAR ET AL. an appropriate condition is a key step to retain maximum antioxidant fact, plants have been historically used as a source of food and folk value of these herbs. medicine through the history of mankind to treat various ailments However, according to Mimica‐Dukic et al. (2003), free radical and diseases (United Nations Educational, Scientific and Cultural scavenging capacity of EO from M. piperita was higher than that of Organization, 1996). Plant‐based drugs and phytomedicines not only either M. aquatica or M. longifolia. In their experiment, M. piperita EO act as natural remedies to treat different diseases but also serve as scavenged DPPH radicals effectively (IC50, 2.53 μg/mL) as well as prototype to develop novel, safer, and effective modern medicines inhibited the generation of OH radical by 24% in Fenton reaction. (Anwar et al., 2016; Muhammad et al., 2015; Sahib et al., 2013). The EO from peppermint (M. piperita) exhibited even stronger antiox- Likewise several other plant species, the EOs from lamiaceae herbs idant effect than butylated hydroxyl toluene against sunflower oil per- have been searched as a potential source of antimicrobial agents with oxidation (Gurdip, Kapoor, & Pandey, 1998). Similarly, methanol broad spectrum activities (Hussain et al., 2008; Hussain, Anwar, extract of M. pulegium offered appreciable amounts of phenolics and Ashraf, et al., 2010, Hussain, Anwar, Nigma, et al., 2010; Hussain flavonoids (157.99 mg GAE/g DW and 16.96 mg RTE/g DW, respec- et al., 2013;Anwar et al., 2017, Saba & Anwar, 2018). The antimicro- tively) as well as exhibited ferric reducing activity almost comparable bial activities of Mentha EOs have mainly been attributed to volatile to vitamin C (Osman, 2013). bioactives such as oxygenated monoterpenoids alongwith monoter- In another study, Poonam and Anshu (2012) examined superoxide pene hydrocarbons (MHs) and sesquiterne hydrocarbons (Anwar radical scavenging activity of different solvent (fractions) of M. spicata et al., 2017; Mikaili et al., 2013). Mentha EOs are found to exhibit anti- and noted that ethyl acetate and aqueous fractions of ethanol extract bacterial activities against pathogenic bacteria including both Gram‐ of M. spicata have higher superoxide radical scavenging among others. negative and Gram‐positive such as Pseudomonas aureus, Bacillus According to Anwar et al. (2017), MLEOs of different chemotypes, subtilis, Escherichia coli, Pseudomonas aerogenosa, Serratia marcesens, harvested from different regions of Saudi Arabia, exhibited reasonably and Streptococcus aureus (Anwar et al., 2017; Bupesh et al., 2007; Saba high extent of DPPH free radical scavenging that was mainly corre- & Anwar, 2018). Jazani, Ghasemnejad‐Berenji, and Sadegpoor (2009) lated to the variable polyphenols and carvone contents of the tested studied Mentha pulegium EOs for antibacterial activity and found that oils. Recently, Saba and Anwar (2018) evaluated the effect of harvest- they showed strong antibacterial activity against all the isolates of ing regions on physico‐chemical and biological attributes of supercrit- Klebsiella spp. ical fluid‐extracted spearmint (Mentha spicata L.) leaves EO. The Saba, Muneeba, and Hira (2011) investigated that Mentha piperita researchers noted that the oils tested effectively scavenged DPPH had broadspectrum antibacterial activity against bacterial strains such free radicals as well as inhibited linoleic acid peroxidation depending as Escherichia coli, Salmonella typhius, Bacillus subtilius, Staphylococcus upon variable contents of total phenolics and flavonoids. In another aureus, Pseudomonas aeruginosa, Staphylococcus epidermititis, and Kleb- study reported by Ed‐Dra et al. (2018), Mentha suaveolens EO showed siella pneumoniae. According to another study, MLEO exhibited strong a significant ferric reducing antioxidant potential and DPPH free radi- antibacterial effects especially against Gram‐negative strains including cal scavenging activity. The antioxidant potential of Mentha plants as Pseudomonas aerginosa, E. coli, and S. enterica (Haris et al., 2012). supported by the literature advocates their potential utilization as nat- Mahady, Pendland, and Stoia (2005) investigated that methanol ural additives for stabilization and preservation of vegetable oils and extract from peppermint is weakly active against 15 strains of other lipid containing food products. Helicobacter pylori with minimum inhibitory concentration (MIC) in the range of 25–100 μg/ml. However, the reported antibacterial effects of peppermint oil against different bacteria are random type, 4.2 | Antibacterial activity possibly due to difference of the plant varieties and bacterial strain used and/or testing conditions employed (Arakawa & Osawa, 2000; Infectious diseases are considered to be one of the growing concerns Mckay & Blumberg, 2006; Pattnaik, Subramanyam, & Rath, 1995). in medical science world‐over (Nathan, 2004). The microorganisms In another study, Preeti (2013) evaluated the antibacterial poten- such as pathogenic bacterial and fungal strains are one of major causes tial of different solvent extracts from M. piperita leaves against patho- of infectious diseases. More importantly, most of such microorganisms genic bacteria including S. aureus, E. coli, Proteus vulgaris, Klebsiella have the ability to survive under harsh environmental conditions and pneumonia, and Pseudomonas aeruginosa and found that strongest anti- can develop multidrug resistance. Regardless of the availability and bacterial effect was exhibited by aqueous and ethyl acetate extracts. use of effective antibiotic drugs, a range of multidrug‐resistant Similarly, Padmini, Valarmathi, and Usha (2010) reported M. spicata strains of microorganisms are appearing posing health threats as a potential natural antibacterial agent. (Ahameethunisa & Hoper, 2010). Moreover, in the developing and Anwar et al. (2017) investigated that MLEOs are an effective nat- under developed countries, synthetic drugs are not only expensive ural antimicrobial agents against different strains of bacteria, but their and have limited supply to treat infectious diseases, but these are also activity varied with respect to the concentration of volatile chemical often substandard and exhibit least and/or side effects. This prompts constituents. The antibacterial potential of the oils tested was some- the need to to search novel and safer natural antimicrobial agents to what comparable with synthetic drug and the major chemical constit- control and fight against microbial infections (Ahameethunisa & uent, carvone. In another report, the EO, isolated by SCFE from Hoper, 2010; Anwar et al., 2017; Sieradzki, Wu, & Tomasz, 1999). In Mentha spicata leaves, also revealed good antibacterial potential ANWAR ET AL. 7 against selected strains of bacteria such as E. coli, S. aureus, B. aereus, against selected strains of bacteria and fungi, respectively. In another B. pumilis, B. subtilis, P. aeruginosa, and S. poona. The authors noted reprot, Hussain, Anwar, Nigma, et al. (2010) investigated M. spicata that the antibacterial activity of the tested oils was varied with respect EO to be a good natural antifungal agent against pathogenic molds to composition of the oil depending upon harvesting regions; how- such as Mucor mucedo, Aspergillus niger, Fusarium solani, Botryodiplodia ever, it was quite comparable with positive control (synthetic drug). theobromae, and Rhizopus solani. Generally, the oil extracted from drought stressed spearmint popula- Furthermore, recent report on the antifungal activity of chitosan in tions offered greater antimicrobial activity and those from both its natural and nanoparticle forms revealed that incorporation of colder/hilly region exhibited greater extent of antioxidant activity mint extract into chitosan nanoparticles resulted in increased antifun- and total phenolics and flavonoids (Saba & Anwar, 2018). gal effects against mycelium growth of A. niger (El‐Aziz, Al‐Othman, Likewise, Ed‐Dra et al. (2018) evaluated the antimicrobial effect of Mahmoud, Shehata, & Abdelazim, 2018). This supports the potential Mentha suaveolens EO against pathogenic bacteria and results showed uses of Mentha extracts and oil as antifungal agents in that the EO of this species has antibacterial effect against Gram‐ nanocapsulation of different food bioactives such as biopeptides. negative and Gram‐positive bacteria and hence can be used as a food The extract from M. longifolia (5 μl/ml) has shown an effective fun- additive to enhance the shelf‐ life of food products. gicidal potential against Aspergillus, Fusarium, Penicillium funiculosum, The antibacterial potential of genus Mentha against multiple and Trichoderma viride. The most sensitive strains were Cladosporium strains of bacteria as mentioned above might be due to the occurrence fulvum, Penicillium ochrochloron, and Cladosporium cladosporioides of bioactives such as luteolin, rosmarinic acid, caffeic acid, where a concentration of as small as 2.5 μl/ml was found to be lethal gallocatechin, epigallocatechin gallate and catechins, menthone, (Dzamic et al., 2010). Similarly, Moghtader (2013) evaluated antifungal isomenthone, and hexadecanoic acid in this species. This can probably activity of M. piperita EO against A. niger and reported that the oil pos- explain the long‐term and wide spread uses of Mentha species as folk sessed stronger antifungal activity than standard antibiotic, medicine against infectious disorders. Traditional uses of Mentha gentamycin. Antifungal activity of M. piperita oil can be mainly plants in folk medicine, backed by bioactivity‐directed scientific evi- ascribed to high content of oxygenated monoterpenoids such as dences, support the exploration of these species as a natural and safer menthone and menthol. Another study by Hussain, Anwar, Nigma, alternative remedy for the treatment of multiple bacterial infections. et al. (2010) revealed antifungal activity of M. piperita and M. arvensis against fungi such as Fusarium solani, Aspergillus niger, Botryodiplodia theobromae, Mucor mucedo, and Rhizopus solani (Hussain, Anwar, 4.3 | Antifungal activity Nigma, et al., 2010). The broad spectrum antifungal activityof Mentha EOs can be linked to the presence of major chemical constituents such Fungal diseases are emerged as a severe health issue, especially, in as menthone, menthol, piperitenone oxide, and carvone (Dzamic et al., subtropical and tropical regions of the world (Portillo, Vila, Freixa, 2010). In the light of broad spectrum antimicrobial activity of Mentha Adzet, & Canigueral, 2001). Due to microbial resistance against com- plants, it can be suggested that these herbs have significant potential mon antifungal drugs, there is prompt need for discovery and develop- to be explored as a viable source of natural antimicrobial agents to ment of novel plant‐based natural antifungal agents (Carvalho & control infectious diseases. On the other hand, due to their antimicro- Ferreira, 2001; Fortes et al., 2008). Besides antibacterial activity, bial efficacy, these can be employed as natural food preservatives to Mentha species have also been searched as a potential source of anti- control growth of pathogens. Different modes of action of antimicro- fungal agents to control pathogenic molds (Saba & Anwar, 2018). Anti- bial agents against microorganism are depicted in Figure 2. fungal activity of M. spicata was studied by Simin, Seyyed, Abolfzl, Mahmoud, and Yeganeh (2011), and it was found that the EO restricted significantly the mycelia growth of Fusarium oxysporum sp. 4.4 | Antiviral activity Radicis cucumerinum in a dose‐dependent manner. Marina et al. (2009) appraised the antifungal effects of M. spicata and M. piperita Viral oriented infectious diseases are a dilemma in medical sciences EOs and their main components against 17 micromycetal food poison- world over. Many viruses are resistant to different therapies due to ing, and human pathogens, and it was discovered that Mentha sp. their adaptable life style. This peculiar characteristic has rendered exhibit effective antifungal activity. Antifungal potential of EO from the development of long‐term effective antiviral chemotherapeutic four Mentha species including M. arvensis, M. piperita, M. longifolia, agents as a challenging task. A limited number of antiviral drugs such and M. spicata was evaluated by Hussain, Anwar, Ashraf, et al. as acyclovir, famciclovir, ganciclovir, sorivudine, zidovudine, didano- (2010). The results from the disc diffusion method followed by MIC sine, zalcitabine, and stavudine are available in the market for treat- revealed that M. arvensis exhibited maximum antimicrobial activity ment of viral diseases (Clark, 1996; Cragg, Newman, & Sander, with larger IZ (14–33 and 16–30 mm) and smallest MIC values 1997). Natural products have always been valued as the best source (20.0–330.3 and 56.2–139.0 μg/ml) against selected strains of bacte- for isolation of chemically diverse new lead molecules and chemical ria and fungi, respectively. Meanwhile, Mentha piperita, M. longifolia, entities and served as a platform for the future development of potent and M. spicata also exhibited considerable antimicrobial potential with and safer antiviral agents. As far as antiviral potential of Mentha plants IZ 15–20, 16–31, and 12–29 mm and 11–32, 19–30, and 16–29 mm is concerned, it is reported that Mentha spicata and Mentha piperita 8 ANWAR ET AL.

prostaglandin E2 (56.6%), leukotriene B4 (64.4%), and interleukin (IL)‐β2 (64.2%). Using Caco‐2 cells, Satsu et al. (2004) reported an increased secretion of IL‐8 using extracts of Mentha, most probably attributable to the occurrence of monocyclic sesquiterpene, α‐ humulene. The presence of antiallergic compounds such as menthol and α‐humulene in Mentha plants supports their potential uses as a natural and safer source of antiallergic agents.

4.6 | Antitumor, anticarcinogenic, cytotoxic, and thromobolytic activities

FIGURE 2 Modes of action of antimicrobial agents against microorganisms Cancer has been a continuing health problem in the medical sciences globally with a lot of developments being made in the treatments of EOs contain some compounds that act as an antiviral agent (Ilkay, this chronic via use of different preventive and curing therapies. The Berrin, Murat, & Yuksel, 2012). Studies showed that phenolic constit- disease is characterized by the cells in the human body, which contin- uents such as rosmarinic acid, luteolin, and phytol present in the ually multiply with the inability to be controlled or stopped and conse- extracts of Mentha spicata are effective for their antimicrobial and quently form tumors of malignant cells with the potential to be antiviral actions (Mckay & Blumberg, 2006). Yamasaki, Nakano, and metastatic (Ochwang et al., 2014). Current treatments include chemo- Kawahata (1998) reported that water soluble extract (16 μg/ml) of therapy, radiotherapy, and chemically derived drugs. Treatments such M. piperita exhibited strong antihuman immuno deficiency virus‐1 as chemotherapy can put patients under a lot of strain and further (HIV)‐1 activity in MT‐4 cells assay. Water‐soluble (polar substances) damage their health. Therefore, there is a focus on using alternative extract of M. piperita also exhibited inhibitory activity against HIV‐ treatments and therapies against cancer (Greenwell & Rahman, 2015). reverse transcriptase. Mentha piperita EO is also reported to have For many years herbal medicines have been used and are still used direct virucidal activity against Herpes simplex virus type 1 (HSV‐1) in developing countries as the primary source of medical treatment and reduced plaque formation effectively (Schuhmacher, Reichling, & (Anwar et al., 2016; Gull, Anwar, Sultana, Alcayde, & Nouman, 2015). Schnitzler, 2003). Preliminary evidence suggested that the main pep- Recently, research is being directed on investigating the potential uses permint oil component, menthol, might have served as natural antiviral of terrestrial plant extracts as reducing and capping agents for the agent and protected against herpes simplex (Melzer, Rosch, Reichling, preparation of nanomaterial oriented drugs for cancer control (Sivaraj, Brigmoli, & Saller, 2004). Rahman, Rajiv, Vanathi, & Venckatesh, 2014). Many plant species have been screened by the researchers for their anticancer potential, and several of those are also employed in herbal medicine for relief in can- 4.5 | Antiallergic activity cer (Cai, Sun, Xing, Luo, & Corke, 2006; Fouche et al., 2008). Different species of Mentha as tested through clinical trials have There is growing increase in the skin disorders due to allergic reactions also shown anticancer effect in cancer patient (Baliga & Rao, 2010), resulting from environmental pollution. Moreover, the existing allo- in addition to using different in vitro and in vivo assays. Ohara and pathic drugs have certain restrictions especially with regard to safety Matsuhisa (2002) screened 120 medicinal plants for antitumor effects and efficacy (Cota, Bertollo, & de Oliveira, 2016). This provokes the against TPA type promtor and okadaic aid (OA) tumor inducers and need to explore new natural/plant‐based antiallergic agents as alterna- noted that Mentha was one of the most effective species that exhib- tives to achieve better control and treatment of allergic disorders. Sev- ited strong activity (86–100%) towards decreasing the effect of OA. In eral plant‐based natural formulations are known to be safer and another study, Rahimifard et al. (2010) evaluated the cytotoxic effects exhibit additional medicinal effects including synergism as well as of extracts and EOs from Mentha species using different cell lines such modulation of the body immune system (Cota et al., 2016). as Hela (human malignant cervix carcinoma), Hep2 (human laryngeal Antiallergenic effect of genus Mentha was reported by Inoue, carcinoma), and Vero (green African monkey kidney) using cell lines Sugimoto, Masuda, and Kamei (2002) and Satsu et al. (2004). The cultured in a suitable medium and cell viability was assessed by MTT effectiveness of peppermint for nausea can be explained through dif- assay (Alley et al., 1988). Mentha species were proven toxic against ferent mechanisms. A bioactive compound in M. piperita, namely, Vero, Hela, and Hep2 cell lines. The EOs of the plants showed more luteolin‐7‐O‐rutinoside (given at dosage of 100 and 300 mg/kg orally) toxic effect in Hela cell line (IC50 ≤ 42.3 μg/ml), and the extracts were was reported to exhibit strong inhibitory activity on histamine more toxic against Vero cell line (IC50 ≥ 94.3 μg/ml). Among the spe- released in rats (Inoue et al., 2002). Juergens et al. (1998) investigated cies tested, EO of M. spicata was found to be less toxic against Hep2. that menthol (0.1 μg/ml), an important component in Mentha, effec- According to Hussain, Anwar, Ashraf, et al. (2010) hydroditilled EOs tively suppressed the generation of inflammatory agents such as from four commonly cultivated Mentha species such as M. longifolia, ANWAR ET AL. 9

M. spicata, M. arvensis, and M. piperita exhibited good cytotoxicity 2003). Cyclooxygenases are among the key enzymes involved in the against the human breast cancer cell line MCF‐7. Anwar et al., 2017) synthesis of different hormones such as prostacyclins and thrombox- Fatma, Arzu, and Arzu (2012) screened various species of Mentha anes. Such hormones are linked to pain, inflammation, and platelet plant extracts for antitumor activities and found that aqueous extract aggregation (Pilotto, Sancarlo, Addante, Scarcelli, & Franceschi, of M. pulegium showed the best antitumor activity (94%), whereas M. 2010). Inflammation directly or indirectly relates with several human longifolia extracts exhibited reasonable antitumor activity. Another diseases including heart diseases as well as Alzheimer's disease cytotoxic study showed that methanolic extract of M. longifolia at a (Howes & Houghton, 2003; Woodward et al., 2005) and cancer dose of 50 0 μg/ml resulted in 25% cell death and this cytotoxic effect (Mueller, 2006). The drugs used to reduce inflammation are generally was dose‐dependent, that is, further increasing the extract doses up to classed as nonsteroidal antiinflammatory drugs, in addition to 1,000, 1,500, and 2,000 μg/mL produced 25, 50, and 62.5% deaths, steroides, and long‐term use of these is known to cause multiple respectively (Rahmat et al., 2012). In another recent study, Al‐Ali adverse effects such as gastric lesions, cardiovascular disorders, and et al. (2014) reported that water and methanolic extracts of M. renal failure (Huerta, Castellsague, Varas‐Lorenzo, & García Rodríguez, longifolia have significant antimutagenic and anticancer activities as 2002;Wallace, 2001). Hence, there is need for the development of depicted by different bioassays such as Brine shrimp bioassay, Ames new safer antiinflammatory drugs. mutagenicity bioassay. It reflects that Mentha species contain bioac- Currently, investigation on plant‐based extracts and EOs, as tive constituents having anticancer activity that can act as lead mole- antiinflammatory agents, are an interesting research area. Mei‐Lin cule for discovery of some new anticancer drugs with additional et al. (2013) studied antiinflammatory activity of EOs of two mint spe- protective role against different pathogens. cies and revealed that Chocolate mint oil has better antiinflammatory Formation of blood clots within an artery, so called atherothrom- potential than peppermint oil. Filomena et al. (2008) assessed bosis or atherosclerosis, is a serious and challenging health disorder antiinflammatory activity of extract of Mentha aquatica and found that and is medically controlled by the use of thrombolytic drugs. However, it produced 27% oedema inhibition compared with nonsteroidal long‐term uses of synthetic drugs may cause serious side effects antiinflammatory drug indomethacin used as positive control, which (Mannan et al., 2011). On the other hand, intake and supplementation reduced the oedematous response by 57% at dose of 100 μg/cm2. of natural foods with thrombolytic potential (antiplatelet/anticoagu- In another study (Verma, Arora, & Dubey, 2003), methanolic extracts lant effcets) is strongly linked to decrease the prevelance of coronary of Mentha arvensis were evaluated for antiinflammatory activity in heart disease risk (Prasad et al., 2007; Ratnasooriya, Fernando, & albino rats and the results obtained supported that Mentha plants Madubashini, 2008). In this regard, among various plant foods, differ- have antiinflammatory agents that can be explored for potential phar- ent Mentha species such as M. longifolia has exhibited an effective maceutical applications. thrymbolytic (percent clot lysis) activity. In a typical study, Anwar et al. (2017) investigated that volatile oils from different chemotypes of M. longifolia have considerable thrymbolytic effect (in terms of per- 4.8 | Urease inhibitory activity cent clot lysis in the range of 11.6 to 68.4%), compared with positive control streptokinase (87.7 % clot lysis). In this study, the clot lysis Gastric/duodenal ulcers are mostly caused by anti‐H. pylori bacterium potential of the investigated oils was not only correlated to the con- under acidic environment (Amin, Anwar, Naz, Mehmood, & Saari, tent of major monoterpenoid, carvone, but also affected due to vari- 2013; Dunn & Cohen, 1997; Mégraud, 1993). Helicobacter pylori able levels of other classes of terpenoids such as MHs and releases urease that thus converts CO (NH2)2/urea into ammonia; sesquiterpens hydrocarbons and oxygenated sesquiterpens. Rarely the released ammonia provides shelter and protects this organism reports on thrombolytic activity of Lamiaceae plant essential oils are from the acidic environment of the stomach. Inhibition of urease activ- available in the literature; however, different solvent (ethanol, metha- ity can be explored as a vital strategy to eliminate H. pylori in the body nol, chloroform, and acetone) extract from Mentha spicata, Mentha and reduce the incidence of ulcer (Amin et al., 2010; Amin et al., arvensis, and Mentha aviridis have notable (27.55–32.56% clot lysis) 2013). There is greater prevalence of H. pylori‐related infections in thrymbolytic activity (Shahik et al., 2014). This prompts the need to the underdeveloping nations, although in some other parts of the use Mentha species for isolation of potential natural thrombolytic world even more than 50% of the population is stated to have H. pylori agents. infection (Amin et al., 2010; Dunn & Cohen, 1997; Mégraud, 1993). Antibiotics such as amoxicillin, metronidazole, and clarithromycin are mostly used for the treatment of H. pylori infections (Mégraud, 4.7 | Antiinflammatory activity 1993; Mégraud, 2012). However, in addition to antimicrobial drug resistance, the use of such synthetic drugs in the treatment of gastric Inflammatory diseases, caused as result of inflammation, are one of ulcers is linked with different adverse effects (Mégraud, 2012), which major health problems worldwide. Inflammation is a complicated bio- prompts the need to explore some safer and more effective natural logical response of vascular tissue to pathogens and irritants and is antiulcer agents. characterized by swelling, redness, and pain (Ferrero, Nielsen, Ander- Plants have long been employed as a source of food and son, & Girardin, 2007; Palladino, Bahjat, Theodorakis, & Moldawer, phytomedicines due to the fact that they contain a wide array of 10 ANWAR ET AL. medicinally active components (Cowan, 1999; Gilani & Atta‐ur‐ Coats, 1994). More interestingly, some companies in the United King- Rahman, 2005; Gull et al., 2015; Sultana et al., 2010; Sultana, Anwar, dom and the United States have introduced garlic‐oil based pest con- Mushtaq, Aslam, & Ijaz, 2014). A number of medicinal plants have trol products. Moreover, in the United States some consumer been screened as the potential sources of antiulcer agents in terms insecticides, containing mint oil (as the active ingredient), have been of their anti‐H. pylori activity (Amin et al., 2010; Rojas, Ochoa, Saul, marketed for home and garden use. In North American, menthol has & Munoz, 2006; Tabaka, Armonb, & Neeman, 1999). Although studies been approved for control of tracheal mites in beehives. A product on the urease inhibitory activity of Mentha species are scarce, how- produced in Italy (Apilife VARTM), mainly containing thymol and small ever, Ghous, Akhtar, Nasim, and Choudhary (2010) evaluated M. amounts of menthol, cineole, and camphor, is employed to control longifolia for antiurease activity and noted the strong inhibitory effect Varroa mites in honeybees (Khater, 2013). with IC50 value of 57.47 μg/ml. Yasmeen, Hashmi, Anjum, Saeed, and EOs of M. longifolia showed strong insecticidal activity against

Muhammad (2012) evaluated the aqueous and alcoholic extracts of M. stored product insect, T. castaneum with LC50 of 13.05‐μl/L air (Khani piperita for inhibitory activity against urease producing bacteria, Pro- & Asghari, 2012). Mentha pulegium and Mentha spicata EOs along with teus mirabilis and observed that M. piperita showed positive results. their main chemical constituents such as pulegone, menthone, and carvone were also found to be effective insecticidal and genotoxic against Drosophila melanogaster (Franzios et al., 1997). A 0.2% 4.9 | Bio‐pesticidal activity pulegone‐containing diet inhibited reproduction of last‐instar south- ern armyworm, Spodoptera eridania (Cramer; Gunderson, Samuelian, Due to multiple adverse effects of synthetic pesticides, now there is Evans, & Bratisten, 1985). The larvae mortality of variegated cutworm, greater interest towards exploring plant based eco‐friendly green pes- Peridroma saucia Hubner, fed for 6 days with menthone was found ticides (bio‐pesticides) for pest‐insect control and management in agri- positive with median lethal dose of 2,478 μg/g (Harwood et al., culture (Abdel‐Tawab, 2016; Maureen, 2006). In this regard, a 1990). Similarly, menthol, an important component in the EO of significant number of plants derived extracts and EOs have been Mentha arvensis, was noted to be a strong repellent (82–100% at reported for their broad spectrum bio‐pesticidal applications with 0.353 μg/cm2 dose) against four insects including Rhyzopertha domi- promising results (Abdel‐Tawab, 2016; Pavela & Benelli, 2016). In per- nica F., Sitophilus oryzae L., Callosobruchus maculatus F., and Tribolium spective of sustainable agricultural pest management practices, botan- castaneum Herbst, and its derivative, menthyl acetate, was highly ovi- ical pesticides can be the best choice, especially in organic farming and cidal against T. castaneum (Aggarwal et al., 2001). These findings sup- food productions. In this direction, encapsulating EOs seems to be a port that Mentha plants can be explored as a sustainable source of good option to commercialize these products as nanopesticides in broad‐spectrum and safer biopesticides for preservation of food grains modern agriculture (Abdel‐Tawab, 2016; Pavela & Benelli, 2016). and cereal crops. The EOs from different species of the genus Mentha have poten- tial to be used as bioinsecticides and biofungicides (Kordali, Cakir, Mavi, Kilic, & Yildirim, 2005). The volatile oils from Mentha plants 5 | VOLATILES COMPOSITION OF MENTHA have shown pesticidal activity against common grains pests such as EOS Tribolium castanum and Callosobruchus maculatus (Tripathi, Prajapati, Aggarwal, Khanuja, & Kumar, 2000). The major constituent (51 %) of The extraction/isolation of EOs from various plant materials can be spearmint oil (M. spicata), dillapiole, exhibited strong insecticide syner- made by different conventional methods such as steam distillation, gistic effects, whereas pulegone occurring in M. pulegium, and thymol hydro‐distillation (Sokovic & Van‐Griensven, 2006), and low or high and carvacrol in Thymus vulgaris are known as one of the most effec- pressure–distillation, organic solvent extraction (Soxhlet extractor), tive insecticidal constituents (Koul, Walia, & Dhaliwal, 2008). Pulegone and expression or cold pressing etc. (Donelian, Carlson, Lopes, & has been investigated to be very effective against D. virgifera, M. Machado, 2009). Steam distillation and/or hydro‐distillation are domestica, P. saucia, and S. litura with LD50 in the range of 38– known to be the most applicable technique widely employed for the 753.9 μg/insect (Harwood, Modenke, & Berry, 1990; Hummelbrunner extraction of food and pharmaceutical grade EOs. There are some lim- & Isman, 2001). itations in the extraction of EO by these conventional techniques such Moreover, EO from M. citrata, being a rich source of linalool and as long time intake, use of large volume of solvents, and accelerated linalyl acetate, exhibited strong fumigant effect against rice weevils temperature conditions (Deng, Yao, Wang, & Zhang, 2005). Moreover, (Singh, Raghubanshi, Singh, & Srivastava, 1989). Another active com- the loss of some volatile constituents and degradation of unsaturated pound, carvone, mainly detected in M. longifolia and M. spicata has compounds, especially, in case of Soxhlet extraction, as well as con- been reported to be quite effective as adulticide and menthol is more tamination of residual toxic organic solvent may also occur (Gironi & potent fumigant against C. maculatus and T. castaneum. The chemical Maschietti, 2008; Glisica et al., 2007; Jimenez‐Carmona, Ubera, & constituents such as linalool, menthol, carveol, geraniol, carvacrol, thy- Luque‐de‐Castro, 1999). Due to these limitations, efforts have been mol, verbenol, terpineol, menthone, pulegone, thujone, carvones, made by the researchers towards exploring super critical CO2‐based fenchone, verbenone, citral, citronellal, cinnamaldehyde, and cinnamic environment‐friendly alternatives for isolation of plant EOs (Gironi & acid have been evaluated as ovicides against M. domestica eggs (Rice & Maschietti, 2008; Glisica et al., 2007; Hawthorne et al., 1993; ANWAR ET AL. 11

Jimenez‐Carmona et al., 1999; Saba & Anwar, 2018) and related Mentha species (Rajendra et al., 2013). Meanwhile, Verma, Padalia, extracts (Al‐Asheh, Allawzi, Al‐Otoom, Allaboun, & Al‐Zoubi, 2012; and Chauhan (2010) reported that the major constituents in M. citrata Jian‐wei, Lu‐ling, Xiang, Hong‐yan, & Tian‐zhou, 2012; Senorans, oil were linalool, linalyl acetate, and α ‐terpineol with contents in the Ibanez, Cavero, Tabera, & Reglero, 2000). range of 32.86–46.31%, 19.27–37.72%, and 2.90–4.61%, respectively. EOs from Mentha herbs, like other herbal EOs, are generally Josip, Mladen, and Danica (2000) identified linalyl acetate (21.46%, extracted by hydro‐distillation using a Clevenger type apparatus 42.02%), linalool (13.68%, 22.66%), 1,8‐cineole (12.51%, 6.40%), β‐ (Hussain et al., 2008; Simin et al., 2011). However, supercritical fluid myrcene (8.10%, 2.87%), α‐terpineol (7.38%, 0.73%) as the main com- extraction is also gaining popularity in recent years for isolation of pounds in the EO, and pentane extract of Mentha citrata, respectively. herbal EOs due to its green technological benefits (Saba & Anwar, Moreover, the EO and extract from this species also contained 2018; Shojaie, Shirazi, Kargari, & Shirazi, 2011). hedycaryol as high as 4.20% and 9.88%, respectively. Mentha EOs are complex mixture of volatile constituents, and their The EOs of M. longifolia are reported to contain wide range of chemical composition is preferably studied by gas chromatography‐ monoterpenoids such as piperitone oxide, carvone, piperitenone, flame ionization detector (GC‐FID) and further authenticated by gas piperitone, pulegone, 1,8‐Cineole, limonene, β‐caryophyllene, chromatography‐mass spectrometry (GC‐MS; Anwar et al., 2017; menthone, and menthol; however, remarkable chemo‐geographical Hussain et al., 2008; Hussain, Anwar, Ashraf, et al., 2010; Hussain, variations have been noted in the composition of these oils (Oyedeji Anwar, Nigma, et al., 2010; Saba & Anwar, 2018). The chemical com- & Afolayan, 2006). Abbas and Javad (2011) detected piperitenone positions of Mentha EOs vary depending upon the genetic makeup of (43.9%), tripal (14.3%), oxathiane (9.3%), and piperitone oxide (5.9%) the species and variability in agro‐climatic and geographical factors as the main components in MLEO. Although, Iranian‐based MLEO (Abedi, Golparvar, & Hadipanah, 2015; Anwar et al., 2017; Hussain, was dominated by the presence of piperitone (43.9%), limonene Anwar, Ashraf, et al., 2010; Hussain, Anwar, Nigma, et al., 2010; Saeidi (13.5%), and trans‐piperitol (12.9%; Rasooli & Rezaei, 2002). According et al., 2012). Jerkovic and Mastelic (2001) identified 29 components in to Anwar et al. (2017), M. longifolia chemotypes from different regions the hydrodistilled EO of M. aquatic including menthofuran as the of Saudi Arabia were found to be a good source of carvone‐rich EOs. major component. Similarly, Sacco and Maffei (1988) reported Haris et al. (2012) reported that major portion of MLEO is com- menthofuran as the major component of M. aquatica EO. Hefendehl prised of oxygenated monoterpenes (87.1%), sesquiterpene hydrocar- and Murray (1972) also reported menthofuran (66–64%), cineol (7%) bon (6.79%), oxygenated sesquiterpenes (5.57%), and MHs (3.06%). In along with 18–19% of other 12 different compounds in the EO from oxygenated monoterpenes, poperitone oxide (63.58%) was present in Mentha aquatica. Similarly, Maria‐Magdalena et al. (2010) character- a large quantity; these results are also in accordance with Mastelic and ized Mentha aquatica EO by three main components including Jerkovic (2002) and Baser, Kurkcuglu, Tarimcila, and Kaynak (1999). In menthofuran (51.27%), limonene (12.06%), and izomenthone (8.11%). another study (Bohloul, Maryam, Mahtab, & Mohammad, 2013), GC‐ However, M. aquatica EO from Iran contained β‐caryophyllene MS analysis of volatiles of two different populations of M. longifolia (22.4%), viridiflorole (11.3%), and 1,8‐cineole (10.9%) as the main con- revealed the presence of carvone (72.3%), limonene (19.29%), and β‐ stituents (Akbar, Abdolhossein, Shiva, & Kobra, 2006). gurjunene (1.33%) as main constituents in Ghazvin populations; how- The EO from another Mentha species, namely, M. arvensis was ever, Ardebil‐based samples were dominated by carvone (62.3%), dominated by L‐menthone (29.41%), menthol (21.33%), isomenthone 1,8‐cineole (14.31%), and neo‐isomenthol (4.98%). (10.80%), eucalyptol (6.91%), neo‐menthol (4.70%); cis‐Piperitone Mentha piperita essential oil (MPEO) is characterized by the pres- oxide (3.62%), and α‐Phellandrene (3.20%; Sharma et al., 2009). In ence of oxygenated monoterpenes (OM) such as menthol, 1,8 cineole, another study, the main constituents identified in the EO of M. menthone, menthyl acetate, menthofurone, and sabinene hydrateas arvensis were menthol, menthone, isomenthone, menthyl acetate, the main volatiles (Agarwal, 2008; Hussain, Anwar, Ashraf, et al., and limonene (Verma et al., 2010). The volatile oil produced from six 2010). Moreover, menthol and menthone content of different MPEO cultivars of M. arvensis mainly constituted menthol (77.5–89.3%), may vary over a wide range from 10 to 63% and 12 to 76%, respec- menthone (03–7.9%), and isomenthone (3.7–6.1%; Singh et al., tively (Aflatuni, 2005). Zoran, Zika, Slavica, Dusan, and Ibrahim 2005). Menthone, isomenthone, p‐cymene, isopulegol, and decanol (2009) reported that L‐menthone was present in higher amount were also detected as major compounds in the Mentha arvensis EO (37.15%) in MPEO and another important compound, menthol, had a isolated from plants harvested at different stages of crop growth content of 30.67%. In addition, some other prominent compounds (Kumar et al., 2000). such as iso‐menthone (10.33 %) and menthyl acetate (5.46 %) were Meanwhile, 28 components were identified in the EO of M. citrata, also present. Moghtader (2013) identified 23 compounds in MPEO representing about 92.8% of the whole oil with linalool (59.7%), linalyl with menthol (38.33%), menthone (21.45%), and menthyl acetate acetate (18.4%), nerol (2.0%), trans‐p‐menth‐1‐en‐2‐ol (1.8%), α‐ (12.49%) constituting 72.27% of the total oil composition. Fatma and terpineol (1.5%), and limonene (1.1%) as the major constituents Jaime (2012) identified menthone (36.58%), neo‐menthol (40.47%), (Rajendra, Ram, Amit, Velusamy, & Chandan, 2013). According to these and 1,8‐cineol (8.69%) as the major constituents of MPEO. In another researchers, some minor components such as nerol (2.0%), geranyl ace- report (Gokalp, Nese, Mine, Husnu, & Fatih, 2002), GC‐GC/MS analy- tate (0.7%), citronellol (0.2%), and geraniol (≤0.1%) are the characteris- sis of MPEO confirmed the distribution of menthol (28–42%) and tic constituents, which have not been reported in other cultivars of menthone (18–28%) as the principal components. 12 ANWAR ET AL.

On the other hand, the main compounds in M. pulegium EO were of some precautions related to use of pulegone‐based Mentha prod- found to be piperitone (38.0%), pipritonone (33.0%), and α‐terpineol ucts in patients, especially with reflux diseases and liver disorders. (4.7%; Mahboubi & Haghi, 2008). GC‐MS data of M. pulegium EO Meanwhile, the EO of M. rotundifolia showed the occurrence of 39 revealed the occurrence of pulegone and menthone as the main com- compounds with cis‐piperitone oxide as the principal component ponents with contribution of 69.218% and 18.97%, respectively (Brada, Bezzina, Marlier, & Lognay, 2006). According to some other (Rezvan et al., 2011). Derwich, Benziane, Taouil, Senhaji, and Touzani studies, cis‐piperitone oxide was also reported as a main constituent (2010) detected 28 compounds in M. pulegium EO with piperitone of the oil (Kokkini & Papageorgiou, 1988; Shibata & Shimizu, 1973; (35.56%), piperitenone (21.18%), α‐terpineol (10.89%), and pulegone Van & Hendriks, 1975). Derwich et al. (2010) identified 32 volatiles (6.45 as the most important compounds. in EO of M. rotundifolia with menthol (40.50%) being the main com- Leila et al. (2013) studied the composition of M. rotundifolia EO pound, in addition to presence of menthone (5.0%), menthofuran from different locations and found that oils from Beja locality were (4.20%), and menthyl acetate (4.50%). most complex and presented 45 compounds with β‐caryophyllene The EO from M. spicata, another important species, showed the (26.67%), germacrene D (12.31%), and carveol (7.38%) as the principal presence of 30 components representing 87.7% of the oil with volatiles. Although 40 chemical compounds, representing 95.81% of carvone (41.1%) followed by the limonene (20.1%) as the two major the total oil, were detected in the oil from Bizerte site with pulegone constituents (Martins, Tinoco, Almeida, & Cruz‐Morais, 2012). The (32.09%), piperitenone oxide (17.28%), and 5‐acetyl thiazole oil mainly constituted oxygenated monoterpenoids (46.3%), MHs (11.26%) as the main constituents. (25.5%), and sesquiterpenes hydrocarbons (14.1%). The carvone‐rich Pulegone is naturally found in some plants of the Lamiaceae family. M. spicata oil chemotypes are widely distributed (Kofidis et al., 2004; Typically, the EOs of M. pulegium, M. rotundifolia, and M. piperita have Mata et al., 2007; Vimolmangkang, Sitthithaworn, Vannavanich, been characterized by the presence of notable amounts of pulegone. Keattikunpairoj, & Chittasupho, 2010). Mervat, El‐Sayed, Amal, Most of the pharmacological effects of such lamiacea species can be Nagwa, and Marwa (2010) examined that spearmint EO contained linked to the occurrence of pulegone along with other volatiles such carvone (68.58%) and limonene (16.42 %) as the major constituents. as menthone, isomenthone, menthaol, 1,8 cineaole and piperotone Fatma and Jaime (2012) also identified carvone (42.84%), neo‐menthol (Mikaili et al., 2013). However, there are concerns regarding the use (40.47%), α‐pinene (17.77%), and carveol (34.98%) as the major of pulegone based on the reports suggesting that execessive intake comopnents. Several other studies also confirmed that carvone is of this naturally occurring organic compound is associated with hepa- the main component of spearmint EO (Hussain, Anwar, Ashraf, et al., totoxicity (Bakerink, Gospe, Dimand, & Eldridge, 1996). Typically, some 2010; Mkolo et al., 2011; Suleyman, Nesrin, Veysel, Ersin, & Uyan, reports on experimental animals depicted that p‐cresol, a pulegone 2010). In another study by Saba and Anwar (2018), supercritical metabolite, may induce reduced hepatic function, increased liver and fluid‐extracted leaves EO from different spearmint ecotypes kidney weight, and atrophy of female reproductive organs, especially contained variable levels of main component, carvone (30.89–52.31 due to degeneration of cells (Chen, Serag, Sneed, & Zhou, 2011). %) along with other compounds such as menthone (1.09–22.58 %), The amount of pulegone in Mentha oils may vary based on agro‐ limonene (1.31–9.39 %), 1,8‐cineol (1.07–7.31 %), menthol (0.78– climatic and genetic factors such as origin and genetic make up of 6.25%), and cis‐carveol (0.21–5.29 %). the species, weather conditions, harvest time, and location maturity The chemical composition of another less known Mentha species, as well as plant maturity (Dolzhenko, Bertea, Occhipinti, Bossi, & namely, M. suaveolens was also studied by some researchers. For Maffei, 2010; Kumar et al., 2000; Misra & Srivastava, 2000). Besides example, Kasrati et al. (2013) identified 35 and 29 components in medication, humans may be exposed to pulegone as a constituent of EO of wild and cultivated mint timija (Mentha suaveolens subsp.) Timija EOs/flavouring agents, confectionery, and cosmetic products (Briq. and Harley), respectively, accounting for 98.7–98.9% of the total (Barceloux, 2008; Karousou, Balta, Hanlidou, & Kokkini, 2007; Nair, oil. Both the EOs were rich in oxygenated monoterpenes (86.7– 2001). 90.4%) with pulegone (34.3–62.3%) menthone (10.8–39.4%), and Meanwhile, in context of hepatotoxicity, there are limits for the isomenthone (7.8–9.3%) as the key constituents. However, according use of pulegone in food products. For example, in the United States, to two other researchers, the EO of this species was characterized pulegone is not lawful as a synthetic flavoring agent (Department of by a high content of piperitone oxide and piperitenone oxide (Oumzil Health and Human Services, Food and Drug Administration, 2012). et al., 2002; Sutour, Bradesi, Casanova, & Tomi, 2010). El‐Sayeda, According to the Cosmetic Ingredient Review Expert Panel, the con- Hesham, Zeinab, Mohamed, and Amany (2012) noted a considerable centration of pulegone in cosmetic formulations should not exceed seasonal variation in the volatiles composition of M. suaveolens Ehrh. 1% (Nair, 2001). The panel also recommended limiting the contents The total compounds identified were 46 among which 15 compounds of pulegone to less than or equal to than 1% in cosmetic grade Mentha were common in all the tested samples. The oxygenated oils or related extracts. The panel revealed that the concentration of monoterpenoids constituted about 45%, 46%, 63%, and 44% of the pulegone with in permissible limits (≤1%) can be achievable by both total composition of the oils from winter, spring, summer, and autumn controlling the harvest time and screening of specific species as well samples, respectively. Carvone (31‐56%) was the chief constituent in as employing novel agronomic and biotechnological techniques. spring, summer, and autumn samples, and limonene (approximately Keeing in view of the concerns regarding hepatotoxicity, there is need 26%) was the major component of the winter sample followed by ANWAR ET AL. 13 carvone (approximately 25%). Such chemo‐geographical variations in other bioactive components, especially polyphenols (Rice‐Evans, the yield and composition of Mentha oils have been documented in Miller, & Paganga, 1997). In addition to the presence of volatile con- the literature and can be attributed to variability of agro‐climatic and stituents (Anwar et al., 2017; Mikaili et al., 2013), M. longifolia is genetic factors (Al‐Okbi, Fadel, & Mohamed, 2015; Anwar et al., reported to contain five flavonoids such as luteolin‐7,3′‐O‐diglycoside, 2017; Hussain, Anwar, Ashraf, et al., 2010). The profiles of important luteolin‐7‐O‐glycoside, quercetin‐3‐O‐glycoside, apigenin, and chemical components of some common Mentha species are presented kaempferol‐3‐O‐glycoside. Of these polyphenols, quercetin‐3‐O‐glu- in Table 2. The structure of some common chemical constituents of coside exhibited high antibacterial activity (Akroum, Bendjeddou, Mentha EOs is also shown in Figure 3. Satta, & Lalaoui, 2009). In another study, the extract of naturally dried M. longifolia offered a higher content of phenols (113.8 ± 2.0 mg of gallic acid/g of the dry extract) and flavonoids (106.7 ± 0.3 mg of 6 | OTHER BIOACTIVES/HIGH‐VALUE rutin/g of the dry extract) among others. Kaempferol 3‐O‐glucoside COMPONENTS IN MENTHA was noted to be the major phenolic component in the tested Mentha extracts (Stanisavljević et al., 2012). Besides the main volatile terpenoid compounds, the biological activi- According to some reports, total polyphenols content in peppermint ties of various Mentha species can be linked to the presence of several leaves constituted approximately 19–23% of total flavonoids including

TABLE 2 Composition of major chemical components of essential oils from various species of Mentha

Major Mentha Mentha Mentha Mentha Mentha Mentha Mentha Mentha Mentha component aquatica arvensis citrata longifolia piperita pulegium rotundifolia spicata suaveolens

Cineol 7% ‐‐ ‐ 8.69% ‐ 2.4% ‐‐ Limonene 4–9% 1.47% 1.1% 4.3% ‐ 1.02% 1.8% ‐‐ Menthol 0–2% 21.33% ‐‐‐ ‐‐‐ 40.47% 3.28% 40.50% 40.47% ‐ Menthone 0–1% 29.41% ‐‐36.58% 3.09% 5.0% ‐ 39.4–10.8% Menthofuran 66–64% ‐‐ ‐ ‐ 2.15% 4.20% ‐‐ Isomenthone ‐ 10.80% ‐‐ ‐ 1.56% 2.5% ‐ 9.3–7.8% Eucalyptol ‐ 6.91% ‐‐ ‐ ‐‐‐ ‐ Linalool ‐ 2.20% 59.7% ‐‐‐2.0% ‐‐ Linalyl ‐‐18.4% ‐‐‐3.5% ‐‐ acetate Nerol ‐‐2.0% ‐‐‐‐ ‐ α‐terpineol ‐‐1.5% ‐‐10.89% ‐‐ ‐ Trans‐p‐ ‐‐1.8% ‐ ‐ ‐‐‐ ‐ menth‐1‐ en‐2‐ol Piperitenone ‐‐‐43.9% ‐ 21.18% ‐‐ ‐ Tripal ‐‐‐14.3% ‐ ‐‐‐ ‐ Oxathiane ‐‐‐ 9.3% ‐ ‐‐‐ ‐ Piperitone ‐‐‐ 5.9% ‐ 4.02% ‐‐ ‐ oxide Menthol ‐‐‐ ‐ 4.33% ‐‐‐ ‐ acetate Sabinene ‐‐‐ ‐ 1.64% ‐‐‐ ‐ α‐pinene ‐‐‐ ‐ 1.11% ‐‐17.77% ‐ Piperitone ‐‐‐ ‐ ‐ 35.56% 3.10% ‐‐ Pulegone ‐‐‐ ‐ ‐ 6.45% ‐‐62.3‐34.3% Carvone ‐‐‐ ‐ ‐ 1.13% ‐ 42.84% ‐ Menthyl ‐‐‐ ‐ ‐ ‐4.5% ‐‐ acetate Carveol ‐‐‐ ‐ ‐ ‐ ‐34.98% ‐ Reference Hefendehl and Sharma Rajendra Abbas and Fatma and Derwich Derwich Fatma and Kasrati Murray (1972) et al. (2009) et al. (2013) Javad (2011) Jaime (2012) et al. (2010) et al. (2010) Jaime (2012) et al. (2013) 14 ANWAR ET AL.

The qualitative phytochemical analysis of M. arvensis leaf extract revealed the presence of secondary metabolites such as alkaloids, phe- nolic compounds, flavonoids, tannin, and diterpenes, and saponins were absent (Suryawanshi & Ahirrao, 2013). Similar results were reported by John, Sebastian, and Sujin (2012); Suresh et al. (2012); and Sugandhi and Meera Bai (2011). Maffei and Scannerini (1992) reported that the nonpolar lipid fraction of peppermint leaves is dom- inated by palmitic, linoleic, and α‐linolenic (18:3 acid). These results reveal that Mentha plants are a good source of secondary metabolites having important biological activities and medicinal health functions and can be explored for functional food and nutra‐pharmaceutical applications.

7 | COMPUTATIONAL STUDIES ON MENTHA CHEMICAL COMPOUNDS

During the discovery of new drugs, the effect of natural antioxidants on human body has been investigated. The plant EOs contain various FIGURE 3 Chemical structure of some important compounds in Mentha essential oils biologically active compounds in different concentrations (Abbas et al., 2017; Gull et al., 2015; Hussain et al., 2008). In order to evaluate anti- 7–12% luteolin 7‐O‐rutinoside, 59–67% eriocitrin and rosmarinic acid oxidant potential of plant products, the biologically active (collective), 6–10% hesperidin, and smaller quantities of pebrellin, compounds/antioxidant bioactives should be isolated by appropriate gardenin B, apigenin and 5,6‐dihydoxy‐7,8,3′,4′‐tetramethoxyflavone methods based upon their chemical composition and nature (Mushtaq (Areias, Valentao, Andrade, Ferreres, & Seabra, 2001; Hoffmann & et al., 2017; Qadir et al., 2019). The traditional chemical means Lunder, 1984; Samejima, Kanazawa, Ashida, & Danno, 1995; Zakharov, employed for the identification of bioaactive molecules in EOs are Zakharova, & Smirnova, 1990; Zheng & Wang, 2001). In another study, costly and time‐consuming and generally unable to indicate synergism it was revealed that around 75% of the total polyphenols present in pep- and antagonism effects of the active compounds. Recently, the com- permint leaves can be extracted in an infusion (Duband et al., 1992). As putational techniques have been explored as an efficient means with per investigation of Tekel'ova, Fialova, Szkukalek, Mrlianova, and greater throughput to predict new components with desirable biolog- Grancai (2009), the amount of total hydroxycinnamic derivative pheno- ical properties. It is believed that successful drug discovery requires lics in the leaves (2.30–7.00 %) and flowers (2.54–7.68 %) of different multiobjective optimization, which can help to develop new drugs Mentha species was higher compared with that in stems (1.24–2.66 (Abbasi, Gharaghani, Benvidi, & Latif, 2018). %). The content of flavonoids (expressed as luteolin) was also noted to In a recent study conducted by Abbasi et al. (2018), the integration be higher in the leaves (0.54–2.29%) and flowers (0.91–1.66 %) com- of chemoinformatics methods with chromatographic techniques was pared with the stems (0.16–0.58 %). used to predict the antioxidant activity of some medicinal plants The level of anthocyanidins in aerial parts (leaves, stems, and including some species of genus Mentha. The study developed a flowers) of different Mentha species ranged from 0.01 to 0.07 %. new drug discovery strategy for the quantitative chemical The presence of high content of phenolic compounds in M. piperita component‐antioxidant activity relationship (QCAR) model. This and M. longifolia leaves and flowers supports the potential uses of included multiobjective feature selection algorithms based on artificial these species as a natural source of antioxidants. Similarly, total phe- neural network to identify novel antioxidants. This method helped to nolics and flavonoids content in methanol extract of M. pulegium were discover the new synergistic effects of nonphenolic compounds (i.e., 157.99 mg GAE/g DW and 16.96 mg RTE/g DW, respectively γ‐terpinene, p‐cymene, and caryophyllene). In order to evaluate the (Osman, 2013). Karray‐Bouraoui et al. (2010) reported that phenolic performance of new developed method, the volatile components of contents of M. pulegium varied over a wider range (20.1–56.6 mg hydrodistilled Mentha EO were analyzed using GC‐MS and their anti- GAE/g DW) and total flavonoids (12.9–52.1 mg CE/g DW). Yumrutas oxidant activities were measured by DPPH radical scavenging assay. and Saygideger (2012) examined a high level of phenols and flavonoids The samples were also analysed using QCAR model. The result from in methanol extract of M. pulegium, 206.58 mg GAE/g DW and the computational approaches showed good agreement with the 46.54 mg CE/g DW, respectively. In a comparative study of Mentha actual values obtained from DPPH assay. species grown wild in Egypt, it is reported that aqueous and methano- In another related study, the selected chemical structures were lic extracts of Mentha longifolia and Mentha pulegium contain 43 com- studied using computational chemistry; the geometry optimizations pounds belonging to different chemical classes including flavone, were performed in all the cases (Gende et al., 2014). The composition flavonol, phenolic acid, and their glycosides (Marzouk et al., 2018) of Mentha arvensis and Mentha rotundifolia EOs were analyzed by ANWAR ET AL. 15

GC/MS. The bioautography assay resulted that menthol, menthone, CONFLICT OF INTEREST menthofuran, and piperitone oxide are responsible for the antimicro- The authors state that they have no conflict of interest. bial activity of these oils. A quantitative structure‐activity relationship (QSAR) model was developed for four terpenoids with significant ORCID antimicrobial activity using Hyperchem 8.0 and Gaussian 03 software. Farooq Anwar https://orcid.org/0000-0002-2704-7947 This study revealed the systematic use of QSAR to correlate antimicrobial activity of natural EO substances against P. larvae.It REFERENCES can be inferred that QSAR approach gave a comprehensive Abbas, A., Anwar, F., & Ahmad, N. (2017). Variation in physico‐chemical knowledge about the structural properties of biologically active EO composition and biological attributes of common basil essential oils compounds/terpenoids. produced by hydro‐distillation and super critical fluid extraction. 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