Flavonoids: a Potential Group of Phytoconstituents Against Mycobacterial Infections

Journal of the North for Basic and Applied Sciences (JNBAS). (2018/1439 H), Vol. (3), Issue (1), 44-60

KINGDOM OF SAUDI ARABIA Northern Border University (NBU) Journal of the North for Basic & Applied Sciences (JNBAS) p- ISSN: 1658-7022 / e- ISSN: 1658-7014 www.nbu.edu.sa http://jnbas.nbu.edu.sa

Review Article Flavonoids: A Potential Group of Phytoconstituents against Mycobacterial Infections

1* 1 2 Naira Nayeem , Mohd Imran , Abdulhakim Bawadekji

)Received 26/02/2018; accepted 17/04/2018)

Abstract: Phenolic compounds form one of the main classes of secondary metabolites. Flavonoids constitute one of the most important groups of plant phenolics. Several flavonoids are reported to possess various activities, such as antioxidative, wound healing, hepatoprotective, antibacterial, anti-viral, anti- inflammatory, and anticancer. They are classified as flavanes, flavones, flavanols, flavanones, flavonols, flavonolignans, isoflavones, isoflavanones, chalcones and anthocyanins, depending on their structural differences, which are known for their antimycobacterial activity. Mycobacterial diseases like leprosy, tuberculosis, bovine tuberculosis, paratuberculosis, etc., are caused by a member of the Actinobacteria family. Mycobacterial infections are chronic due to the composition of the cell wall and their adaptability and hence can survive in different habitats for years. The control of these diseases is a challenging task in several ways. A plethora of data is available on the plants which have been screened for their antimycobacterial activity. Some of them report the active phytoconstituents while others report the mechanisms of action of these phytoconstituents. Furthermore, many researches have evaluated and reported the anti-mycobacterial activity of the extract containing flavonoids and fractions of plants extracts rich in flavonoids. In this paper, an attempt is made to summarize and highlight the plants that have been evaluated for anti-mycobacterial activity, the various mechanisms of action, the various flavonoids involved and their biological sources. Keywords: Flavonoids; Antimycobacterial; Phytoconstituents; Extracts; Secondary metabolites.

(1) * Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, P.O. Box 840, Rafha 91911, Kingdom of Saudi Arabia.

e-mail: [email protected] & [email protected]*

(2) Deanship of Scientific Research, Northern Border University, P.O. Box 1321, Arar 91431, Kingdom of Saudi Arabia. jnbas.nbu.edu.sa

DOI: 10.12816/0046700 e-mail: [email protected] & [email protected]

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بحث مرجعي

الفالفـوووئيذاث: مجموعت كامىت مه المركبـاث الىبـاتيـت المضـادة لإلصـاباث ببكتـريا الذرن (المايكوبكتيريت)

نيرة نعيم1 ، *دمحم عمران1، عبدالحكيم بوادقجي2

(قدم للنشر في 05/01/ 1439هـ؛ وقبل للنشر في 02/06/ 1439هـ(

ُمل َّخص ال ِّ ذراست: تشكل المركبات الفٌنولٌة أحد أهم منتجات األٌض الثانوٌة للخالٌا النباتٌة، وتشكل الفالفونوئٌدات المجموعة األهم من هذه المنتجات. وهناك العدٌد من الفالفونوئٌدات التً تمتلك خواص أو نشاطات متعددة كالنشاط المضاد لألكسدة وشفاء الجروح وحماٌة الكبد والنشاط المضاد للبكتٌرٌا والفٌروسات، وكذلك أنشطة ضد االلتهابات والسرطان. وتصنف المركبات التً تتبع الفالفونوئٌدات بشكل عام إلى الفالفانات والفالفونات والفالفانول والفالفانون والفالفونول والفالفولٌغنان واآلٌزوفالفون واآلٌوزفالفانون والشالكون واألنثوسٌانٌنات وتختلف فٌما بٌنها بالتركٌب والتً تعرف بنشاطها المضاد لألمراض الماٌكوبكتٌرٌة. إن هذه األمراض كمرض الجذام والسل البقري ونظٌر السل وغٌرها من األمراض تسببها الكائنات الدقٌقة التً تتبع أشباه البكتٌرٌا )أكتٌنوبكتٌرٌا(. وتتمٌز االصابات الناتجة عن الماٌكوبكتٌرٌا بأنها حادة، وٌعود ذلك إلى التركٌب الخاص لجدرها الخلوٌة وتأقلمها السرٌع فً الوسط المحٌط وبالتالً إمكانٌة بقاءها حٌة فً العدٌد من األوساط ولسنوات متعددة. وتشكل المكافحة أو السٌطرة على األمراض المذكورة تحد كبٌر واسع التشعب، ومن جهة أخرى نجد أن هناك غزارة فً البٌانات المتاحة عن النباتات التً تشٌر إلى إمتالك بعض منها خاصٌة النشاط المضاد للماٌكوبكتٌرٌا، حٌث تشٌر بعض التقارٌر األخرى إلى مركبات كٌمٌائٌة نشطة بٌنما تسجل أخرى نشاط لخالصات نباتٌة تحتوي على الفالفونوئٌدات أو أجزاء من مستخلصات غنٌة بالفالفونوئٌدات. وتمثل هذه الدراسة المرجعٌة محاولة لتلخٌص وتسلٌط الضوء على النباتات التً تم تقٌٌمها على أساس نشاطها المضاد للماٌكوبكتٌرٌا وآلٌة هذا التأثٌر إضافة للتطرق إلى األنواع المتعددة من الفالفونوئٌدات المشمولة بهذا النشاط ومصادرها الحٌوٌة.

الكلماث المفتاحيت: : الفالفونوئٌدات؛ مضادات الماٌكوبكتٌرٌا؛ المركبات النباتٌة؛ المستخلصات النباتٌة؛ مركبات األٌض الثانوٌة.

JNBAS ©1658-7022. 9441هـ/8192م. نشر بواسطة جامعة الحدود الشمالٌة. جمٌع الحقوق محفوظه.

*للمراسلت:

)1( * قسـن الكيويـاء الصيـدليـت، كليـت الصيـدلـت، جـاهعـت الحـدود الشوـاليـت، ص.ب. 040، رفحـاء 91911، الوولكـت العـربيت السعوديت. e-mail: [email protected] & [email protected] *

)2( عوادة البحث العلوي، جاهعت الحدود الشواليت، ص.ب. 1321، عرعر 91431، الوولكت العربيت السعوديت. jnbas.nbu.edu.sa e-mail: [email protected] & [email protected] DOI: 10.12816/0046700

Naira Nayeem1, Mohd Imran, Abdulhakim Bawadekji: Flavonoids: A Potential Group of Phytoconstituents……

1. INTRODUCTION about herbal medicines from traditional healers from different parts of the world. It has been Nature is the important source of medicinal reported that secondary metabolites of plants can plants having bioactive principles. The last few affect the microbial cell in several ways. They years have seen a surge of interest in herbals as may bring about a change in membrane function, they are considered to be safe and more interfere with the process of Deoxyribonucleic dependable when compared to synthetic drugs Acid (DNA) replication and Ribonucleic Acid which are expensive and may possess various (RNA) transcription, they may disrupt protein side effects. The phytoconstituents present in synthesis and coagulation of cytoplasmic plants have been reported to possess various contents and to a certain extent interrupt the gene activities, some of them being anti-oxidant, anti- regulation and quorum sensing (Radulović, microbial, anthelmintic, etc. Furthermore, there Blagojević, Stojanović-Radić,& Stojanović, is a large scope for research in the field of herbal 2013). medicines as traditional knowledge can be A significant amount of literature is available utilized for the development of drugs of which report the reistance of bacteria to the medicinal importance (Chew, Jessica, & effects of the antibiotic. Hence, plant based Sasidharan, 2012; Vinayaka, Nandini, Rakshitha, medicine is being implemented in recent times as Martis, Shruthi, Hegde, Prashith, & therapy for anti-mycobacterial diseases; so as to Raghavendra, 2010). decrease the occurence of these infections in Mycobacteria are pathogens that cause a range of humans as well as animals, (Tiwari, Chakraborty, mycobacterioses in humans and animals. Due to Dhama, Rajagunalan, & Singh, 2013). Plants the composition of their cell walls and ability to serve as the main source of natural compounds as adapt to their habitat they can survive for years. a result of their vast biodiversity. Plant secondary Mycobacterial diseases are caused by a member metabolites like alkaloids, flavonoids, of the Actinobacteria family. Mycobacterial phytosterols, saponins, tannins etc. have been infections like leprosy, tuberculosis etc are screened for anti-mycobacterial properties. chronic diseases and hence it is challenging to Flavonoids consist of a group of polyphenolics control these diseases. Symptoms of diseases are that contain a benzo-γ-pyrone ring structure and fever, weight loss and fatigue. There are several are synthesized by phenylpropanoid mycobacterial species like Mycobacterium pathway. The literature reports several studies leprae, Mycobacterium tuberculosis, indicating the effects of flavonoids against Mycobacterium smegmatis Mycobacterium bovis microbial infections and certain non- etc. Several important antibiotics have originated communicable diseases i.e. cardiovascular from plant products and have received diseases, cancers, and other age-related diseases. considerable attention as potential anti- The structure of flavonoids consists of a fifteen- mycobacterial agents. Many other compounds carbon skeleton inclusive of two benzene rings that have been reported and proven to be of use linked by a heterocyclic pyran ring. They can be as leads for newer drugs for treatment of divided into a variety of classes based on the Tuberculosis (TB) have been obtained from the variations in the structure; such as flavones, natural sources (Nguta, Appiah-Opong, Nyarko, flavonols, flavanones, anthocyanidines, flavans, Yeboah-Manu, Addo, Otchere, & Kissi-Twum, flavonolignans, isoflavones, isoflavanones, and 2016). chalcones (Pandey, 2007; Cook & Samman, From time immemorial traditional herbs have 1996; Rice-Evans, Miller, Bolwell, Bramley, & been enormously used in various regions of the Pridham, 1995). world for treating mycobacterial diseases. Lately, The activities and chemical nature of flavonoids efforts have been made by various researchers to depend on the structure, pattern of hydroxylation, probe and investigate the knowledge obtained polymerization, conjugations and substitutions

46 Journal of the North for Basic and Applied Sciences, Vol. (3), Issue (1), Northern Border University, (2018/1439 H)

(Balogun & Ashafa, 2018). It has been reported along with their mechanisms of action. that for a significant antitubercular activity, if the positions C-5 and C-7 are substituted with 2. MECHANISM OF ACTION OF hydroxyl group there is loss of activity while FLAVONOIDS hydroxyl group at C-5, C-6, C-7 or C-3 and C-4 are important for activity (Paragas, Gehle, Flavonoids exhibit a number of pharmacological Krohn, Franzblau, & Macabeo, 2014). and anti-bacterial activities. Flavonoids harm the Furthermore, another important aspect has been bacterial cells in various ways like their ability reported with reference to the structure activity against microbial adhesins, cell-wall or transport proteins restriction activation in drug metabolism relationship of the flavonoid i.e. O-methylation etc. (Kumar & Pandey, 2013). i.e. methylation at the oxygen atom or The general chemical structures of different glycosylation at any of the hydroxyl substitutions classes of flavonoids are as shown in Figure (1). inactivates the anti-tubercular activity of the The literature review reports several mechanisms flavonoids (Yadav, Thakur, Prakash, Khan, of action of flavonoids in mycobacterium Saikia, & Gupta, 2013). The objective of this species. These compounds effectively inhibit the review article is to highlight and to outline the targets which are important for the growth and biological origin of flavonoids that have been virulence. Scientists have reported that evaluated for their anti-mycobacterial activity flavonoids have the ability to inhibit the enzyme

+ O O O

OH OH General structure Flavan-3-ol Anthocyanidin O

O O

O OH Isoflavone O O Flavone Flavonol

O Flavanone

Figure 1: The chemical structures of different classes of flavonoids

47 Naira Nayeem1, Mohd Imran, Abdulhakim Bawadekji: Flavonoids: A Potential Group of Phytoconstituents……

Rv0636 which is present in the fatty acyl DNA gyrase & Santhosh, synthase complex II (Brown, Papaemmanouil, 2013). Bhowruth, Bhatt, Dover, & Besra, 2007). (Zheng, Jiang, Myricetin and quercetin-3-O-β-D-glucoside were Myricetin, Mtb Gao, Song, isolated from the aqueous extract of Pelargonium 5 kaempferol, proteasome Sun, Wang, reniforme and have been reported to increase the biacalein inhibitors Sun, Lu, & intracellular uptake of mycobacterium by Zhang, 2014). macrophages and thereby bringing about the (Xiao, Wang, removal of bacilli (Kim, Griffiths, & Taylor, Wang, Zhou, Inhibition & Zhang, 2009). Fushiya et. al have reported that the Fluoroquino properties Zhang, Zhou, flavone 5,4′-Dihydroxy- 6,7,8,3′- lone- 6 against Zhou, tetramethoxyflavone isolated from the flavonoid efflux Ouyang, Lin, methanolic extract of Cleome droserifolia (hybrid) suppressed the nitric oxide production and pumps Mustapa, decreased the oxidative stress in activated Reyinbaike, & macrophages (Fushiya, Kishi, Hattori, Batkhuu, Zhu, 2014). (Zhang, Sun, Takano, Singab, & Okuyama, 1999). Inhibit the Wang, He, Baicalin phosphorylat Currently, research is being focused by various 7 Wang, Zheng, ion of NF- researchers to throw light on the various Wu, Zhang, & κB mechanisms of action of flavonoids in inhibiting Jiang, 2017). Mycobacteria (Ramachandran & Inhibiting Soh, Pan, Balasubramanian, 2014). Epigallocate Mtb enoyl- Chee, Wang, 8 Various mechanisms of the flavonoids against chin gallate acyl Yuan, & Koh mycobacteria reported in the literature are as reductase (2017). depicted in Table (1). Inhibit de novo fatty (Brown, Table 1: Mechanism of action of certain acid Papaemmanou flavonoids. biosynthesis il, Bhowruth, 9 Fisetin in S. Bhatt, Dover, Compounds Mechanism References mycobacteri No & Besra, a as well as (Tran, Marks, 2007). mycolic acid Effective Duke, biosynthesis Chrysin - inhibitors on Bebawy, 1 flavone multidrug Duke & transporters Roufogalis, 3. ANTIMYCOBACTERIAL 2011). Effective ACTIVITY Genistein - inhibitors on (Jaganathan, 2 isoflavone multidrug 2011). 3.1 Anti Mycobacterial Activity of Plant transporters Extracts Inhibit the (Brown, fatty acid Papaemmanou It has been reported that when the individual synthase II Isoliquirtige il, Bhowruth, isolated compound is tested at a particular 3 responsible nin, Butein Bhatt, Dover, concentration it is often less active than the for mycolic- & Besra, acid whole plant itself, which may imply that crude 2007). synthesis plant extracts may be exerting their activity Toprim (Suriyanaraya through synergistic or additive effect (Wagner & 4 Quercetin domain of nan, Ulrich-Merzenich, 2009). Hence, many plant subunit B of Shanmugam, extracts containing flavonoids (in the preliminary

48 Journal of the North for Basic and Applied Sciences, Vol. (3), Issue (1), Northern Border University, (2018/1439 H)

phytochemical investigation) / flavonoid rich hirta (Rajasekar, Anbarasu, Manikkam, Joseph, fractions have been investigated for their anti- & Kumar, 2015), Acalypha indica, Allium cepa, mycobacterial activity by various groups of Allium sativum, Adhatoda vasica and Aloe vera. researchers. Most of the literature reported the All plants showed good antimycobacterial anti-mycobacterial activity against activity (Gupta,Thakur, Singh, Singh, Sharma, Mycobacterium tuberculosis H37Rv, while a few Katoch, & Chauhan,2010), Quercus infectoria, reported activity against other mycobacterial Citrus aurantium, Caesalphinia pulcherima, Mimosa pudica, Mentha spicata and species. Chysanthemum parthenium (Sheeba, Gomathi, & Citarasu, 2015). Eucalyptus camaldulensis, 3.2 Anti Mycobacterial Activity of Plant Ocimum basilicum, Calpurnia aurea, Artemisia Extracts against Mycobacterium abyssinica, Croton macrostachyus (Gemechu, Tuberculosis Giday, Worku, & Ameni, 2013), Cissampelos owariensis (Rebecca, Koma, Ibrahim, & Otu, Mycobacterium tuberculosis H37Rv strain was 2013), Glycyrrhiza glabra (Nair, Pharande, used to evaluate aqueous extracts i.e. Bannalikar, & Mukne, 2015), Syzygium RhoeoSpathacea,Centella asiatica, Annona aromaticum, Aegele marmelos, Glycyrrhiza muricata, Pluchea indica, and Andrographis glabra,Piper nigrumand Lawsonia inermis. paniculata. The results revealed that Pluchea (Kaur & Kaur, 2015), Rubia cordifolia indica, and Rhoeo spathacea showed the best (Makgatho, Nxumalo, Ndaba, Masilo, Tsindane, activity when compared to the other extracts & Sedibane, 2017) Artemisia afra, Dodonea (Radji, Kurniati, & Kiranasari, 2015). angustifolia, Drosera capensis and Galenia The activity of petroleum ether, ethyl acetate, africana against Mycobacterium smegmatis and methanol extracts of Stachys thirkei, Stachys (Mativandlela, 2008). A study by Khlifi et al. tmolea, Thymus sipthorpii, Satureja aintabensis, who have evaluated the activity of G. alypum Ballota acetabulosa and Micromeria Juliana was leaves have reported the presence of reported in another study. The extracts anthocyanins,polyphenols, flavonoids and containing favonoids i.e., T. sibthorpii, S. tannins in methanolic and petroleum ether aintabensis, and M. juliana developed significant extracts. The petroleum ether extract was activity against M. tuberculosis with the particularly active against M. tuberculosis. minimum inhibitory concentration of 12.5-100 (Khlifi, Hamdi, El μg/ml. (Askun, Tekwu, Satil, Modanlioglu, & Hayouni,Cazaux,Souchard,Couderc, & Bouajila, Aydeniz, 2013). The petroleum ether extract and 2011). chloroform extract of Leucas marrubioides The methanolic extracts of nine plants i.e. exhibited significant activity against M. Salvadora persica, Acacia senegal, Acokanthera tuberculosis (Gowrish, Vagdevi, & Rajashekar, friesiorum, Plumbago dawei, Loranthus acacia, 2015). The crude ethanolic extract of the Cordia sinensis, Acacia horrida, Albizia Morinda citrifolia fruits was subjected to a anthelmitica and Euphorbia scarlatica were preliminary qualitative screening of evaluated against the M. kansasii, phytoconstitiuents which revealed the presence M.tuberculosis, M. smegmatis, M. fortuitum. The of flavonoid, scopoletin, anthraquinone and extracts of S. persica and C. sinensis exhibited alkaloids. The anti-mycobacterial activity was antituberculosis activity against M. tuberculosis attributed to these constituents (Novie, Mauliku, and M. kansasii (Richard, Callistus, Nick, & Hendro, Suharyo, & Tri, 2017). The methanolic Paul, 2010). extracts of the seeds of Peganum harmala were reported to exhibit significant activity and this 3.3 Anti Mycobacterial Activity of Plant was attributed to the flavonoid content of the Extracts against Mycobacterium plant ( Davoodi, Ghaemi, Mazandarani, Shakeri, Lapreae Javid, & Klishadi, 2015). Several other plants have been evaluated for their antimycobacterial Very little data is available about plants being effect some of them are as follows Euphorbia evaluated for the activity against Mycobacterium

49 Naira Nayeem1, Mohd Imran, Abdulhakim Bawadekji: Flavonoids: A Potential Group of Phytoconstituents……

lapreae. Review reports the use of Humulus 3.5 Anti Mycobacterial Activity of japonicas, Calliandra portoricensis, Cassia Isolated Flavonoids nigricans, Manilkara hexandra, and Bauhinia variegate for the treatment of Mycobacterium The literature review also reports the lapreae was due to the presence of flavonoids antimycobacterial activity of several isolated flavonoids. The antimicrobial activity of the (Gadekar,Singour,Chaurasiya, Pawar, & Patil, ethyl acetate extract of Argyreia speciosa was 2010). reported by Habbu et al. This activity was attributed to quercetin 3′7 di-O methyl 3-sulphate 3.4 Anti Mycobacterial Activity of Plant and kaempferol 7-O methyl 3-sulphate which Extracts against other Mycobacteria was found to be synergistic with the usual antimycobacterial agents (Habbu, Mahadevan, The flavonoid and alkaloid fractions Dioscorea Shastry, & Manjunatha, 2009). The methanolic oppositifolia,Corallocarpus epigaeus, Dioscorea extract of Bromelia balansae showed moderate bulbifera, Dioscorea hispida,Dioscorea activity and the various flavonoid glycosides pentaphylla, Amorphophyllus sylvaticus, identified from this extract were kaempferol-3- Andrographis paniculata, Morinda citrifolia, O-α-Lrhamnopyranoside,quercetin-3-O-α-L- Enicostema axillare, Gloriosa superba were rhamnopyranosyl-(1→6)-β-D-glucopyranoside screened for their activity against two kaempferol-3-O-α-L-rhamnopyranosyl- (1→6)- mycobacteria i.e. M. smegmatis and M. phlei. β-D-glucopyranoside, and kaempferol 3,7-di-O- The results revealed that the chloroform extract α-L-rhamnopyranoside (Coelho, Honda, Vieira, of A. paniculata was most effective growth Brum, Pavan, Leite, & Cardoso, 2010). inhibitor of M. smegmatis. (Rajesh & Archana, The review reveals that most of the flavonoids 2017) i.e., methanol, n-hexane and active against mycobacteria belong to the classes dichloromethane of rhizomes of Zingiber of flavones and flavonones. Some of the officinale and Curcuma longa were evaluated for flavonoids that have been reported to be mycobacterial activity against Mycobacterium responsible for the antimycobacterial activity are abscessus, Mycobacterium smegmatis, as depicted in Table (2). The table also gives information regarding the botanical source, Mycobacterium phlei and Mycobacterium chemical class and the mycobacteria. fortuitum. The methanol and n-hexane extracts of Curcuma longa showed the highest zone of The structures of some of the isolated inhibition for M. abscessus (Ogudo, Lawal, & compounds that have exhibited activity against Adeniyi, 2014). mycobacyteria are as shown in Figures (2-20).

Table 2: Flavonoids responsible for the antimycobacterial activity. S. Botanical N Chemical Class Phytoconstituent Mycobacteria Reference Source o isobavachalcone, (Kuete, Ngameni, kanzanol C, 4- Dorstenia barteri M. tuberculosis, Mbaveng, 1 Flavonoid hydroxylonchocarpi (Moraceae) M. smegmatis Ngadjui, Meyer, n, stipulin, & Lall,2010). amentoflavone 7- (Moreira, Paepalanthus methylquercetagetin Martins, Pietro, Methoxylated M. tuberculosis, 2 Latipes -4′-O-β-D- Sato, Pavan, Flavonoid M. avium (Eriocaulaceae) glucopyranoside,7- Leite, Vilegas, & methylquercetagetin Leite, 2013).

50 Journal of the North for Basic and Applied Sciences, Vol. (3), Issue (1), Northern Border University, (2018/1439 H)

Table 2 (Cont.) S. Botanical N Chemical Class Phytoconstituent Mycobacteria Reference Source o M. (Christopher, Heritiera 3- Cinnamolyglico madagascarien Nyandoro, 3 littoralis cinnamoyltribulosid ce M. indicus Chacha, & Flavonoids (Sterculiaceae) e pranii. Koning, 2014). Spondias mombincone, and (Olugbuyiro, & 4 Flavonoids mombin M. tuberculosis mombinol, Moody, 2013). (Anacardiaceae) (Prawat, Dasymaschalon 7-hydroxy-6,8- Chairerk, 5 Flavanone dasymaschalum dimethoxyflavanon M. tuberculosis Lenthas, Salae, & (Annonaceae) e, Tuntiwachwuttik ul, 2013). Cryptocarya (Chou, Chen, Pinocembrin 6 Flavonones chinensis M. tuberculosis Peng, Cheng, & cryptocaryone (Lauraceae) Chen, 2011). (Mutai, Heydenreich, 3- Dalbergia kenusanone F 7 Thoithi, 7 hydroxyisoflavanon melanoxylon M. tuberculosis methyl ether Mugumbate, es (Fabaceae) Chibale, & Yenesew, 2013).

(2S)- 5, 7, 2'- Galenia Africana 8 Flavone trihydroxy M. tuberculosis (Aizoaceae) flavanone (Mativandlela, 2009). (Birdi, D'Souza, Ocimum sanctum Tolani, Daswani, 9 Flavone Luteolin M. tuberculosis Nair, Tetalib, (Lamiaceae) Toroc, & Hoffnerc, 2012). Garcinia Amentoﬂavone and (Kaikabo & Eloff, 10 Biflavonoids livingstonei 41monomethoxy M.smegmatis 2011). (Clusiaceae) amentoﬂavone genistein (Chen, Cheng, Isoflavone Ficus nervosa prunetin (O- 11 M. tuberculosis Peng, & Chen, Flavanone (Moraceae) methylated isoflavone), and 2010). (2S)-naringenin (Suksamrarn, Limnophila Poomsing, geoffrayi nevadensin Aroonrerk, 12 Flavones M. tuberculosis (Scrophulariacea isothymusin Punjanon, e) Suksamrarn, & Kongkun, 2003).

51 Naira Nayeem1, Mohd Imran, Abdulhakim Bawadekji: Flavonoids: A Potential Group of Phytoconstituents……

Table 2 (Cont.) S. Botanical N Chemical Class Phytoconstituent Mycobacteria Reference Source o Pelargonium myricetin and M tuberculosis (Kim, Griffiths, 13 Flavonoids reniforme quercitin-3-O-β-d- M. fortuitum & Taylor, (2009). (Geraniaceae) glucoside

Trifolium (Lechner, O-Methylated Biochanin A 14 pretense M. smegmatis Gibbons, & isoflavone (Fabaceae) Bucar, 2008). Trihydroxy Pisonia aculeate (Wu, Peng, Chen, 15 Pisonianone M. tuberculosis flavanone (Nyctaginaceae). & Tsai, 2011). Lantana camara (Begum, Wahab, 16 Flavonoids Linaroside M. tuberculosis & Siddiqui, (Verbenaceae) 2008). cycloartocarpin (Boonphong, artocarpin Artocarpus altilis Baramee, 17 Prenylated flavones M.tuberculosis Kittakoop, & (Moraceae) cudraflavone B Puangsombat, cudraflavone C 2007). Pelargonium (Sannah, Jacobus, 18 Flavan 3-ol sidoides Catechin M tuberculosis Ahmed, & (Geraniaceae) Namrita, 2007). (Suksamrarn, Chotipong, Suavansri, Chromolaena isosakuranetin (5,7- Boongird, 19 Flavanones odorata dihydroxy-4'- M. tuberculosis Timsuksai, (Asteraceae) methoxyflavanone) Vimuttipong, & Chuaynugul, 2004). 7,3',4'- trihydroxyflavone (Chokchaisiri, four, (-)-butin, (-)- Suaisom. Butea butrin, (+)- Sriphota, Flavone Flavanones 20 monosperma isomonospermoside M. tuberculosis Chindaduang, Isoflavones (Fabaceae) and (-)- Chuprajob, & liquiritigenin, Suksamrarn. formononetin, 2009). afrormosin 5,4′-Dihydroxy- Couroupita (Aravind, 3,7,8,3′- 21 Flavone guianensis M. tuberculosis Karthikeyan, & tetramethoxyflavon (Lecithydaceae) Babu, 2017). e (Mativandlela, Galenia Africana 5,7,2′- M. smegmatis 22 Flavone Meyer,Hussein, trihydroxyflavone. (Aizoaceae) M. tuberculosis & Lall, 2008).

52 Journal of the North for Basic and Applied Sciences, Vol. (3), Issue (1), Northern Border University, (2018/1439 H)

Table 2 (Cont.) S. Botanical N Chemical Class Phytoconstituent Mycobacteria Reference Source o 5-hydroxy-3,7,4'- (Murillo, trimethoxyflavone. Encarnación, Haplopappus 5,4'-dihydroxy-3,7- Malmstrøm, 23 Flavones sonorensis M. tuberculosis. dimethoxyflavone Christophersen, (Asteraceae) 5,7-dihydroxy-3,4'- & Franzblau, dimethoxyflavone. 2003). (Odumosu,, Pavetta crassipes Lough, Yakubu, 24 Flavonoid Rutin M.aurum Thomas, (Rubiaceae) Williamson, & Haroune, 2016). (Adaikkappan, Pueraria Kannapiran, & 25 Isoflavone tuberosa Puerarone M. tuberculosis. Anthonisamy, (Fabaceae) 2012). 5,4′-dihydroxy- 3,7,8- Larrea tridentate trimethoxyflavone (Favela, García, 26 Flavone (Zygophyllaceae 5,4′-dihydroxy- M. tuberculosis Garza, Rivas, & ) 3,7,8,3- Camacho, 2012). tetramethoxyflavon e 5,7-dihydroxy-8-C- methylflavanone 7-hydroxy-5- methoxy-6-C- (Pavan, Leite, methylflavanone Coelho, Campomanesia 5,7-dihydroxy-6-C- Coutinho, Honda, 27 Flavanone adamantium M. tuberculosis methylflavanone Cardoso, Vilegas, (Myrtaceae) 2´,4´-dihydroxy-6´- Leite, & Sato, methoxychalcone, 2009). 5,7-dihydroxy-6, 8- di-C- methylflavanone OH OH

HO O

OH O

Figure 2: The chemical structure of amentoflavon. Figure 3: The chemical structure of luteoline.

53 Naira Nayeem1, Mohd Imran, Abdulhakim Bawadekji: Flavonoids: A Potential Group of Phytoconstituents……

HO O CH3

CH3 OH O CH3

OH O H3C OH OH H3C Figure 4: The chemical structure of genistein. O O

O O OH H3C Figure 9: The chemical structure of artocarpin.

CH OH O 3 OH HO O Figure 5: The chemical structure of prunetin.

OH H3C O HO O OH O HO Figure 10: The chemical structure of pisonianone.

OH O CH3 Figure 6: The chemical structure of naringenin. OH O CH3 OH

OH O H3C HO O OH O O H3C OH OH

OH O Figure 11: The chemical structure of cudraflavone. Figure 7: The chemical structure of myricetin. H3C O HO O O CH3 HO O

H3C O OH O CH3 O OH O Figure 8: The chemical structure of biochanin A. Figure 12: The chemical structure of nevadensin.

54 Journal of the North for Basic and Applied Sciences, Vol. (3), Issue (1), Northern Border University, (2018/1439 H)

OH HO O OH O O H3C O CH3 H3C O O Figure 18: The chemical structure of OH O formononetin. Figure 13: The chemical structure of isothymusin. O CH OH 3 OH HO O

HO O

OH O OH Figure 19: The chemical structure of OH isosakuranetin. Figure 14: The chemical structure of catechin. OH

HO O OH HO O

OH O OH O Figure 20: The chemical structure of quercetin. Figure 15: The chemical structure of pinocembrin. OH 4. CONCLUSION

HO O Flavonoids with their widespread occurrence, diversity and vast array of biologically active compounds can prove to be indispensable moities for further development and design of O novel therapeutic agents for mycobacterial infections. In this review an attempt was made to Figure 16: The chemical structure of liquiritigenin. give an insight into the structural aspects, the OH plants and the individual isolated constitiuents that have shown promising anti-mycobacterial activity against the various tested mycobacteria HO O and the various probable mechanisms of action OH of the flavonoids. The data also suggest that the flavones and flavonones were the class of flavonoids that have exhibited significant antimycobacterial activity. It is evident from the O review that most of the data that is available is Figure 17: The chemical structure of butin. for Mycobacterium tuberculosis. There is a

55 Naira Nayeem1, Mohd Imran, Abdulhakim Bawadekji: Flavonoids: A Potential Group of Phytoconstituents……

scarcity of data for the other types of antiplasmodial prenylated flavones from the mycobacterial infections. roots of Artocarpus altilis. Chang Mai Journal Science, 34(3), 339-344. Brown, A. K., Papaemmanouil, A., Bhowruth,V., Bhatt, A., Dover, L. G., & Besra, G. S. (2007). ACKNOWLEDGEMENTS Flavonoid inhibitors as novel antimycobacterial agents targeting Rv0636, a putative dehydratase enzyme involved in Mycobacterium The authors are thankful to the Dean of Faculty tuberculosis fatty acid synthase II. of Pharmacy and the Deanship of Scientific Microbiology, 153(10), 3314-3322. doi: Research of Northern Border University for their 10.1099/mic.0.2007/009936-0. support during the preparation of this paper. Chen, L. W., Cheng, M. J., Peng, C. F., & Chen, I. S. (2010). Secondary metabolites and antimycobacterial activities from the roots of REFERENCES Ficus nervosa. Chemistry & Biodiversity, 7(7), 1814–1821. doi: 10.1002/cbdv.200900227. Chew, A. L., Jessica, J. A. J., & Sasidharan, S. Adaikkappan, P., Kannapiran, M., & Anthonisamy, (2012). Antioxidant and antibacterial activity of A. (2012). Anti-Mycobacterial activity of different parts of Leucas aspera. Asian Pacific Withaniasomnifera and Puerariatuberosa Journal of Tropical Biomedicine, 2(3), 176-180. against Mycobacterium tuberculosis H37Rv. doi: 10.1016/S2221-1691(12)60037-9. Journal of Academia and Industrial Research, Chokchaisiri, R., Suaisom. C., Sriphota, S., 1(4), 153- 56. Chindaduang, A., Chuprajob, T., & Suksamrarn. Aravind, D. S., Karthikeyan, R., Babu, P. S. (2017). (2009). Bioactive flavonoids of the flowers of In – vitro anti-tubercular activity of flowers of Butea monosperma. Chemical and Couroupita guanensis. Journal of Applied Pharmaceutical Bulletin, 57(4), 428-432. Pharmaceutical Research, 5(1), 27–29. ISSN PMID: 9336944. No. 2348 – 0335. Chou, T. H., Chen, J. J., Peng, C. F., Cheng, M. J., & Chen, I. S. (2011). New flavanones from the Askun, T., Tekwu, E. M., Satil, F., Modanlioglu, S., leaves of Cryptocarya Chinensis and their & Aydeniz H. (2013). Preliminary antituberculosis activity. Chemistry & antimycobacterial study on selected Turkish Biodiversity, 8(11), 2015-2024. doi: plants (Lamiaceae) against Mycobacterium 10.1002/cbdv.201000367 tuberculosis and search for some phenolic Christopher, R., Nyandoro, S. S., Chacha, M., & constituents. BMC Complementary and Koning, C. B. (2014). A new Alternative Medicine, 13(365), 1-12. doi: cinnamoylglycoflavonoid, antimycobacterial 10.1186/1472-6882-13-365. and antioxidant constituents from Heritiera Balogun, F. O. & Ashafa, A. O. (2018). Cytotoxic, littoralis leaf extracts. Natural Product kinetics of inhibition of carbohydrate- Research, 28(6), 351-358. doi: hydrolysing enzymes and oxidative stress 10.1080/14786419.2013.863202. mitigation by flavonoids roots extract of Coelho, R. G., Honda, N. K., Vieira, M. C., Brum, Dicoma anomala (Sond.). Asian Pacific Journal R. L., Pavan, F. R., Leite, C. Q., & Cardoso, C. of Tropical Medicine, 11(1), 24-31. doi: A. (2010). Chemical composition and 10.4103/1995-7645.223530. antioxidant and antimycobacterial activities of Begum, S., Wahab, A., & Siddiqui, B. S. (2008). Bromelia balansae (Bromeliaceae). Journal of Antimycobacterial activity of flavonoids from Medicinal Food, 13(5), 1277–1280. doi: Lantana camara Linn. Natural Product 10.1089/jmf.2009.0032. Research, 22(6), 467-470. doi: Cook, N. C. & Samman S. (1996). Review: 10.1080/14786410600898714. flavonoids-chemistry, metabolism, Birdi, T., D'Souza, D., Tolani, M., Daswani, P., cardioprotective effects and dietary sources. Nair, V., Tetalib, P., Toroc, J. C., & Hoffnerc, Journal of Nutritional Biochemistry, 7(2), 66– S. (2012). Assessment of the activity of selected 76. https://doi.org/10.1016/S0955- Indian medicinal plants against Mycobacterium 2863(95)00168-9. tuberculosis: A preliminary screening using the Davoodi, H., Ghaemi, E., Mazandarani, M., microplate alamar blue assay. European Journal Shakeri, F., Javid, S. N., & Klishadi, M. (2015). of Medicinal Plants, 2, 308-323. doi: Anti-mycobacterial and anti-inflammatory 10.9734/EJMP/2012/1638. activity of Peganum harmala. Journal of Boonphong, S., Baramee, A., Kittakoop, P., & Chemical & Pharmaceutical Research, 7(4), Puangsombat, P. (2007). Antitubercular and 1611-1616. doi: 10.13140/RG.2.1.3820.5603.

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59 Naira Nayeem1, Mohd Imran, Abdulhakim Bawadekji: Flavonoids: A Potential Group of Phytoconstituents……

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