Antibacterial Activity of Flavonoids and Their Structure–Activity Relationship: an Update Review

Home , Liquiritin, Ochnaflavone, Pinocembrin, Sophoraflavanone G, Techtochrysin

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/328423406

Antibacterial activity of ﬂavonoids and their structure–activity relationship: An update review

Article in Phytotherapy Research · October 2018 DOI: 10.1002/ptr.6208

CITATIONS READS 24 1,003

4 authors:

Faegheh Farhadi Bahman Khameneh Mashhad University of Medical Sciences Mashhad University of Medical Sciences

5 PUBLICATIONS 25 CITATIONS 35 PUBLICATIONS 444 CITATIONS

SEE PROFILE SEE PROFILE

Mehrdad Iranshahi Milad Iranshahi Mashhad University of Medical Sciences Mashhad University of Medical Sciences

234 PUBLICATIONS 5,009 CITATIONS 35 PUBLICATIONS 582 CITATIONS

SEE PROFILE SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Study the effect of natural products on autoimmune diseases View project

Antibacterial Activity of Silver Nanoparticle- Loaded Soft Contact Lens Materials: The Effect of Monomer Composition . View project

All content following this page was uploaded by Faegheh Farhadi on 29 October 2018.

The user has requested enhancement of the downloaded file. Received: 18 January 2018 Revised: 5 August 2018 Accepted: 12 September 2018 DOI: 10.1002/ptr.6208

REVIEW

Antibacterial activity of flavonoids and their structure–activity relationship: An update review

Faegheh Farhadi1 | Bahman Khameneh2 | Mehrdad Iranshahi3 | Milad Iranshahy1,3

1 Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Based on World Health Organization reports, resistance of bacteria to well‐known Sciences, Mashhad, Iran antibiotics is a major global health challenge now and in the future. Different strate- 2 Department of Pharmaceutical Control, School of Pharmacy, Mashhad University of gies have been proposed to tackle this problem including inhibition of multidrug resis- Medical Sciences, Mashhad, Iran tance pumps and biofilm formation in bacteria and development of new antibiotics 3 Biotechnology Research Center, with novel mechanism of action. Flavonoids are a large class of natural compounds, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, have been extensively studied for their antibacterial activity, and more than 150 arti- Mashhad, Iran cles have been published on this topic since 2005. Over the past decade, some prom- Correspondence ising results were obtained with the antibacterial activity of flavonoids. In some cases, Milad Iranshahy, Pharm. D., PhD, Department of Pharmacognosy, School of Pharmacy, flavonoids (especially chalcones) showed up to sixfold stronger antibacterial activities Mashhad University of Medical Sciences, than standard drugs in the market. Some synthetic derivatives of flavonoids also Mashhad, Iran. Email: [email protected] exhibited remarkable antibacterial activities with 20‐ to 80‐fold more potent activity Funding information than the standard drug against multidrug‐resistant Gram‐negative and Gram‐positive Mashhad University of Medical Sciences bacteria (including Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). This review summarizes the ever changing information on antibacterial activity of flavonoids since 2005, with a special focus on the structure–activity relationship and mechanisms of actions of this broad class of natural compounds.

KEYWORDS

antibacterial, biofilm, chalcones, flavonoids, multidrug resistance, natural compounds

1 | INTRODUCTION therapy via natural antibacterial substances and also using drug deliv- ery systems are important approaches in this field. Over the past Antibacterial resistance is the major global health challenge and decade, many classes of natural products intensively studied for this threats the public health. (Seleem, Pardi, & Murata, 2017). The anti- purpose, especially against multidrug‐resistant Gram‐negative and bacterial resistance mechanisms can be divided into two categories: Gram‐positive bacteria (Barbieri et al., 2017; Hassanzadeh, (a) innate or intrinsic resistance and (b) acquired resistance. Intrinsic Rahimizadeh, Bazzaz, Emami, & Assili, 2001; Iranshahi, Fata, Emami, resistance is mainly a feature of a particular bacterium and is based Jalalzadeh Shahri, & Bazzaz, 2008; Iranshahi, Hassanzadeh‐Khayat, on biological properties of bacteria. The second mechanism of resis- Bazzaz, Sabeti, & Enayati, 2008; Salar Bashi, Bazzaz, Sahebkar, tance is mainly due to the acquisition of resistance genes by other Karimkhani, & Ahmadi, 2012). The results of these efforts were devel- pathogenic bacteria or chromosomal mutation and combination of opment of new antibacterial agents, such as quinine (quinolones and these two mechanisms. Regulatory genes controlling multidrug resis- bedaquiline) and coumarin derivatives (novobiocin; Venugopala, tance by expression of efflux pump and bacterial biofilm formation Rashmi, & Odhav, 2013). also show important roles in antibacterial resistance (Frieri, Kumar, & Flavonoids are a large and structurally diverse group of natural Boutin, 2016). Various strategies have been pursued to combat micro- products obtained from nature, and some of them as ingredients of bial resistance. Employing new generations of antibiotics, combination propolis and honey were used in some traditional systems of medicine for the treatment of infectious diseases. The basic structure of flavo- Abbreviations: (FAB), fatty acid biosynthesis; (MOAs), mechanisms of action noid compounds is diphenylpropane (C6–C3–C6) skeleton. The

Phytotherapy Research. 2018;1–28. wileyonlinelibrary.com/journal/ptr © 2018 John Wiley & Sons, Ltd. 1 2 FARHADI ET AL. various structure types of flavonoids differ in the degree of oxidation (Kuete et al., 2007; Mbaveng et al., 2008) and licoflavone C (19; from of the C ring and in the substituents patterns in the A and/or B rings, Retama raetam flowers) was active against Escherichia coli via forma- and these differences lead to the diversity of these compounds tion of complexes with extracellular and soluble proteins (MIC (Kumar & Pandey, 2013). Some of the flavonoids (i.e., quercetin) with 7.81 μg/ml; Edziri et al., 2012). a strong background of use in clinical trials are good candidates for Another proposed mechanism is inhibition of bacterial enzymes further clinical studies as antibiotics alone or in combination with (such as tyrosyl‐tRNA synthetase) that was mediated by artocarpin conventional antibiotics (Amin, Khurram, Khattak, & Khan, 2015). (23) extracted from leaves of Artocarpus anisophyllus against B. cereus, In 2005, Cushnie et al. reviewed antibacterial properties of flavo- E. coli, and Pseudomonas putida (Jamil, 2014). Baicalein is an effective noids. However, a large amount of information has been published since bactericide and when combined with cefotaxime, the synergistic then. In the present review, the antibacterial properties of flavonoid effects were observed (Cai et al., 2016). The possible mode of action compounds, which were studied in the last 12 years, have been of baicalein has been studied extensively. It was shown that this com- reviewed. The aim of the present review is the investigation of antibac- pound is able to reduce the Pseudomonas aeruginosa‐induced secretion terial properties of natural, semisynthetic, and synthetic flavonoids, of the inflammatory cytokines IL‐1β,IL‐6, IL‐8, and TNFα, which are their structure–activity relationships and mechanisms of action (MOAs). important for inflammatory injury after P. aeruginosa infection (Luo All relevant databases were searched for the terms “flavonoids” et al., 2016). The results of Chen study indicated that baicalein at con- and “antibacterial,” without limitation from 2005 till December 30, centrations of 32 and 64 μg/ml was able to downregulate the quo- 2017. Information was collected via electronic search using Scopus, rum‐sensing system regulators agrA, RNAIII, and sarA, and gene Pubmed, Web of Science, and Science Direct. expression of intercellular adhesin (ica) in Staphylococcus aureus biofilm producer cells (Chen et al., 2016). Other reports include gancaonin G (27) and semilicoisoflavone B | 2 FLAVONOIDS (28) from Glycyrrhiza uralensis toward vancomycin‐resistant Entero- coccus bacteria with the MIC values of 32 and 64 μg/ml (Orabi, Flavonoids are a group of low‐molecular‐weight polyphenolic sub- Aoyama, Kuroda, & Hatano, 2014). Neocyclomorusin (33) and stances. Chemically, the core structure of flavonoids is based upon a neobavaisoflavone (34) among 19 natural products belonging to terpe- C6–C3–C6 skeleton in which the three‐carbon bridge is usually noids, alkaloids, thiophenes, and phenolics from the methanolic cyclized with oxygen. These compounds are considered as chemotax- extract of Cameroon plants were active against Gram‐negative onomic markers according to the biosynthesis pathway (combination bacteria (Klebsiella pneumonia and Enterobacter cloacae) with the MIC of phenylalanine with three malonyl‐CoA units to form a C‐15 value of 4–8 μg/ml (Mbaveng et al., 2015). Other biological activities chalcone), and they provide attractive color pigments such as yellow, of flavones are summarized in Table 1. red, blue, and purple in plants. The chemical nature of flavonoids Inhibition of the bacterial efflux pump and increase in the suscep- depends on the degree of unsaturation and oxidation of the three‐car- tibility of existing antibiotics (by inducing depolarization of the cell bon chain. Several subgroups of flavonoids have been found in higher membrane) is another possible MOA, and artonin I (24) from Morus plants. Flavonols [most abundant flavonoids in foods, including quer- mesozygia was effective against S. aureus by this mechanism (69– cetin (48), kaempferol (55), and myricetin (46)], flavanones [found in 89% inhibition; Farooq, Wahab, Fozing, Rahman, & Choudhary, 2014). citrus fruits such as naringin (77)], flavones [e.g., luteolin (20) in celery], Potential antibacterial synergy of the desired compound in combi- and chalcones [licochalcone A (122), licochalcone E (123)] as well as nation with well‐known antibiotics is measured by fractional inhibitory catechins in green and black teas, anthocyanin in strawberries and concentration index (Khameneh, Diab, Ghazvini, & Fazly Bazzaz, other berries and isoflavonoids [with ring C in position 3 instead of 2016). In 2012, in vitro activity of flavones in combination with position 2], such as sophoraisoflavone A (94) found in legumes (Patra, vancomycin and oxacillin against vancomycin‐intermediate S. aureus 2012), are only few examples. (multidrug‐resistant bacteria) was evaluated and results showed synergism with fractional inhibitory concentration index values of 3 | ANTIBACTERIAL ACTIVITY OF 0.094 and 0.126, respectively (Bakar, Zin, & Basri, 2012). In addition, FLAVONOIDS diosmetin )25) and alpinumisoflavone (26) from Sophora moorcroftiana in combination with ciprofloxacin and baicalin (37) in combination with oxacillin, tetracycline, and ciprofloxacin exerted synergistic activity 3.1 | Flavones against S. aureus by inhibition of the NorA efflux protein (Qiu, Meng, Different studies evaluated the inhibitory effects of plant flavonoid‐ Chen, Jin, & Jiang, 2016; Wang et al., 2014). rich extracts and pure flavonoids against some pathogenic bacteria. Various mechanisms have been proposed for the antibacterial activi- 3.2 | Flavonols ties of flavones. As a mechanism, flavones form a complex with the cell wall components and consequently inhibit further adhesions and Flavonols such as quercetin, myricetrin, morin, galangin, entadanin, the microbial growth as well. As an example, gancaonin Q (1; prenyl rutin, piliostigmol, and their derivatives are among the most important flavone; Figure 1) and amentoflavone (2) isolated from Dorstenia spp. class of flavonoids that show potent antibacterial activities. For exam- showed activity against Bacillus cereus (Minimum Inhibitory Concen- ples, quercetin (48) and its derivatives showed a significant antibacte- tration (MIC): 2.4 and 3 μg/ml, respectively) via the same mechanism rial activity against some strains of bacteria, including S. aureus, FARHADI ET AL. 3

FIGURE 1 Chemical structures of flavone compounds methicillin‐resistant S. aureus (MRSA), and Staphylococcus epidermidis. active against Bacillus subtilis whereas myricetrin‐3‐O‐rhamnoside (56) In vitro investigation of this compound against several oral microbes was the most active compound against E. coli, K. pneumonia, and showed that quercetin had potent activity against Porphyromonas S. aureus. These results validated the ethnomedicinal use of the plant gingivalis with MIC value of 0.0125 μg/ml (Geoghegan, Wong, & in folk medicine (Aderogba, Ndhlala, Rengasamy, & Van Staden, 2013). Rabie, 2010). In another study, the antibacterial activities of quercetin Babajide, Babajide, Daramola, and Mabusela (2008) found that against amoxicillin‐resistant S. epidermidis were assessed. The results piliostigmol (47) from Piliostigma reticulatum exhibited strong activity indicated that upon combination of quercetin and amoxicillin, the syn- against E. coli (MIC: 2.57 μg/ml), which was three times stronger than ergistic activity was observed and bacterial resistance to this tradi- amoxicillin. Recently, antibacterial study of lipophilic compounds tional antibiotic was remarkably reversed (Siriwong, Teethaisong, galangin (44) and galangin‐3‐methyl ether (72) against Gram‐positive Thumanu, Dunkhunthod, & Eumkeb, 2016). and Gram‐negative bacteria showed that compounds were active Morin (45) is well‐known to be effective against Gram‐positive against Gram‐positive bacteria with MIC values of 0.5–1 μg/μl bacteria. Combination of this plant‐derived flavonol with conventional (Echeverría, Opazo, Mendoza, Urzúa, & Wilkens, 2017). In 2017, anti- β‐lactam antibiotics against MRSA showed that the susceptibility of bacterial properties of eight compounds isolated from Entada abyssinica MRSA toward oxacillin was enhanced significantly (Mun et al., 2015). (traditionally used against gastrointestinal bacterial infections caused by Bioactive constituents from Croton menyharthii evaluated for their Salmonella typhimurium) were assayed, and the results showed that inhibitory effects on selected bacteria. Among them, quercetin was among them, compounds entadanin (73) and quercetin‐3‐O‐α‐l‐ 4 FARHADI ET AL.

FIGURE 1 Continued.

rhamnoside (74) were active against S. typhimurium with the lowest MIC and cellular leakages (Musa et al., 2011). It was inferred that the antibac- values of 1.56 and 3.12 μg/ml, respectively (Dzoyem et al., 2017). terial mechanism of galangin is related to the alteration of topoisomer- Galangin (44) is a well‐known antibacterial agent, and the plants con- ase IV enzyme activity (Cushnie & Lamb, 2006). As mentioned above, taining this flavonol were used traditionally in South African indigenes morin is effective against Gram‐positive bacteria. The possible mode to treat infections. This compound was effective against S. aureus of action of the compound is related to the suppressing expression of (Cushnie & Lamb, 2005a, 2005b), and in another study, galangin, quer- penicillin‐binding protein encoded by mecA (Mun et al., 2015). cetin, and baicalein were able to reverse bacterial resistance to conven- Biofilm eradication is another antibacterial mechanism of flavo- tional β‐lactam antibiotics against penicillin‐resistant S. aureus (Eumkeb, noids, for example, rutin (49) at concertation of 50 μg/ml reduced Sakdarat, & Siriwong, 2010; Figure 2). biofilms of foodborne pathogens (E. coli and S. aureus;Al‐Shabib et al., Many research groups investigated possible antibacterial MOA of 2017) and inhibited biofilm formation of Streptococcus suis with 1/4 flavonols. It is well‐known that three types of β‐ketoacyl carrier pro- MIC value (78.1 μg/ml) without changing the structure of S. suis tein synthases are predominant targets for the design of novel antibi- (Wang et al., 2017). In another study, myricetin (46) inhibited biofilm otics. 3,6‐Dihydroxyflavone (50) exhibited antibacterial activity against formation of S. aureus by MBIC50 values of 1 μg/ml (Lopes, dos Santos the multidrug‐resistant E. coli through inhibition of β‐ketoacyl acyl car- Rodrigues, Magnani, de Souza, & de Siqueira‐Júnior, 2017). rier protein synthase I (related to the elongation of unsaturated fatty Antifouling properties of purified quercetin (48) from marine acids in bacterial fatty acid synthesis) and III with MIC value of derived Streptomyces spp. against 18 biofouling bacteria confirmed 512 μg/ml (Lee, Lee, Jeong, & Kim, 2011). Kaempferol‐3‐rutinoside with MIC range between 1.6 and 25 μg/ml (Gopikrishnan, (68), isolated from Sophora japonica flowers, was active against Radhakrishnanauthor, Shanmugasundaramauthor, Pazhanimuruga- Streptococcus mutans by inhibition of the action of sortase A that plays nauthor, & Balagurunathanauthor, 2015). In another study, among a key role in the adhesion to and invasion of hosts by Gram‐positive the nine flavonoids (from the leaves of Scutellaria oblonga), quercitin‐ bacteria (Yang et al., 2015). 3‐glucoside (65) could successfully kill S. aureus and reduction in Some research groups studied the correlation between antimicro- biofilms (90–95%) was observed (Rajendran et al., 2016). Other reports bial properties and liposome interaction activities of different flavo- of the antibacterial activity of flavonols are summarized in Table 2. noids. The lipophilicity properties and the interaction of antibacterial agents with the cell membrane attribute the success or failure of them 3.3 | Flavanones to access their target (Echeverría et al., 2017). Liposomal models were used for investigation of antibacterial mechanism of four flavonoids Several studies have reported antibacterial activity of flavanones against E. coli. Among them, kaempferol (55) showed bacterial cell dis- (Table 3). For example, the result of in vitro investigation of prenylated ruption by interaction with the polar head‐group of the model mem- flavanones from Paulownia tomentosa fruits showed that compounds brane (He, Wu, Pan, & Xu, 2014). In a previous study, it was shown 3′,5‐O‐dimethyldiplacone (79), 3′,5‐di‐O‐methyl‐diplacone (80), that plants with high level of flavonoids can disrupt bacterial surface mimulone (81), and diplacone (82) had a strong antibacterial activity FARHADI TABLE 1 Antibacterial effect of flavone compounds

Compounds Source Bacteria Method Activity Ref. TAL ET Gancaonin Q (1) Dorstenia angusticornis Bacillus subtilis Liquid dilution MIC: 2.44 μg/ml (Kuete et al., 2007) . Amentoflavone (2) Dorstenia barteri Bacillus cereus Disc diffusion MIC: 3 μg/ml (Mbaveng et al., 2008) Bacillus megaterium Erysubin F (3) Erythrina subumbrans Taphylococcus aureus Disc diffusion MIC: 50 μg/ml (Rukachaisirikul et al., 2007) Heveaflavone (5) Ouratea multiflora Staphylococcus aureus Agar plate diffusion ZI: 10–12 mm (Carbonezi et al., 2007) Amentoflavone‐7″,4‴‐dimethyl‐ether (6) Bacillus subtilis Podocarpusflavone‐A(7) Cycloartocarpesin (8) Morus mesozygia Pseudomonas aeruginosa Liquid microdilution MIC: 156 μg/ml (Rukachaisirikul et al., 2007) Genistein 7‐O‐glucoside (9) Azadirachta indica Lactobacillus Microbroth dilution Inhibition: 52–99.8% (Kanwal, Hussain, Siddiqui, & Javaid, 2011) 5‐Hydroxy‐7‐methoxy‐flavone (10) Populus nigra/Populus deltoides Ralstonia solanacearum Broth dilution MTT MIC: >300, 25 μg/ml (Zhong et al., 2012) 5,7‐Dihydoxy‐flavone (11) Pseudomonas lachrymans 5′‐Methyl 4′, 5, 7 trihydroxy flavone (12) Bryophyllum pinnatum Pseudomonas aeruginosa Filter paper disc diffusion MIC: 625 μg/ml (Okwu & Nnamdi, 2011) 5,7‐Dihydroxy‐4,6,8‐trimethoxyflavone (13) Limnophila heterophylla Bacillus subtilis Broth microdilution MIC: 300 μg/ml (Activity: (Brahmachari et al., 2011) 5,6‐Dihydroxy‐4,7,8‐trimethoxyflavone (14) effect on key enzyme) 5,7‐Dihydroxy‐4′‐methoxyisoflavanone Astragalus adsurgens Erwinia carotovora Microbroth dilution MIC ≥250 μg/ml (Chen et al., 2012) (15), 5,7,2′‐trihydroxy‐4 Staphylococcus aureus methoxyisoflavanone (16), 7,3′‐ dihydroxy‐4′‐methoxyisoflavanone (17) 5,4′‐Dihydroxy‐7‐methoxyflavone (18) Larrea tridentata Mycobacterium tuberculosis Broth dilution MTT MIC: 250–500 μg/ml (Favela‐Hernández, García, Staphylococcus aureus Garza‐González, Rivas‐ Galindo, & Camacho‐ Corona, 2012) Licoflavone C (19) Retama raetam Escherichia coli Microdilution broth MIC: 7.5 μg/ml (Edziri et al., 2012) Luteolin (20) Pure Escherichia coli Microbroth dilution MIC: 36.72 and 67.25 μg/ml (Wu et al., 2013) Chrysin (21) Luteolin (20) Litchi spp. Staphylococcus aureus Microdilution titer MIC: 14.6 μg/ml (Wen et al., 2014) Escherichia coli Shigella dysenteriae Luteolin (20) Diospyros virginiana Staphylococcus aureus Microdilution MIC: 1.5 ± 0.0003, μg/ml (Rashed, Ćirić, Glamočlija, & Bacillus cereus MBC: 2.5 ± 0.0003, μg/ml Soković, 2014) Psiadiarabin (22) Saudi Arabian propolis Mycobacterium marinum Alamar blue MIC: 61.9 μg/ml (Almutairi et al., 2014) Atocarpin (23) Artocarpus anisophyllus Pseudomonas putida Disc diffusion ZI: 13.7 mm (Jamil, 2014) MBC: 450 μg/ml Artonin I (24) Morus mesozygia Stapf Staphylococcus aureus Microplate Alamar blue Inhibition: % 69–89 (Farooq et al., 2014) Diosmetin (25) Sophora moorcroftiana Staphylococcus aureus Broth microdilution MIC: 8 μg/ml (Wang et al., 2014) Alpinumisoflavone (26) Gancaonin G (27) Glycyrrhiza uralensis Enterococcus faecium Liquid dilution MIC: 32 μm (Orabi et al., 2014) Semilicoisoflavone B (28) 6‐Methoxy‐2‐[2(3‐hydroxy‐4 Aquilaria sinensis Staphylococcus aureus Filter paper disk agar ZI: 9.10 ± 0.06 mm (Li et al., 2014) ‐methoxyphenyl)ethyl]chromone (29) diffusion

(Continues) 5 6 FARHADI ET AL.

against Gram‐positive bacteria including B. cereus, B. subtilis, Enterococ- cus faecalis, Listeria monocytogenes, and S. aureus with MIC values of 2– 4 μg/ml (Šmejkal et al., 2008). It has also been demonstrated that abyssione‐V4′‐O‐methyl ether (88) from the stem bark of Erythrina caffra inhibit activity of E. coli with MIC value of 3.9 μg/ml (Chukwujekwu, Van Heerden, & Van Staden, 2011). Katerere, Gray, Nash, and Waigh (2012) reported excellent activity of pinocembrin (Zou et al., 2016) (Rajendran et al., 2016) (87) isolated from Combretum apiculatum toward S. aureus with MIC of 12.5 μg/ml. In another study, this compound from the leaves of Cryptocarya chinensis was potent against Mycobacterium tuberculosis μ ′‐ ‐ g/ml (Fan et al., 2015) (MIC 3.5 g/ml). Navrátilová et al. (2016) demonstrated that 3 O μ methyldiplacol and mimulone have promising antibacterial activities 128 –

g/ml (Activity: when used alone or in combination with conventional antibiotics μ

g/ml against MRSA (Figure 3). 32 g/ml (Cui et al., 2015) g/mlg/ml (Allison et al., 2017) g/ml (Qiu et al., 2016) reduced) μ ‐ – g/ml (Mbaveng et al., 2015) μ μ μ μ

μ In 2012, among three prenylated flavanones from the Mundulea sericea, lupinifolin (90) has been reported to have significant antibacte- biofilm acetylcholinesterase inhibition) MBC: 50 (Activity: rial activity against S. aureus with minimum inhibitory quantity value of 0.5 μg (Mazimba, Masesane, & Majinda, 2012). Synergism has been demonstrated between various combination of flavanones and antibiotics. For example, Su‐Hyun et al. determined the antibacterial synergism of sophoraflavanone B (94) with antibiotics including ampicillin, oxacillin, and gentamicin against MRSA (Mun et al., 2013). Synergism has also been reported between flavonoid and other antibacterial kill curves MICs: 24 ‐ agents. Sophoraflavanone has been reported as a phytochemical com- Colorimetric MIC: 4 Time Liquid dilution MIC: 16 Enzyme inhibitionAgar dilution MIC: 10 MIC: 25 Microdilution MIC: 64 Broth microdilution MIC/MBC: 320 pound with potent antibacterial activity (Tsuchiya & Iinuma, 2000). Sophoraflavanone G (83; from Sophora flavescensn), for example, poten- tiated the effect of ampicillin or oxacillin against MRSA infection (Cha, Moon, Kim, Jung, & Lee, 2009). In addition, sophoraflavanone G (83) showed significant antibiofilm formation against S. epidermidis, S. aureus, and B. subtilis with MIC values ranging from 3.1 to 12.5 μg/ml (Oh et al., 2011; Wan, Luo, Ren, & Kong, 2015). Sophoraflavanone B showed antimicrobial activity against MRSA (Mun et al., 2014). Enterobacter cloacae Klebsiella pneumonia Enterococcus faecalis Bacillus subtilis Dzoyem, Hamamoto, Ngameni, Ngadjui, and Sekimizu (2013) reported that 6, 8‐diprenyleriodictyol (95) from Dorstenia species deactivated S. aureus via depolarization of membrane and inhibition of DNA, RNA, and protein synthesis. This compound rapidly reduced the bacterial cell density and caused lysis of S. aureus. In 2016, the potential of C‐6‐geranylated flavonoids for the use in controlling the growth of antibiotic‐resistant microorganisms were evaluated against S. aureus. Out of them, mimulone (81), (geranylated flavonoids) was more effective than the oxacillin (antibiotic standard) with MIC values of 2/4.9 μg/ml (Navrátilová et al., 2016). The relationship Pure Scutellaria oblongaPsoralea corylifolia Escherichia coli Staphylococcus aureus Artemisia californicaSelaginella moellendorffii Escherichia Escherichia coli coli Scutellaria baicalensis Staphylococcus aureus Oroxylum indicum Staphylococcus aureus between lipophilicity and the structure of flavonoid analogues in growth inhibition of Gram‐positive and Gram‐negative bacteria were evaluated by flavones from Heliotropium filifolium. Compounds pinocembrin (87) and 7‐O‐methyleriodictyol (99) were active with MIC values of 0.5–

‐ μ

b 4 g/ml, and these results showed that the amphipathic properties ‐ ‐ O ‐ ,7 (lipophilic and hydrophilic moieties of flavones) were important for anti- ′ 8 ) ‐ 4 ‐ ) ) bacterial activity and selectivity, respectively (Echeverría et al., 2017). 36 ) ) 34 35 33 39 ) 30 ) ) )

) | ‐ 32 baicalein ( 3.4 Flavane 3 ols 38 ‐ 31 37 (Continued) One of the main group of flavonoids is flavane‐3‐ol compounds, and the Trimethoxyflavone ‐

glucopyranoside ( antibacterial activity of these compounds is well documented (Table 4). Carbomethoxymethyl Methoxy ‐ ‐ ‐ dihydroxyflavone ( D Neocyclomorusin ( 5,6,7 5 Compounds Source Bacteria Method Activity Ref. Corylifol C ( Jaceosidin ( Techtochrysin ( Baicalein ( Neobavaisoflavone ( Negletein ( 6

TABLE 1 In vitro investigation (Figure 4) showed strong antibacterial activity of FARHADI ET AL. 7

FIGURE 2 Chemical structures of flavonol compounds

3′‐O‐methyldiplacol (100) against Gram‐positive bacteria including well diffusion and broth dilution methods against 10 microorganisms. B. subtilis, E. faecalis, L. monocytogenes, S. aureus, and S. epidermidis with This compound exhibited good activity against six out of 10 tested MICs ranging from 2 to 4 μg/ml (Šmejkal et al., 2008). The MIC value of microorganisms, including two resistant strains (MRSA and vancomy- quercetin 3‐O‐methyl ether (101) isolated from Cistus laurifolius flowers cin resistant) with MIC/MBC values of (25/50) and (12.5/50), respec- was found to be 3.9 μg/ml against Helicobacter pylori (Ustün, Ozçelik, tively (Tajuddeen et al., 2016). Akyön, Abbasoglu, & Yesilada, 2006).Some researchers have reported synergy between naturally occurring flavane‐3‐ols and antibiotic | agents. An, Zuo, Hao, Wang, and Li (2011) reported significant synergis- 3.5 Chalcones tic effect between taxifolin‐7‐O‐α‐l‐rhamnopyranoside (102) and anti- Some researchers have reported significant increase in antibacterial biotics including ceftazidime and levofloxacin against S. aureus with activity of chalcones in combination with other antibiotics. Example FIC: 0.3–0.5. Navrátilová et al. (2016) evaluated the antibacterial activ- of these includes THIPMC (115) extracted from the plants of the ity of 3′‐O‐methyldiplacol (100) alone and in combination with oxacillin genus Dorstenia (widely used in African and South American folk med- against MRSA strain. Based on MIC/Minimum Bactericidal Concentra- icine for their pharmacological relevance) was active against tested tion (MBC) result (4/4 and 2/4 μg/ml, alone, and combined, respec- bacteria alone as well as in combination with ampicillin or gentamicin. tively), this combination had a synergistic effect against MRSA and The MIC values (0.188 to 0.375 μg/ml) showed that the combined this compound was more potent than the standard drug. effect of this compound is greater than their individual effect (Lee The activity of the 2‐(3,5‐dihydroxy‐4‐methoxy‐phenyl)‐3,5‐dihy- et al., 2010). The investigation of bactericidal/bacteriolysis activities droxy‐8,8‐dimethyl‐2,3‐dihydro‐8H‐pyrano[3,2]chromen‐4‐one (106) of flavonoid compounds by time‐kill kinetic method exhibited that 4‐ isolated from Commiphora pedunculata has been investigated by agar hydroxyonchocarpin (118; Figure 5) plays a greater role in increasing 8 FARHADI ET AL.

FIGURE 2 Continued.

the antibacterial activity against S. aureus with MIC values of 1–8 μg/ml in another study, this compound was potent against and had no toxicity effects 24 hr after injection (Dzoyem et al., 2013). In methicillin‐resistant Staphylococcus strains (MIC: 8 μg/ml; Cui, 2008, the antimicrobial activity of five flavonoids (from twigs of Taniguchi, Kuroda, & Hatano, 2015). Dorstenia barteri) was evaluated against Gram‐positive and About 300 flavonoids have been isolated from licorice, and among Gram‐negative bacteria by disc diffusion assay. The lowest MIC them, chalcones [licochalcone A (122) and licochalcone E (123)] value (0.3 μg/ml) of Gram‐positive bacteria was obtained only with showed inhibitory activity of bacterial infection by decreasing expres- isobavachalcone (110), which was fourfold lower than the MIC value sion of bacterial genes, inhibiting bacterial growth, and reducing the (4.9 μg/ml) of the antibiotics (gentamicin; Mbaveng et al., 2008), and production of bacterial toxin (Wang, Yang, Yuan, Liu, & Liu, 2015). FARHADI TABLE 2 Antibacterial effect of flavonol compounds

Compounds Source Bactria Method Activity Ref. TAL ET 5,7‐Dihydroxy‐3,8‐dimethoxyflavone Achyrocline satureioides Staphylococcus aureus Broth microdilution MIC: 128 μg/ml (Casero et al., 2014)

(gnaphaliin A) (40) . Quercetin‐3‐O‐α‐l‐arabinopyranoside (41) Psidium guajava Streptococcus mutans Agar well diffusion MIC: 400 μg/ml (Activity: (Prabu, Gnanamani, & antiplaque agent by inhibiting Sadulla, 2006) the growth cell) Quercetin 3‐O‐β‐D‐rutinoside (42) Marrubium globosum Enterobacteraerogenes Broth dilution MIC: 320 μg/ml (Rigano et al., 2007) Proteus vulgaris 3,4‐Methylenedioxy‐10‐methoxy‐7‐ Derris indica Mycobacterium tuberculosis Microplate Alamar blue MIC: 6.25 and 200 μg/ml (Koysomboon, Van oxo[2]benzopyrano[4,3‐ Altena, Kato, & b]benzopyran (43) Chantrapromma, 2006) Galangin (44) Helichrysum aureonitens Staphylococcus aureus Agar dilution MIC: 500 μg/ml (Cushnie, Hamilton, Chapman, Taylor, & Lamb, 2007) Galangin (44) Propel Staphylococcus aureus Time‐kill MIC: 50 μg/ml (Activity: (Cushnie & Lamb, 2006) aggregation of bacterial cells) Morin (45) Psidium guajava Aeromonas salmonicida Microbroth dilution MIC: 150–200 μg/ml (Rattanachaikunsopon & Phumkhachorn, 2007) Myricetin (46) Pure Mycobacterium Microtiter plate MIC: 32 μg/ml (Lechner, Gibbons, & Bucar, 2008) Piliostigmol (47) Piliostigma reticulatum Escherichia coli Microdilution titer MIC: 2.57 μg/ml (Babajide et al., 2008) Quercetin (48) Pure Escherichia coli Microbroth dilution MIC: 33 μg/ml (Alvarez, Debattista, & Rutin (49) Staphylococcus aureus (Activity blocking the charges Pappano, 2008) of amino acids in the porins) Quercetin (48) Pure Porphyromonas gingivalis Broth dilution MIC: 0.0125 μg/ml (Geoghegan et al., 2010) Quercetin (48) Pure Staphylococcus aureus Activity: 50 μM (Hirai et al., 2010)

Morin (45) Pure Escherichia coli IC50 : 0.7 μg/ml (Activity (Chinnam et al., 2010) inhibition of ATP synthase) 3,6‐Dihydroxyflavone (50) Pure Escherichia coli Broth microdilution MIC: 512 μg/ml (Activity: (Lee et al., 2010) Staphylococcus aureus inhibition of β‐ketoacyl acyl carrier protein synthase III) Elatoside A (51) Epimedium elatum Pseudomonas aeruginosa Agar diffusion ZI: 11, 16, 19, 20 mm (Tantry, Dar, Idris, Elatoside B (52) Staphylococcus aureus Akbar, & Shawl, 2012) Escherichia coli Salmonella typhi 5,7‐Dihydroxy‐flavonol (53) Populus nigra × Populus deltoides Ralstonia solanacearum Modified broth MICs: 150 μg/ml (Zhong et al., 2012) dilution MTT Kaemklebsiella pneumoniazpferol‐ Farsetia aegyptia Turra Klebsiella pneumoniae Paper disc IZ: 19 mm (Atta, Hashem, & 7,8‐diglucoside (54) Eman, 2013) Kaempferol (55) Pure Escherichia coli MIC: 25.00 μg/ml (Wu et al., 2013) Quercetin‐3‐O‐rutinoside (42) Calotropis procera Staphylococcus aureus Agar well‐diffusion IZ: 19.5 mm (Nenaah, 2013) Bacillus subtilis MIC: 80 μg/ml Myricetrin‐3‐O‐rhamnoside (56) Croton menyharthii Bacillus cereus Microdilution bioassay MIC: 30–250 μg/ml (Aderogba et al., 2013)

(Continues) 9 TABLE 2 (Continued) 10

Compounds Source Bactria Method Activity Ref. Quercetin (48) Escherichia coli Staphylococcus aureus Quercetin (48) Alnus japonica Staphylococcus aureus Microwell plate (Activity inhibition biofilms (J.‐H. Lee et al., 2013) formation >70% at 20 μg/ml) Quercetin (48) Psidium guajava Pseudomonas aeruginosa Disc diffusion Concentrate: 50 and 100 μg/ml (Vasavi, Arun, & Rekha, 2014) Quercetin‐3‐O‐arabinoside (41) Quercetin (48) Diospyrs virginiana Staphylococcus aureus Microdilution MIC: 50 μg/ml (Rashed et al., 2014) Myricetin (46) Rutin (49) Litchi chinensis Staphylococcus aureus Microdilution titer MIC: 62.5 μg/ml (Wen et al., 2014) Escherichia coli Shigella dysenteriae 3‐Cinnamoyltribuloside (57) Heritiera littoralis Mycobacterium Microtiter dilution MIC: 80–160 μg/ml (Christopher, Nyandoro, madagascariense Chacha, & de Mycobacteriumindicus Koning, 2014) pranii Kaempferol (55) Pure Escherichia coli Microdilution in broth MIC >10,000 μg/ml (He et al., 2014) Kaempferol (55) Commiphora pedunculata Staphylococcus aureus MIC: 6.25 μg/ml (Tajuddeen, Sani Sallau, Muhammad Musa, James Habila, & Yahaya, 2014) Kaempferol (55) Apocynum venetum Bacillus thuringiensis Active (Kong et al., 2014) Pseudomonasaeruginosa 3,4′,5‐Trihydroxy‐3′,7‐ Dodonaa angustifolia Escherichia coli, Bacillus Agar well‐diffusion MIC <31.25 μg/well (Omosa et al., 2014) dimethoxyflavone (58) pumilus Kaempferol‐3‐O‐(2″,3″,4″‐tri‐O‐ Calliandra tergemina Staphylococcus aureus Microdilution MIC: 256 μg/ml (Chan, Gray, Igoli, galloyl)‐a‐L‐rhamnopyranoside (59) Lee, & Goh, 2014) Quercetin‐3‐O‐(3″,4″‐di‐O‐galloyl)‐a‐L‐ rhamnopyranoside (60) Astragalin (61) Garcinia preussii Staphylococcus aureus Broth dilution MIC: 128 μg/ml (Biloa Messi et al., 2014) Quercetin‐3‐O‐β‐rhamnoside (62) Ficus exasperata Bacillus subtilis Agar diffusion ZI: 2–2.5 mm (Taiwo & Igbeneghu, 2014) 6‐Hydroxyquercetin7‐O‐β‐ Tagetesminuta Micrococcusleteus Agar well‐diffusion ZI: 14.2 19 mm (Shahzadi & Shah, 2015) glucopyranoside (63) 6‐Hydroxy quercetin7‐O‐β‐(6‐ galloylglucopyranoside) (64) Quercitin‐3‐glucoside (65) Scutellaria oblonga Staphylococcus aureus Time‐kill curves MIC: 32 μg/ml (Rajendran et al., 2016) (Activity: biofilm‐reduction) Rhamnetin‐3,3′‐di‐O‐β‐D‐ Diplotaxis. SPP. Escherichia coli Diffusion agar IZ: 17.60 ± 0.04, (Salah et al., 2015) glucopyranoside (66) Staphylococcus aureus 13.00 ± 0.01 mm Isorhamnetin 3‐O‐b‐D‐ rutinoside (67)

Kaempferol‐3‐rutinoside (68) Sophora japonica Staphylococcus aureus MIC >320.2 μg/ml (Yang et al., 2015) FARHADI (Activity: inhibition the action of sortase A) TAL ET (Continues) . FARHADI ET AL. 11

In addition, biofilm inhibition reported as an important activity of chalcones, for example, in vitro investigation of antibiofilm activity

Seoud, was evaluated by natural and synthetic chalcones against Haemophilus ‐ influenza. Out of them, 3‐hydroxychalcone (120) exhibited approximately sixfold more activity than the reference drug, azithromycin

(MBIC50 16 μg/ml; Kunthalert, Baothong, Khetkam, Chokchaisiri, & ′ ′ ‐ ‐

Madboly, & Ikeda, 2016) Suksamrarn, 2014). Rodríguez et al. found that 2 ,4 ,4 trihydroxy ‐ Shabib et al., 2017) Aasr, Kabbash, El ‐ ‐ Al 3,6′‐dimethoxychalchone (121) isolated from Piper delineatum (Al (Tebou et al., 2017) displayed a potent quorum sensing inhibitory activity in Vibrio harveyi (bacterial model) by inhibitory effect on biofilm formation, without inhibition of bacterial growth up to 16.5 μg/ml (Martín‐Rodríguez et al., 2015). Recently, a new prenylated chalcone 4,4′,6′ trihydroxy‐ 3‐methoxy‐3′‐pentene chalcone (124) has been extracted from g/ml (Echeverría et al., 2017) g/ml (Lopes et al., 2017)

μ Elatostema parasiticum, which inhibited the growth of S. aureus and μ g/ml (Gopikrishnan et al., 2015) g/ml (Randhawa et al., 2016) g/ml (Dzoyem et al., 2017) μ

0.5 B. subtilis with the MIC values of 7.8 and 1.95 g/ml, respectively μ μ μ g/ml (Wang et al., 2017) g/ml g/ml (Activity: – μ μ μ :1,32

20 mm (El (Mariani, Suganda, & Sukandar, 2016). Several antibacterial activities – 50 of other chalcones compounds are summarized in Table 5. complex with bacterial cell walls) MIC: 78 (Activity: inhibition of biofilm)

4 | SYNTHETIC DERIVATIVES OF FLAVONOIDS

Developing novel, potent, and unique antibacterial drugs is important to overcome bacterial resistance and increase effectiveness of thera- pies. Many researchers reported that new derivatives of flavonoids Antifouling assay MIC: 1.62 Microdilution MIC: 0.25 Microbroth dilution MIC: 25 Microdilution in broth MBIC Broth microdilution MIC: 16 Well diffusion ZI: 14 Microdilution MIC: 62.5 Liquid dilution MIC: 1.56 were more active than natural flavonoids against bacteria strains (Table 6; Babii et al., 2016). For evaluation of the antibacterial activity of hybrids of chalcones and oxazolidinones, N‐{3‐[3‐fluoro‐4‐(3‐ pyridin‐2‐yl‐acryloyl)‐phenyl]‐2‐oxo‐oxazolidin‐5‐ylmethyl}‐acetamide (126; containing both chalcone and oxazolidinone moieties) was synthesized and showed potent activity toward S. aureus with MIC values of 4–8 μg/ml (Selvakumar et al., 2007). More studies revealed that the primary target of this agent is cytoplasmic membrane (Cushnie Streptococcus suis Staphylococcus aureus Proteus mirabilis Staphylococcus aureus Escherichia coli Staphylococcus aureus Staphylococcus saureus Streptococcu pyogenes Enterococcus feacalis Escherichia coli Acinetobacter baumanii et al., 2008). Konduru, Dey, Sajid, Owais, and Ahmed (2013) investigated sulfone and bisulfone chalcone synthetic derivatives. Among them, 1‐(4‐bromophenyl)‐3‐(3,4‐dimethoxyphenyl)‐3‐(phenylsulfonyl) propane‐1‐one (130), 1‐(4‐bromophenyl)‐3‐(3,4,5‐trimethoxyphenyl)‐ 3‐(phenylsulfonyl) propane‐1‐one (131), and 1‐phenyl‐3‐phenyl‐3‐ . phenylsulfonylpropane‐1‐one (132) had good antibacterial activity against S. typhimurium (MIC 1.95 μg/ml) in comparison with reference drugs ampicillin and kanamycin (Figure 6). Tran, Do, et al. (2012) investigated in vitro antibacterial activity of Pure Maytenus buchananii Staphylococcus aureus Atriplex halimus L Alpinia calcarata Staphylococcus aureus Entada abyssinica Salmonella typhimurium synthetic chalcone analogues alone or in combination with nonbeta lactam antibiotics (ciprofloxacin, chloramphenicol, erythromycin, van- ) comycin, and doxycycline) toward S. aureus (MRSA). Ciprofloxacin in 69 ) ) ‐ ′‐ ‐ ‐

44 combination with 4 bromo 2 hydroxychalcone (136), doxycycline ) 70

64 with 4‐hydroxychalcone (137), and doxycycline with 2′,2‐ ) Pure )

75 dihydroxychalcone (138) were active against MRSA with MIC values 72 Dihydroxy ‐ – μ rutinoside ( of 0.125 0.25 g/ml via inhibition of efflux pump. ) ‐ glucopyranoside ( D ‐ 72 rhamnoside(

β Biological evaluation for discovering urease inhibitors of synthetic ‐ ‐ D l ) ‐ ‐ O trihydroxyflavoe) ( β α ‐ ‐

‐ ′ ‐ ‐

71 derivatives of flavonoids against H. pylori urease indicated that 4 ,7,8 ) Pure ) ), myricitrin ( O O ‐ ‐ methyl ether ( 48 73 46 ‐ 3 3 trihydroxy‐isoflavene (141) was the most active compound with IC (Continued)

‐ 50 ‐ 3 ) Pure ) Pure ‐ ‐ 49 49 0.85 mM, which was 20 fold more potent than standard urease inhibi- Methylgalangin (5,7 ‐ tor (acetohydroxamic acid; Xiao et al., 2013). Bozic, Milenkovic, Ivkovic, O ‐ Rutin ( CompoundsQuercetin ( Source Bactria Method Activity Ref. Rutin ( Myricitrin ( 3methoxyflavone) ( Quercetin Isorhamnetin 3 Galangin Entadanin ( Galangin (3,5,7 3 Artiplexoside ( Quercetin

TABLE 2 and Cirkovic (2014) reported that among three newly synthesized 12

TABLE 3 Antibacterial effect of flavanone compounds

Compounds Source Bacteria Method Activity Ref. 7‐Dihydroxy‐2′‐methoxy‐3′,4′‐ Uraria picta Staphylococcus aureus Microdilution titer MIC: 12.5 μg/ml (Rahman, Gibbons, & Gray, 2007) methylenedioxyisoflavanone (76) Naringenin (77) Pure Escherichia coli Generation time: 25–39 (Ulanowska, Majchrzyk, Moskot, Bacillus subtilis (Activity: inhibition Jakóbkiewicz‐Banecka, & of nucleic acid synthesis) Węgrzyn, 2007) 5,7‐Dibenzyloxyflavanone (78) Helichrysum gymnocomum Staphylococcus aureus Quick microplate method MIC ≤125 μg/ml (Drewes & van Vuuren, 2008) 3′‐O‐methyl‐5′‐hydroxydiplacone (79) Paulowniatomentosa Enterococcus faecalis Broth microdilution method MIC: 2 μg/ml (Šmejkal et al., 2008) 3′‐O‐methyl‐5′‐O‐methyldiplacone (80) Bacillus subtilis Mimulone (81), Diplacone (82) Sophoraflavanone G (83) Sophora flavescens Staphylococcus aureus Broth dilution method MIC/MBC: 0.5/1 μg/ml (Cha et al., 2009) 5,7‐Dimethoxyflavanone‐4′‐O‐b‐D‐ Retama raetam Escherichia coli Microdilution broth methods MIC: 7.5 μg/ml (Orhan, Özçelik, Özgen, & glucopyranoside (84) Ergun, 2010) 5,7,3′‐Trihydroxy‐flavano‐ne‐40‐O‐b‐ D‐glucopyranoside (85) Naringenin‐7‐O‐b‐D‐glucopyranoside (86) Sophoraflavanone G (83) Sophora flavescens Staphylococcus aureus Microtiter dilution assay MIC: 7.12–7.36 μg/ml (Oh et al., 2011) Kurarinol (89) IC50 : 107.7 ± 6.6 μM Pinocembrin (87) Cryptocarya chinensis Mycobacterium tuberculosis MIC: 3.5 μg/ml (Chou, Chen, Peng, Cheng, & Chen, 2011) Abyssione‐V4′‐O‐methyl ether (88) Erythrina caffra Escherichia coli Microbroth dilution assay MIC: 3.9–62 μg/ml (Chukwujekwu et al., 2011) Staphylococcus aureus 7‐Hydroxyflavanone (91) Zuccagnia punctata Streptococcus pneumoniae Agar macrodilution method MIC: 1,000 μg/ml (Zampini et al., 2012) 5,7‐Dihydroxyflavanone (Pinocembrin) (87) Combretum hereroense Staphylococcus aureus Microtiter dilution assay MIC: 12.5 μg/ml (Katerere et al., 2012) Lupinifolin (90) Mundulea sericea Staphylococcus aureus MIQ: 0.5 μg (Mazimba et al., 2012) Ochnaflavone (92) Ochna pretoriensis P. aeruginosa MIC 31.3, 62.5 μg/ml (Makhafola, Samuel, Ochnaflavone 7‐O‐methyl ether (93) S. aureus Elgorashi, & Eloff, 2012) Sophoraflavanone B (94) Pure Staphylococcus aureus Broth microdilution method MIC: 31.5 μm (Mun et al., 2013) 6‐8 Diprenyleriodictyc (95) Pure Staphylococcus aureus Microbroth dilution method MIC: 0.5 μg/ml Activity: (Dzoyem et al., 2013) depolarization of membrane Sophoraflavanone B (94) Desmodium caudatum Staphylococcus aureus Checkerboard dilution test MIC: 15.6 μg/ml (Mun et al., 2014) 4′,7‐Di‐O‐methylnaringenin (96) Macaranga trichocarpa Escherichia coli Broth microdilution MIC: 62.4–124.9 μg/ml (Fareza, Syah, Shigella dysenteriae Mujahidin, Juliawaty, & Kurniasih, 2014) Sophoraflavone G (83) Sophora alopecuroides Staphylococcus epidermidis Microdilution method MIC: 3.1 to (Wan et al., 2015) 12.5 μg/ml

Liquiritigenin (97) Pure Escherichia coli IC50 : 198.6, 337.8 μg/ml (Kong et al., 2015) Liquiritin (98) FARHADI Mimulone (81) Paulownia tomentosa Staphylococcus aureus Agar dilution method MIC: 2/4.9 μg/ml/μM (Navrátilová et al., 2016) Pinocembrin (87) Pure Proteus mirabilis Microdilution method MIC: 0.25–0.5 μg/ml (Echeverría et al., 2017) ‐ ‐ 7 O Methyleriodictyol (99) Staphylococcus aureus AL ET . FARHADI ET AL. 13

FIGURE 3 Chemical structures of flavanone compounds

chalcones with OH at positions 2, 3, and 4 of B ring of 1,3‐bis‐(2‐ of 0.25 and 1 μg/ml against S. aureus and E. coli, respectively (Bahrin, hydroxy‐phenyl) (145; with hydroxy group in position 2) exhibited sig- Apostu, Birsa, & Stefan, 2014). In the other study, the antimicrobial nificant effect on adherence and biofilm formation of MRSA strains. In activity of synthesized flavones along with natural flavonoids was the synthetic fluoroquinolone‐flavonoid hybrids, naringenin‐ethyli- assayed against Flavobacterium columnare by rapid bioassay. Compound dene‐ciprofloxacin (146; with cyclopropan on the N atom) was the most 153 (a tricyclic flavonoid) containing S atoms on the heterocyclic ring active compound and showed eightfold to 88‐fold more potent activity was found to have a stronger antibacterial effect at low concentrations than the standard drug ciprofloxacin against E. coli, B. subtilis, and than other synthetic compounds against S. aureus and E. coli with MIC S. aureus. These results suggested that covalently binding of this com- values of 0.24 and 3.9 μg/ml, respectively (Babii et al., 2016). 2,3‐ pound with an efflux pump is a good strategy to overcome bacterial Dibromo‐1,3‐diphenylpropan‐1‐one derivative (154) with two Br sub- resistance and increase the antibacterial activity of flavonoids (Xiao stitution at the positions α and β (the synthetic chalcone derivatives) et al., 2014). Asiri et al. investigated synthetic heterocyclic compounds possessed antibacterial activity against S. aureus and E. faecalis with (pyrazolines and pyrimidines) for activity against two Gram‐positive MIC values of 6.25 and 12.5 μg/ml, respectively. This compound and two Gram‐negative bacteria by the disk diffusion assay, and among showed similar activity to standard antibiotic nalidixic acid (MIC: them, thiosemicarbazide (147) was better antibacterial agent against 6.25 μg/ml; Alam, Rahman, & Lee, 2015). S. aureus, compared than the reference drug chloramphenicol (Khan, The MIC value (8 μg/ml) of 27 chalcones and their pyrazoline and Asiri, & Elroby, 2014). Evaluation of the antibacterial activity of modified hydrazone derivatives showed that (E)‐1‐(4‐hydroxyphenyl)‐3‐p‐ structures of olympicin A from Hypericum olympicum showed that (E)‐3‐ tolylprop‐2‐en‐1‐one (155) was active against E. faecalis (the equal (2‐(allyloxy) phenyl)‐1‐(2,4,6‐trihydroxyphenyl)prop‐2‐en‐1‐one (148) activity with gentamicin; Evranos‐Aksöz, Onurdağ, & Özgacar, 2015). had a good activity against MRSA with MIC value of 0.39 μg/ml (Feng Fatty acid biosynthesis (FAB) is an attractive target for new antibac- et al., 2014). Between the synthetic tricyclic flavonoids, compounds terial agents. Inhibitory effects of chrysin derivatives on FabH were 149 and 150 (1,3‐dithiolium derivative) showed good activity with MICs evaluated toward E. coli, P. aeruginosa, and S. aureus. Results showed 14 FARHADI ET AL.

TABLE 4 Antibacterial effect of flavane 3‐ol compounds

Compounds Source Bacteria Method Activity Ref. 3′‐O‐methyldiplacol (100) Paulownia Bacillus Cereus Broth microdilution MIC: 2 to (Šmejkal et al., 2008) tomentosa Bacillus subtilis 4 μg/ml Staphylococcus epidermidis Conrauiflavonol (104) Ficus conraui Escherichia coli Rapid p‐ MIC: 64 μg/ml (Kengap et al., 2011) iodonitrotetrazolium violet (INT) 2‐(3,5‐Dihydroxy‐4‐methoxy‐ Commiphora Staphylococcus aureus Agar well diffusion MIC/MBC: (Tajuddeen et al., 2014) phenyl)‐3,5‐dihydroxy‐8,8‐ pedunculata and broth dilution 27 μg/ml dimethyl‐2,3‐dihydro‐8H‐ pyrano [3,2]chromen‐ 4‐one (106) Quercetin 3‐O‐methyl Cistus laurifolius Helicobacter pylori Agar dilution MIC: 3.9 μg/ml (Ustün et al., 2006) ether (101) Ericoside (107) Erica mannii Escherichia coli Broth microdilution MIC: 64 μg/ml (Bitchagno et al., 2016) 3′‐O‐methyldiplacol (100) Paulownia Staphylococcus aureus Agar dilution MIC: 2.4 μg/ml (Navrátilová et al., 2016) tomentosa fruits Taxifolin‐7‐O‐α‐l‐ Hypericum japonicum Staphylococcus aureus Microdilution MIC: 32 μg/ml (An et al., 2011) rhamnopyranoside (102) Lupinifolin (103) Mundulea sericea Staphylococcus aureus MIQ: 0.5 μg (Mazimba et al., 2012) Bacillus subtilis E. coli P. aeruginosa Dihydrokaempferol (105) Commiphora Entrococci MIC: 625 μg/ml (Tajuddeen et al., 2016) pedunculata Staphylococcus aureus

that compound 156 with heterocycle group at the C‐7 position was antibiotic ciprofloxacin). The result showed that R4 (N‐containing het- active against S. aureus and E. coli with MIC values of 1.25 ± 0.01 and erocyclic compounds) were more active than alkyl or aromatic amino 1.15 ± 0.12 μg/ml, respectively (Li et al., 2017). Evaluation of the anti- containing analogues at the C‐7 side chain (Xiao et al., 2017) bacterial activity of structural analogues of xanthohumol (157)by agar‐diffusion method revealed that chalconaringenin (158), with at least one hydroxy group at C‐4 position, demonstrated good activity. 5 | STRUCTURE–ACTIVITY RELATIONSHIP

Replacing this substituent by a halogen atom, nitro group (NO2), ethoxy group, or aliphatic group caused the loss of activity towards S. aureus The amphipathic features of flavonoids play an important role in the (Stompor & Żarowska, 2016). The synthetic compound (S)‐5‐hydroxy‐ antibacterial properties. In these compounds, hydrophilic and hydro- 4′‐hydroxy‐7‐(2‐morpholino‐2‐oxoethoxy)‐2,3‐dihydroflavone (160; phobic moieties must be present together (Echeverría et al., 2017). containing the flavanone core) displayed excellent activity against E. coli, The hydrophobic substituents such as prenyl groups, alkylamino chains, P. aeruginosa, and S. aureus (sixfold more potent than the marketed alkyl chains, and nitrogen or oxygen containing heterocyclic moieties

FIGURE 4 Chemical structures of flavane 3‐ ols compounds FARHADI ET AL. 15

FIGURE 5 Chemical structures of chalcone compounds

usually enhance the antibacterial activity for all the flavonoids (Xie, 5.2 | Flavanes and flavanols Yang, Tang, Chen, & Ren, 2015). The structure–activity relationships In many studies, flavanes with prenyl group at the A ring are the most have been found in the recent studies are summarized as follows. The potent antibacterial compounds against S. aureus, and the number and results showed that between different classes of flavonoids, mainly position of prenyl groups on this ring increase the activity (Figures 8 chalcones, flavanes, and flavan‐3‐ol exhibit better results, respectively. and 9). For example, Mazimba et al. (2012) proved that between com- These findings are comparable to that of previous studies (Cushnie & pounds lupinifolin (90) and 165 with almost similar structures, but dif- Lamb, 2011). ference at position 3 on the ring C, compound 90 inhibited the growth of S. aureus and B. subtilis (minimum inhibitory quantity: 0.5 μg). Pres- 5.1 | Chalcones ence of the hydroxy group at different positions of A and B rings has also been reported to improve antibacterial activity. Šmejkal et al. According to the result of many types of researches, chalcones with a (2008) reported that 3′‐O‐methydiplacol (100) with OH at positions lipophilic group such as isoprenoid and methoxy groups at positions 5, 3′, and 4′ on the A and B rings, respectively, geranyl group at C‐6 3′,5′, and 2′ of ring A are the most potent inhibitors of MRSA strains and OMe at C‐5′ showed good activity towered S. aureus with MIC (Lee et al., 2010; Omosa et al., 2016). Based on the activity of value of 4 μg/ml. Also, sophoraflavanone G (83) with isogeranyl at isobavachalcone (110; MIC: 30 μg/ml), Mbaveng et al. (2008) suggest C‐8 and OH at 3, 2′, and 4′ on the A and B rings was active against that A ring with prenyl group display good activity but cyclization or S. aureus with MIC value of 7.3 μg/ml (Oh et al., 2011). Recently, addition of the prenyl group to another ring in addition to the ring Bitchagno et al. (2015) found that the tetraflavonoids (166, 167) A (B ring) decrease the activity. Also, hydroxy group at 4′, 4, and 6 without OH on the C ring were moderate activity against E. coli. of A and B rings increase the activity (Figure 7). For example, between compounds kuraridin (168) and THIPMC (115) with the same structure, compound 168 with only one difference (with com- 5.3 | Flavonols pound 115) in position of OH on the B ring (2 and 4 instead of 4 and 6) showed high activity against MRSA strain (Lee et al., 2010; In the ring A, many studies have confirmed that hydroxylation at posi- Oh et al., 2011). tion 5 and 7 together are important on antibacterial activity of 16

TABLE 5 Antibacterial effect of chalcone compounds

Compounds Source Bacteria Method Activity Ref. Angusticornin B (108) Dorstenia angusticornis Bacillus cereus Liquid dilution MIC: 0.61–1.22 μg/ml (Kuete et al., 2007) Bartericin A (109) Isobavachalcone (110) Dorstenia barteri Staphylococcus aureus Disc diffusion MIC: 0.3 μg/ml (Mbaveng et al., 2008) Bacillus stearothermophilus 2′‐Hydroxy‐4′,6′‐dibenzyloxychalcone (111) Helichrysum gymnocomum Staphylococcus aureus Microplate MIC: 63 μg/ml (Drewes & van Vuuren, 2008) 2,4‐Dihydroxychalcone (112) Pure Slaphylococcus aureus Turbidimetric‐kinetic MIC: 25.3 μg/ml (Alvarez et al., 2008) 2,3′‐Dihydroxychalcone (113) 2,4′‐Dihydroxychalcon (114) THIPMC (115) Sophora flavescens Ait Staphylococcus aureus Microdilution broth MIC: 0.188–0.375 μg/ml (Lee et al., 2010) resistant enterococci 4,2′,4′‐Trihydroxychalcone (116) Astragalus adsurgens Escherichia coli Microbroth dilution MIC: 7.8–31.3 μg/ml (Chen et al., 2012) Bacillus cereus, Staphylococcus aureu Isoliquiritigenin (117) Pure Porphyromonas gingivalis, Microdilution MIC: 5–25 μg/ml (Feldman, Santos, & Grenier, 2011) Fusobacterium nucleatum 4‐Hydroxyonchocarpin (118) Dorstenia spp. Staphylococcus aureus Time‐kill kinetic MIC: 1–8 μg/ml (Dzoyem et al., 2013) Macatrichocarpins D (119) Macaranga trichocarpa Enterobacter aerogenes Broth microdilution MIC: 26.5 μM (Fareza et al., 2014)

3‐Hydroxychalcone (120) Pure Haemophilus influenzae Broth microdilution MBIC50 : 71.35 Antibiofilm (Kunthalert et al., 2014) Isobavachalcone (110) Artocarpus anisophyllus Staphylococcus aureus Disc diffusion ZI: 9.8 ± 0.65 mm (Jamil, 2014) MBC: 450 μg/ml Isobavachalcone (110) Psoralea corylifolia Staphylococcus aureus Liquid dilution MIC: 8 μg/ml (Cui et al., 2015) 2′,4′,4‐Trihydroxy‐3,6′‐ Piper delineatum Enterobacter aerogenes MIC: 500 μg/ml (Activity: (Martín‐Rodríguez et al., 2015) dimethoxychalchone (121) quorum sensing inhibition) Licochalcone A (122) Licorice Staphylococcus aureus Active Activity: (Wang et al., 2015) Licochalcone E (123) 1. Inhibit the biofilm formation and prevent yeast‐hyphal transition 2. Reduce the production of α‐toxin 4,4′,6′‐Trihydroxy 3 methoxy‐ Elatostema parasiticum Staphylococcs aureus Microdilution broth MIC: 1.95–7.8 μg/ml (Mariani et al., 2016) 3‐′pentene chalcone (124) Bacillus subtilis Ardisiaquinone (125) Pure Escherichia coli Colorimetric MIC: 125 μg/ml (Omosa et al., 2016) (Activity: combined to efflux pump inhibitor in the fight against MDR bacterial infections) FARHADI TAL ET . FARHADI TABLE 6 Antibacterial effect of synthetic compounds

Compounds Bacteria Method Activity Ref. TAL ET N‐{3‐[3‐Fluoro‐4‐(3‐pyridin‐2‐yl‐acryloyl)‐phenyl]‐ Staphylococcus aureus — MIC: 4–8 μg/ml (Selvakumar et al., 2007) 2‐oxo‐oxazolidin‐5‐ylmethyl}‐acetamide (126) . 3‐O‐octanoyl‐(−)‐epicatechin (127) Staphylococcus aureus Broth microdilution MIC: 50 μg/ml (Cushnie et al., 2007) 4‐Chloro‐flavanone (128) Escherichia coli MIC: 17 μg/ml (Fowler et al., 2011) Thiosemicarbazide derivatives (129) Salmonella typhimurium, Escherichia coli Disc diffusion ZI: 18.5, 18.6 mm (Asiri & Khan, 2012) 1‐(4‐Bromophenyl)‐3‐(3,4‐dimethoxyphenyl)‐3‐ Salmonella typhimurium Microwell dilution MIC: 1.95 μg/ml (Konduru et al., 2013) (phenylsulfonyl)propane‐1‐one (130), 1‐(4‐ bromophenyl)‐3‐(3,4,5‐trimethoxyphenyl)‐3‐ (phenylsulfonyl)propane‐1‐one (131), 1‐phenyl‐ 3‐phenyl‐3‐phenylsulfonylpropane‐1‐one (132) 1‐(Pyridine‐2‐yl)‐3‐(2‐hydroxyphenyl)‐2‐propene‐ Staphylococcus aureus Microdilution method MIC: 32–64 μg/ml (Tran, Nguyen, et al., 2012) 1‐one (133), 1‐(furan‐2‐yl)‐3‐(3‐hydroxyphenyl)‐ 2‐propene‐1‐one (134), 1‐(thiophene‐2‐yl)‐3‐ (2‐hydroxyphenyl)‐2‐propene‐1‐one (135) 4′‐Bromo‐2‐hydroxychalcone (136), 4‐ Staphylococcus aureus Disc diffusion MIC: 0.125–0.25 μg/ml (Tran, Do, et al., 2012) hydroxychalcone (137), 2′,2‐ dihydroxychalcone (138) 1‐(2′‐Hydroxy‐6′‐methoxy‐phenyl)‐3‐ Staphylococcus epidermidis Broth dilution method MIC: 37–150 μg/ml (Mallavadhani, Sahoo, (5‐dodecyl‐2‐methoxy‐phenyl)‐ Escherichia coli Kumar, & Murty, 2014) propen‐1‐one (139) (E)‐6‐ferrocenylvinyl‐chromen‐4‐one‐3‐ Staphylococcus aureus Liquid microdilution MIC: 32 μg/ml (Kowalski et al., 2013) propionic acid (140)

4′,7,8‐Trihydroxy isoflavene (141) Helicobacter pylori IC50 : 0.85 mM (Xiao et al., 2013) 4‐(6‐Hydroxyspiro [1,2,3,3a,9a‐ Staphylococcus aureus MIC: 20–40 μg/ml (Manner, Skogman, Goeres, pentahydrocyclopenta [1,2b]chromane‐ Vuorela, & Fallarero, 2013) 9,1′‐cyclopentane]‐3a‐yl)benzene‐1,3‐diol (143) 7‐O‐butyl naringenin (144) Helicobacter pylori Disc diffusion Inhibitory effect: 70.75 ± 3.56 (%) (Moon et al., 2013) 7‐O‐butyl naringenin (144) Staphylococcus aureus MIC: 0.625 μg/ml (K. A. Lee et al., 2013) 1,3‐Bis‐(2‐hydroxy‐phenyl)‐propenone (145) Staphylococcus aureus Biofilm production 6.25 μg/ml: 2/15 (Bozic et al., 2014) Naringenin‐ethylidene‐ciprofloxacin (146) Bacillus subtilis Colorimetric, MTT MIC: 0.062 μg/ml (Xiao et al., 2014) Thiosemicarbazide (147) Staphylococcus aureus Disk diffusion MIC: 16 μg/ml (Asiri & Khan, 2012) (E)‐3‐(2‐(allyloxy) phenyl)‐1‐(2,4,6‐ Staphylococcus aureus MIC: 0.39 μg/ml (Feng et al., 2014) trihydroxyphenyl)prop‐2‐en‐1‐one (148) 1, 3‐Dithiolium derivatives (149, 150) Staphylococcus aureus Disk diffusion MIC: 0.25–1 μg/ml (Bahrin et al., 2014) Escherichia coli Chrysin (151) Flavobacterium columnar MIC: 0.3 μg/ml (Tan, Schrader, Khan, & 5,7‐Dihydroxy‐4′‐methoxyflavone (152) Rimando, 2015) Tricyclic flavonoid derivatives (153) Staphylococcus aureus Microbroth dilution MIC: 0.24 and 3.9 μg/ml (Babii et al., 2016) Escherichia coli 2,3‐Dibromo‐1,3‐diphenylpropan‐1‐one Staphylococcus aureus Filter paper disc diffusion MIC: 6.25, 12.5 μg/ml (Alam et al., 2015) derivative (154) Enterococcus faecalis

(Continues) 17 18 FARHADI ET AL.

flavonols against S. aureus strains, (Figure 10), (Woźnicka et al., 2013). In addition, hydroxylation on the B and C rings also increases the antimicrobial activity of these compounds. For example, comparison of compounds with the same structure showed that kaempferol (55) with

arowska, 2016) a hydroxy group at C‐4′ had less activity than galangin (44; without Ż

Aksöz et al., 2015) OH at C‐4′) against S. aureus (Echeverría et al., 2017). ‐ The number of glycosylic group instead of the hydroxy group at position 3 also plays an important role on antibacterial activity. For example, among the compounds extracted from Maytenus buchananii, quercetin‐3‐O‐[α‐L‐rhamnopyranosyl‐(1 → 6)‐β‐D glucopyranoside] (9) with a disaccharide group at the same position was the better g/ml (Li et al., 2017) μ inhibitor of S. aureus growth than amentoflavone‐7″,4‴‐dimethyl‐ ether (6) with monosaccharide group (quercetin‐3‐O‐β‐D‐ glucopyranoside; Tebou et al., 2017). Substitution that decrease g/ml (Xiao et al., 2017)

g/ml (Patel & Patel, 2017) activity is methoxylation at position 3. For example, piliostigmol (with μ μ OMe and Me groups at position 6 and 7 of A ring and OH at g/ml (Evranos g/ml (Zainuri et al., 2017) 100 μ μ – position 3) was more active against S. aureus than 6‐C‐ methylquercetin‐3,3′,7‐trimethyl ether (163; with OMe at the C‐3 position; Babajide et al., 2008). MIC: 1.25 ± 0.01, 1.15 ± 0.12

5.4 | Flavones

As it was mentioned in many studies have been conducted on antibacterial activity of flavones (Hung et al., 2008; Novak et al., 2012; Xiao et al., 2011), possessing at least one hydroxy group in the ring A (especially at C‐7) is vital for antibacterial activity, and in another position such as C‐5 and C‐6 can increase the activity (Figure 11; Wu et al., MTT proliferation MIC: 11, 29, 59 Broth dilution MIC: 8.16 Disc diffusion ZI: 6.84 mm (Stompor & Microwell dilution MIC: 250 Broth dilution method MIC: 62.5 2013). Also, substitution of OH with OMe at C‐7 decrease the activity. For instance, between 5,7‐dihydroxy‐flavone (11) with two OH at positions 5 and 7 and 5‐hydroxy‐7‐methoxy‐flavone (10) with OMe at position 7 and OH at position 5, compound 11 was more potent against Ralstonia solanacearum (MIC: 25 and 300 μg/ml; Zhong et al., 2012). Presence of the prenyl (C5) group at position 6 without cyclization of this substituent with A ring has also been reported to improve antibacterial activity. As an example, Kuete et al. (2009) showed that the antibacterial activity of artocarpesine (164) toward E. coli was much higher than cycloatocarpesin (8; MIC: 39, 156 μg/ml).

6 | MECHANISM OF ANTIBACTERIAL Escherichia coli Pseudomonas aeruginosa Staphylococcus aureus Enterococcus faecalis Staphylococcus aureus Staphylococcus aureus Escherichia coli Staphylococcus aureus Staphylococcus aureus Staphylococcus epidermidis Escherichia coli ACTIVITY

) The proposed antibacterial mechanisms of flavonoids are mainly as ‐ ‐ ‐ ‐ ‐ 162 ) ‐ follows: nucleic acid synthesis inhibition, alteration in cytoplasmic ) en yl) ‐ ‐ 2 158 2 one ( ‐ membrane function, energy metabolism inhibition, reduction in cell ‐ methyl 160 ‐ ‐ (thiophen 4 ‐ ‐ (4

‐ attachment and biofilm formation, inhibition of the porin on the cell (4 6 ‐ ‐ morpholino 3 fluorophenyl) ‐ ‐ ‐ membrane, changing of the membrane permeability, attenuation of yl) tolylprop ‐ (2 (4 ‐ pyrimidin ‐ ‐ iodophenyl)prop ‐ 2 p ‐ ‐ 7 ‐ the pathogenicity (Cushnie & Lamb, 2005a, 2005b; Cushnie & Lamb, ‐ 3 (4 ), 2 ) ‐ ‐ methyl ‐ yl)thiazolidin 3 2011; Xie et al., 2015), cytoplasmic membrane damage (possibly by ‐ ‐ 5 dihydroflavone ( ‐ 161 2 156 ‐ phenyl) ‐ ‐ ) ), Chalconaringenin ( generating hydrogen peroxide [Cushnie & Lamb, 2005a, 2005b]) with hydroxy (thiophen 2, 3 ‐ ′‐ ‐ one ( 159 4 ‐ 157 ‐ ‐

(4 flavonols (Cushnie & Lamb, 2005a, 2005b), flavan 3 ol, and flavanol ‐ ) ‐ 4 ‐ methyl 3 ‐ ‐

pyrimidin compounds (Tamba et al., 2007). It was shown that combination of one ( (Continued) (4 ‐ 155 ‐ ‐ hydroxyphenyl) bromophenyl) ‐ 1 6 ‐ ‐ ‐ ceftazidime and apigenin damages cytoplasmic membrane of ceftazi- (4 Hydroxy (4 Hydroxyphenyl) yl) one ( methyl en oxoethoxy) ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 1 5 1 ‐ ‐ 2 1 thiazolidin 5 2 ‐ phenyl) 2 ‐ dime resistant Enterobacter cloacae and causes subsequent leakage of (2 ) ) ‐ E E Compounds( Bacteria Method Activity Ref. 2 Chrysin derivatives ( Xanthohumol ( ( (S)

TABLE 6 intracellular components (Eumkeb & Chukrathok, 2013). Inhibition of FARHADI ET AL. 19

FIGURE 6 Chemical structures of synthetic derivatives of flavonoids

nucleic acid synthesis (through inhibition of topoisomerase) and Inhibition of the quorum‐sensing (cell‐to‐cell communication system dihydrofolate reductase by flavan‐3‐ols and isoflavones. Decreasing in biofilm formation) signal receptors TraR and RhlR (Zeng et al., the energy metabolism with flavonols, flavan‐3‐ols, and flavones clas- 2008). In the new research findings, additional evidence has been ses (Chinnam et al., 2010; Gradišar, Pristovšek, Plaper, & Jerala, presented in support of each of the mechanisms. The antimicrobial 2007; Wang, Wang, & Xie, 2010). Suppression of cell wall synthesis potential of two bioflavonoids was evaluated by scanning electron (caused by D‐alanine–D‐alanine ligase inhibition; Wu et al., 2008). microscopy (Biva, Ndi, Griesser, & Semple, 2016) against B. subtilis, Sophoraflavanone B caused cell wall weakening and consequently S. aureus, E. coli, and S. typhimurium. The result showed the bactericidal membrane damage had occurred and intracellular constituents leaked effect of 5,7‐dihydroxy‐4,6,8‐trimethoxyflavone (13; Figure 12) from the cell (Mun et al., 2014). Inhibition of cell membrane synthesis against E. coli and S. aureus, whereas 5,6‐dihydroxy‐4,7,8‐ (caused by inhibition of FabG, FabI, FabZ, Rv0636, or KAS III; Jeong trimethoxyflavone (14) was found to effectively kill B. subtilis by cell et al., 2009; Li, Zhang, Du, Sun, & Tian, 2006; Zhang et al., 2008). Inhi- lysis (Brahmachari et al., 2011). When screening natural products for bition of enzymes such as dihydrofolate reductase (Navarro‐Martínez inhibition of β‐ketoacyl acyl carrier protein synthase (Chitsazian‐Yazdi et al., 2005), listeriolysin O (Ruddock et al., 2011; virulence factor et al., 2015), Lee et al. (2011) found that the 3,6‐dihydroxyflavone (50) of the intracellular pathogen L. monocytogenes; Kohda, Yanagawa, & was very effective. This compound inhibition activity against a Shimamura, 2008; Shi & Czuprynski, 2009), and urease (secretion β‐ketoacyl acyl carrier protein synthase of multidrug‐resistant E. coli. from H. pylori at the low pH of the stomach; Xiao et al., 2007). Inhi- It was shown that compound 50 selectively inhibited β‐ketoacyl acyl bition of sortase (the enzymes that catalyze the assembly of surface carrier protein synthase III and I (important for fatty acid synthesis in proteins at Gram‐positive bacteria; Maresso & Schneewind, 2008). bacteria). 20 FARHADI ET AL.

FIGURE 6 Continued.

A synthetic flavanone, 4‐chloro‐flavanone (128) has been three flavonoids were isolated from Dorstenia species. Flavonoids reported to inhibit efflux pump and reduce the growth ability of E. coli responsible for this activity were 6,8‐diprenyleriodictyol (95), with MIC value of 70 μg/ml (Fowler, Shah, Panepinto, Jacobs, & isobavachalcone (110), and 4‐hydroxyonchocarpin (118). Koffas, 2011). It was shown that baicalein could remarkably reverse the cipro- In the study of antibacterial activity (against Gram‐positive and floxacin resistance of MRSA possibly by NorA efflux pump inhibitory Gram‐negative bacteria) by radioactive precursors, Dzoyem et al. effect. Additionally, the inhibition of MRSA pyruvate kinase could lead (2013) showed that DNA, RNA, and protein synthesis inhibited by to a deficiency of ATP (Chan et al., 2011). A research team (Wu et al., 2013) reported the MOA of five flavonoids against E. coli. These compounds were effective via rigidifying the liposomal membrane. The authors suggested that the molecular hydrophobicity (C log P) and charges on the C atom at position 3 may play a role in the intercalation of liposomal model membranes (Wu et al., 2013). He et al. (2014) screened antimicrobial mechanism of flavonoids [kaempferol (55), hesperetin (170)] for inhibitory activity against E. coli through the cell membranes and liposomal model. They found that interaction between the polar head‐group of the model membrane and the hydrophobic regions may damage E. coli membrane. In the other study, FIGURE 7 Structure–activity relationship of chalcones Wang et al. (2014) carried out research on genistein (171) and FARHADI ET AL. 21

FIGURE 8 Structure–activity relationship of flavans

FIGURE 9 Structure–activity relationship of flavanols

diosmetin (25) from Sophora moorcroftiana against S. aureus by efflux testing bacteria (Amin et al., 2015). Evaluation of the MOA of flavo- assay. The results showed that genistein inhibited NorA efflux protein noid compounds from Piper species [174 and 2′,4′,4‐trihydroxy‐3,6′‐ of S. aureus. In another study, the mode of action of genistein on dif- dimethoxychalchone (121)] against Vibrio harveyi exhibited a strong ferent bacterial cells was investigated and the results showed that cell dose‐dependent inhibition of biofilm formation without effect on bac- morphology of bacteria changed. Additionally, significant inhibition of terial growth up to 500 μM (Martín‐Rodríguez et al., 2015). In the global synthesis of DNA and RNA was observed immediately after study of three flavonoids [techtochrysin (30), negletein (31), and addition of this compound to a bacterial culture (Ulanowska, Tkaczyk, quercitin‐3‐glucoside (65)] against foodborne pathogens, 90–95% Konopa, & Wȩgrzyn, 2006). Twenty‐one synthetic fluoroquinolone‐ reduction in biofilms was observed (Rajendran et al., 2016). Synthe- flavonoid hybrids were evaluated against drug‐resistant microorgan- sized tricyclic flavonoid (153) at low concentration caused not only isms (including E. coli, B. subtilis, and S. aureus) by DNA gyrase and the inhibition of bacterial growth (MIC: 0.24 μg/ml) but also killing efflux pump. Two compounds (172 and 173) could inhibit DNA gyrase bacterial cells via cell membrane integrity and cell agglutination (Babii and efflux pump (Xiao et al., 2014). Flavonostilbenes (83) exhibit anti- et al., 2016). For investigating the development of new antibiotics, one bacterial and antibiofilm formation activities against S. epidermidis with promising strategy is inhibition of type 2 fatty acid synthase pathway MIC values of 3.1 to 12.5 μg/ml (Wan et al., 2015). It has also been (FAS II; essential for the synthesis of fatty acids). Jaceosidin (38; from demonstrated by Wan et al. that the chalcone compounds [such as Artemisia californica) was evaluated against E. coli, and this compound ardisiaquinone (125)] were active against MRSA strains by inhibition indicated complete inhibition of FabI activity at the concentration of of bacterial efflux pumps (Omosa et al., 2016). In the dose–response 100 μM (Allison et al., 2017). In 2017, the enzyme assays of 20 C‐7 assay, kaempferol (55) at 31.25 μg/ml concentration was found to modified flavonoids for inhibition tyrosyl‐tRNA synthetase in Gram‐ be better efflux pump inhibitor by inhibiting NorA pump in S. aureus positive and Gram‐negative organism revealed that (S)‐5‐hydroxy‐ (Randhawa, Hundal, Ahirrao, Jachak, & Nandanwar, 2016). In the 40‐hydroxy‐7‐(2‐morpholino‐2‐oxoethoxy)‐2,3‐dihydroflavone (160) study of 2015, the combination of morin (45), rutin (49), and quercetin (48) could release the potassium from the cytoplasmic membrane of

FIGURE 10 Structure–activity relationship of flavonols FIGURE 11 Structure–activity relationship of flavones 22 FARHADI ET AL.

FIGURE 12 Chemical structures of flavonoids derivatives

exhibited better activity against Gram‐negative organism with IC50 derivative of flavonoids (129) with heterocyclic furan ring was found lower than 1 mM (Xiao et al., 2017). to be more active than the reference drug chloramphenicol against S. typhimurium and E. coli. Sulfone and bisulfone chalcone synthetic derivatives are other examples of synthetic derivatives that showed 7 | CONCLUSION higher activity than reference drugs that have been used in the market. These findings and many others show that synthetic derivatiza- Since 2005, many studies have been conducted on antibacterial activ- tion of flavonoids is a promising approach for finding new antibiotics ity of different classes of flavonoids, and many others will be added to in the future studies. this list in the future. The main focus of previous studies was on However, the main gap in this research area is the lack of clin- assessment of antibacterial activity of isolated flavonoids on different ical trials. Some of the flavonoids have been clinically tested for bacteria strains specially MRSA and E. coli. Chalcones in some cases other ailments and showed minimum adverse effects. For instance, showed stronger activities than other classes and some of them like quercetin has been used in many clinical trials (not for antibacterial 3‐Hydroxychalcone (120) exhibited approximately sixfold more activ- activity) and passed phase 1 clinical trials successfully. Quercetin ity than the reference drug azithromycin on H. influenza. The results showed remarkable synergistic activity in combination with refer- were obtained from antibacterial activity of flavonoids of the genus ence drugs and can be safely used for further studies in the future. Dorstenia showed that considering traditional usage of plants can be Many other flavonoids can also be added to the list for future helpful for finding active antibacterial flavonoids. Isobavachalcone clinical studies. (110) from twigs of Dorstenia barteri showed fourfold lower MIC value than the conventional drug gentamicin. ACKNOWLEDGMENT In addition, synthetic derivatization of flavonoids showed sub- This study was partially supported by the Mashhad University of Med- stantial increase in antibacterial activity of flavonoids. A pyrazoline ical Sciences. FARHADI ET AL. 23

CONFLICT OF INTEREST Biloa Messi, B., Ho, R., Meli Lannang, A., Cressend, D., Perron, K., Nkengfack, A. E., … Cuendet, M. (2014). Isolation and biological activity The authors declare no conflicts of interest. of compounds from Garcinia preussii. Pharmaceutical Biology, 52(6), 706–711. ORCID Bitchagno, G. T. M., Tankeo, S. B., Tsopmo, A., Mpetga, J. D. S., Tchinda, A. T., Fobofou, S. A. T., … Tane, P. (2016). Ericoside, a new antibacterial Mehrdad Iranshahi http://orcid.org/0000-0002-3018-5750 biflavonoid from Erica mannii (Ericaceae). Fitoterapia, 109, 206–211. Milad Iranshahy http://orcid.org/0000-0002-5339-6294 Bitchagno, G. T. M., Tankeo, S. B., Tsopmo, A., Mpetga, J. D. S., Tchinda, A. T., Fobofou, S. A. T., … Tane, P. (2015). Lemairones A and B: Two new REFERENCES antibacterial tetraflavonoids from the leaves of Zanthoxylum lemairei Aderogba, M. A., Ndhlala, A. R., Rengasamy, K. R., & Van Staden, J. (2013). (Rutaceae). Phytochemistry Letters, 14,1–7. https://doi.org/10.1016/j. Antimicrobial and selected in vitro enzyme inhibitory effects of leaf phytol.2015.08.012 extracts, flavonols and indole alkaloids isolated from Croton Biva, I. J., Ndi, C. P., Griesser, H. J., & Semple, S. J. (2016). Antibacterial con- – menyharthii. Molecules, 18(10), 12633 12644. stituents of Eremophila alternifolia: An Australian aboriginal traditional Alam, M. S., Rahman, S. M., & Lee, D.‐U. (2015). Synthesis, biological eval- medicinal plant. Journal of Ethnopharmacology, 182,1–9. ‐ uation, quantitative SAR and docking studies of novel chalcone Bozic, D. D., Milenkovic, M., Ivkovic, B., & Cirkovic, I. (2014). Newly‐syn- derivatives as antibacterial and antioxidant agents. Chemical Papers, thesized chalcones‐inhibition of adherence and biofilm formation of – 69(8), 1118 1129. methicillin‐resistant Staphylococcus aureus. Brazilian Journal of Microbi- Allison, B. J., Allenby, M. C., Bryant, S. S., Min, J. E., Hieromnimon, M., & ology, 45(1), 263–270. Joyner, P. M. (2017). Antibacterial activity of fractions from three Chu- Brahmachari, G., Mandal, N. C., Jash, S. K., Roy, R., Mandal, L. C., mash medicinal plant extracts and in vitro inhibition of the enzyme Mukhopadhyay, A., … Gangopadhyay, A. (2011). Evaluation of the anti- enoyl reductase by the flavonoid jaceosidin. Natural Product Research, microbial potential of two flavonoids isolated from Limnophila plants. – 31(6), 707 712. Chemistry & Biodiversity, 8(6), 1139–1151. ‐ Almutairi, S., Edrada Ebel, R., Fearnley, J., Igoli, J. O., Alotaibi, W., Cai, W., Fu, Y., Zhang, W., Chen, X., Zhao, J., Song, W., … Zhang, F. (2016). … Clements, C. J., Watson, D. G. (2014). Isolation of diterpenes and fla- Synergistic effects of baicalein with cefotaxime against Klebsiella vonoids from a new type of propolis from Saudi Arabia. Phytochemistry pneumoniae through inhibiting CTX‐M‐1 gene expression. BMC Micro- – Letters, 10, 160 163. biology, 16(1), 181. https://doi.org/10.1186/s12866‐016‐0797‐1 ‐ Al Shabib, N. A., Husain, F. M., Ahmad, I., Khan, M. S., Khan, R. A., & Khan, Carbonezi, C. A., Hamerski, L., Gunatilaka, A., Cavalheiro, A., Castro‐ ‐ J. M. (2017). Rutin inhibits mono and multi species biofilm formation Gamboa, I., Silva, D. H. S., … Bolzani, V. S. (2007). Bioactive flavone by foodborne drug resistant Escherichia coli and Staphylococcus aureus. dimers from Ouratea multiflora (Ochnaceae). Revista Brasileira de – Food Control, 79, 325 332. Farmacognosia, 17(3), 319–324. Alvarez, M., Debattista, N., & Pappano, N. (2008). Antimicrobial activity Casero, C., Machín, F., Méndez‐Álvarez, S., Demo, M., Ravelo, A. G., Pérez‐ and synergism of some substituted flavonoids. Folia Microbiologica, Hernández, N., … Estévez‐Braun, A. (2014). Structure and antimicrobial – 53(1), 23 28. activity of phloroglucinol derivatives from Achyrocline satureioides. Amin, M. U., Khurram, M., Khattak, B., & Khan, J. (2015). Antibiotic additive Journal of Natural Products, 78(1), 93–102. and synergistic action of rutin, morin and quercetin against methicillin Cha, J. D., Moon, S. E., Kim, J. Y., Jung, E. K., & Lee, Y. S. (2009). Antibac- resistant Staphylococcus aureus. BMC Complementary and Alternative terial activity of sophoraflavanone G Isolated from the roots of Sophora Medicine, 15(1), 59. flavescens against methicillin‐resistant Staphylococcus aureus. An, J., Zuo, G., Hao, X., Wang, G., & Li, Z. (2011). Antibacterial and synergy Phytotherapy Research, 23(9), 1326–1331. of a flavanonol rhamnoside with antibiotics against clinical isolates of Chan, B. C., Ip, M., Lau, C. B., Lui, S. L., Jolivalt, C., Ganem‐Elbaz, C., … ‐ methicillin resistant Staphylococcus aureus (MRSA). Phytomedicine, Leung, P. C. (2011). Synergistic effects of baicalein with ciprofloxacin – 18(11), 990 993. against NorA over‐expressed methicillin‐resistant Staphylococcus Asiri, A. M., & Khan, S. A. (2012). Synthesis, characterization, and in vitro aureus (MRSA) and inhibition of MRSA pyruvate kinase. Journal of antibacterial activities of macromolecules derived from bis‐chalcone. Ethnopharmacology, 137(1), 767–773. – Journal of Heterocyclic Chemistry, 49(6), 1434 1438. Chan, E. W. L., Gray, A. I., Igoli, J. O., Lee, S. M., & Goh, J. K. (2014). Atta, E., Hashem, A., & Eman, R. E.‐S. (2013). A novel flavonoid compound Galloylated flavonol rhamnosides from the leaves of Calliandra from Farsetia aegyptia and its antimicrobial activity. Chemistry of Natu- tergemina with antibacterial activity against methicillin‐resistant Staph- ral Compounds, 49(3), 432–436. ylococcus aureus (MRSA). Phytochemistry, 107, 148–154. Babajide, O. J., Babajide, O. O., Daramola, A. O., & Mabusela, W. T. (2008). Chen, J., Li, Y., Yang, L.‐Q., Li, Y.‐Z., Nan, Z.‐B., & Gao, K. (2012). Biological Flavonols and an oxychromonol from Piliostigma reticulatum. Phyto- activities of flavonoids from pathogenic‐infected Astragalus adsurgens. chemistry, 69(11), 2245–2250. Food Chemistry, 131(2), 546–551. Babii, C., Bahrin, L., Neagu, A. N., Gostin, I., Mihasan, M., Birsa, L., & Stefan, Chen, Y., Liu, T., Wang, K., Hou, C., Cai, S., Huang, Y., … Chen, Y. (2016). M. (2016). Antibacterial activity and proposed action mechanism of a Baicalein inhibits Staphylococcus aureus biofilm formation and the quo- new class of synthetic tricyclic flavonoids. Journal of Applied Microbiol- rum sensing system in vitro. PLoS One, 11(4). – ogy, 120(3), 630 637. Chinnam, N., Dadi, P. K., Sabri, S. A., Ahmad, M., Kabir, M. A., & Ahmad, Z. Bahrin, L. G., Apostu, M. O., Birsa, L. M., & Stefan, M. (2014). The antibac- (2010). Dietary bioflavonoids inhibit Escherichia coli ATP synthase in a terial properties of sulfur containing flavonoids. Bioorganic & Medicinal differential manner. International Journal of Biological Macromolecules, Chemistry Letters, 24(10), 2315–2318. 46(5), 478–486. Bakar, N. S., Zin, N. M., & Basri, D. F. (2012). Synergy of flavone with van- Chitsazian‐Yazdi, M., Agnolet, S., Lorenz, S., Schneider, B., Es'haghi, Z., comycin and oxacillin against vancomycin‐intermediate Staphyloccus Kasaian, J., … Iranshahi, M. (2015). Foetithiophenes C‐F, thiophene aureus. Pakistan Journal of Pharmaceutical Sciences, 25, 633–638. derivatives from the roots of Ferula foetida. Pharmaceutical Biology, 53(5), 710–714. Barbieri, R., Coppo, E., Marchese, A., Daglia, M., Sobarzo‐Sánchez, E., Nabavi, S. F., & Nabavi, S. M. (2017). Phytochemicals for human dis- Chou, T. H., Chen, J. J., Peng, C. F., Cheng, M. J., & Chen, I. S. (2011). New ease: An update on plant‐derived compounds antibacterial activity. flavanones from the leaves of Cryptocarya chinensis and their antituber- Microbiological Research, 196,44–68. culosis activity. Chemistry & Biodiversity, 8(11), 2015–2024. 24 FARHADI ET AL.

Christopher, R., Nyandoro, S., Chacha, M., & de Koning, C. (2014). A new Fareza, M. S., Syah, Y. M., Mujahidin, D., Juliawaty, L. D., & Kurniasih, I. cinnamoylglycoflavonoid, antimycobacterial and antioxidant constitu- (2014). Antibacterial flavanones and dihydrochalcones from Macaranga ents from Heritiera littoralis leaf extracts. Natural Product Research, trichocarpa. Zeitschrift für Naturforschung, 69(9–10), 375–380. 28(6), 351–358. Farooq, S., Wahab, A. T., Fozing, C., Rahman, A. U., & Choudhary, M. I. Chukwujekwu, J., Van Heerden, F., & Van Staden, J. (2011). Antibacterial (2014). Artonin I inhibits multidrug resistance in Staphylococcus aureus activity of flavonoids from the stem bark of Erythrina caffra thunb. and potentiates the action of inactive antibiotics in vitro. Journal of Phytotherapy Research, 25(1), 46–48. Applied Microbiology, 117(4), 996–1011. Cui, Y., Taniguchi, S., Kuroda, T., & Hatano, T. (2015). Constituents of Favela‐Hernández, J., García, A., Garza‐González, E., Rivas‐Galindo, V., & Psoralea corylifolia fruits and their effects on methicillin‐resistant Camacho‐Corona, M. (2012). Antibacterial and antimycobacterial staphylococcus aureus. Molecules, 20(7), 12500–12511. lignans and flavonoids from Larrea tridentata. Phytotherapy Research, Cushnie, T., Hamilton, V., Chapman, D., Taylor, P., & Lamb, A. (2007). 26(12), 1957–1960. Aggregation of Staphylococcus aureus following treatment with the Feldman, M., Santos, J., & Grenier, D. (2011). Comparative evaluation of antibacterial flavonol galangin. Journal of Applied Microbiology, 103(5), two structurally related flavonoids, isoliquiritigenin and liquiritigenin, – 1562 1567. for their oral infection therapeutic potential. Journal of Natural Prod- Cushnie, T., & Lamb, A. (2006). Assessment of the antibacterial activity of ucts, 74(9), 1862–1867. ‐ galangin against 4 quinolone resistant strains of Staphylococcus aureus. Feng, L., Maddox, M. M., Alam, M. Z., Tsutsumi, L. S., Narula, G., Bruhn, D. – Phytomedicine, 13(3), 187 191. F., … Simmons, C. J. (2014). Synthesis, structure–activity relationship Cushnie, T., Taylor, P., Nagaoka, Y., Uesato, S., Hara, Y., & Lamb, A. (2008). studies, and antibacterial evaluation of 4‐chromanones and chalcones, Investigation of the antibacterial activity of 3‐O‐octanoyl‐(−)‐epicate- as well as olympicin A and derivatives. Journal of Medicinal Chemistry, chin. Journal of Applied Microbiology, 105(5), 1461–1469. 57(20), 8398–8420. Cushnie, T. T., & Lamb, A. J. (2005a). Antimicrobial activity of flavonoids. Fowler, Z. L., Shah, K., Panepinto, J. C., Jacobs, A., & Koffas, M. A. (2011). International Journal of Antimicrobial Agents, 26(5), 343–356. Development of non‐natural flavanones as antimicrobial agents. PLoS One, 6(10), e25681. Cushnie, T. T., & Lamb, A. J. (2005b). Detection of galangin‐induced cytoplasmic membrane damage in Staphylococcus aureus by measuring Frieri, M., Kumar, K., & Boutin, A. (2016). Antibiotic resistance. Journal of potassium loss. Journal of Ethnopharmacology, 101(1), 243–248. Infection and Public Health. https://doi.org/10.1016/j.jiph.2016.08.007 Cushnie, T. T., & Lamb, A. J. (2011). Recent advances in understanding the Geoghegan, F., Wong, R., & Rabie, A. (2010). Inhibitory effect of quercetin antibacterial properties of flavonoids. International Journal of Antimicro- on periodontal pathogens in vitro. Phytotherapy Research, 24(6), bial Agents, 38(2), 99–107. 817–820. Drewes, S. E., & van Vuuren, S. F. (2008). Antimicrobial acylphloroglucinols Gopikrishnan, V., Radhakrishnanauthor, M., Shanmugasundaramauthor, T., and dibenzyloxy flavonoids from flowers of Helichrysum gymnocomum. Pazhanimuruganauthor, R., & Balagurunathanauthor, R. (2015). – Phytochemistry, 69(8), 1745 1749. Antibiofouling potential of quercetin compound from marine‐derived Dzoyem, J. P., Hamamoto, H., Ngameni, B., Ngadjui, B. T., & Sekimizu, K. actinobacterium, Streptomyces fradiae PE7and its characterization. (2013). Antimicrobial action mechanism of flavonoids from Dorstenia Environmental Science and Pollution Research. – species. Drug Discoveries & Therapeutics, 7(2), 66 72. Gradišar, H., Pristovšek, P., Plaper, A., & Jerala, R. (2007). Green tea cate- Dzoyem, J. P., Melong, R., Tsamo, A. T., Tchinda, A. T., Kapche, D. G., chins inhibit bacterial DNA gyrase by interaction with its ATP binding Ngadjui, B. T., … Eloff, J. N. (2017). Cytotoxicity, antimicrobial and anti- site. Journal of Medicinal Chemistry, 50(2), 264–271. oxidant activity of eight compounds isolated from Entada abyssinica Hassanzadeh, M., Rahimizadeh, M., Bazzaz, B. S. F., Emami, S. A., & Assili, J. (Fabaceae). BMC Research Notes, 10(1), 118. (2001). Chemical and antimicrobial studies of Platycladus orientalis Echeverría, J., Opazo, J., Mendoza, L., Urzúa, A., & Wilkens, M. (2017). essential oils. Pharmaceutical Biology, 39(5), 388–390. Structure‐activity and lipophilicity relationships of selected antibacte- He, M., Wu, T., Pan, S., & Xu, X. (2014). Antimicrobial mechanism of flavo- rial natural flavones and flavanones of Chilean flora. Molecules, 22(4), noids against Escherichia coli ATCC 25922 by model membrane study. 608. Applied Surface Science, 305, 515–521. Edziri, H., Mastouri, M., Mahjoub, M. A., Mighri, Z., Mahjoub, A., & Hirai, I., Okuno, M., Katsuma, R., Arita, N., Tachibana, M., & Yamamoto, Y. Verschaeve, L. (2012). Antibacterial, antifungal and cytotoxic activities (2010). Characterisation of anti‐Staphylococcus aureus activity of of two flavonoids from Retama raetam flowers. Molecules, 17(6), quercetin. International Journal of Food Science and Technology, 45(6), 7284–7293. 1250–1254. El‐Aasr, M., Kabbash, A., El‐Seoud, K. A. A., Al‐Madboly, A., & Ikeda, T. … (2016). Antimicrobial and immunomodulatory activities of flavonol gly- Hung, T. M., Na, M., Dat, N. T., Ngoc, T. M., Youn, U., Kim, H. J., Bae, K. ‐ cosides isolated from Atriplex halimus L. Herb. International Journal of (2008). Cholinesterase inhibitory and anti amnesic activity of alkaloids Pharmaceutical Sciences and Research, 8, 1159–1168. from Corydalis turtschaninovii. Journal of Ethnopharmacology, 119(1), 74–80. Eumkeb, G., & Chukrathok, S. (2013). Synergistic activity and mechanism of action of ceftazidime and apigenin combination against ceftazi- Iranshahi, M., Fata, A., Emami, B., Jalalzadeh Shahri, B. M., & Bazzaz, B. S. F. ‐ dime‐resistant Enterobacter cloacae. Phytomedicine, 20(3–4), 262–269. (2008). In vitro antifungal activity of polysulfides rich essential oil of Ferula latisecta fruits against human pathogenic dermatophytes. Natu- ‐ Eumkeb, G., Sakdarat, S., & Siriwong, S. (2010). Reversing beta lactam anti- ral Product Communications, 3, 1543–1546. biotic resistance of Staphylococcus aureus with galangin from Alpinia officinarum Hance and synergism with ceftazidime. Phytomedicine, Iranshahi, M., Hassanzadeh‐Khayat, M., Bazzaz, B. S. F., Sabeti, Z., & 18(1), 40–45. https://doi.org/10.1016/j.phymed.2010.09.003 Enayati, F. (2008). High content of polysulphides in the volatile oil of Ferula latisecta Rech. F. et Aell. fruits and antimicrobial activity of the Evranos‐Aksöz, B., Onurdağ, F. K., & Özgacar, S. Ö. (2015). Antibacterial, oil. Journal of Essential Oil Research, 20(2), 183–185. antifungal and antimycobacterial activities of some pyrazoline, hydrazone and chalcone derivatives. Zeitschrift für Naturforschung, Jamil, S. (2014). Antimicrobial Flavonoids from Artocarpus anisophyllus Miq 70(7–8), 183–189. and Artocarpus lowii King. J Teknol, 71(1), 95–99. Fan, Q.‐F., Hu, Z.‐Y., Na, Z., Tang, H.‐S., Zuo, G.‐Y., & Song, Q.‐S. (2015). Jeong, K.‐W., Lee, J.‐Y., Kang, D.‐I., Lee, J.‐U., Shin, S. Y., & Kim, Y. (2009). One new flavonoid from Oroxylum indicum. Natural Product Research, Screening of flavonoids as candidate antibiotics against Enterococcus 29(19), 1828–1832. faecalis. Journal of Natural Products, 72(4), 719–724. FARHADI ET AL. 25

Kanwal, Q., Hussain, I., Siddiqui, L. H., & Javaid, A. (2011). Antimicrobial Lee, J.‐Y., Lee, E., Jeong, K.‐W., & Kim, Y. (2011). Antimicrobial flavonoid, 3, activity screening of isolated flavonoids from Azadirachta indica leaves. 6‐dihydroxyflavone, have dual inhibitory activity against KAS III and Journal of the Serbian Chemical Society, 76(3), 375–384. KAS I. Bulletin of the Korean Chemical Society, 32(9), 3219. Katerere, D. R., Gray, A. I., Nash, R. J., & Waigh, R. D. (2012). Phytochem- Lee, K. A., Moon, S.‐H., Lee, J.‐Y., Kim, K.‐T., Park, Y.‐S., & Paik, H.‐D. ical and antimicrobial investigations of stilbenoids and flavonoids (2013). Antibacterial activity of a novel flavonoid, 7‐O‐butyl naringenin, isolated from three species of Combretaceae. Fitoterapia, 83(5), against methicillin‐resistant Staphylococcus aureus (MRSA). Food Sci- 932–940. ence and Biotechnology, 22(6), 1725–1728. Kengap, R. T., Kapche, G. D., Dzoyem, J. P., Simo, I. K., Ambassa, P., Sandjo, Li, B.‐H., Zhang, R., Du, Y.‐T., Sun, Y.‐H., & Tian, W.‐X. (2006). Inactivation L. P., … Ngadjui, B. T. (2011). Isoprenoids and flavonoids with antimi- mechanism of the β‐ketoacyl‐[acyl carrier protein] reductase of bacte- crobial activity from Ficus conrauiWarburg (Moraceae). Helvetica rial type‐II fatty acid synthase by epigallocatechin gallate. Biochemistry Chimica Acta, 94(12), 2231–2238. and Cell Biology, 84(5), 755–762. https://doi.org/10.1139/o06‐047 Khameneh, B., Diab, R., Ghazvini, K., & Fazly Bazzaz, B. S. (2016). Break- Li, H. X., Wang, Z. C., Qian, Y. M., Yan, X. Q., Lu, Y. D., & Zhu, H. L. (2017). throughs in bacterial resistance mechanisms and the potential ways Design, synthesis, and biological evaluation of chrysin derivatives as to combat them. Microbial Pathogenesis, 95,32–42. potential FabH inhibitors. Chemical Biology & Drug Design, 89(1), – Khan, S. A., Asiri, A. M., & Elroby, S. A. (2014). Green synthesis, character- 136 140. ization, antibacterial activity of heterocyclic compounds from chalcone Li, W., Cai, C.‐H., Dong, W.‐H., Guo, Z.‐K., Wang, H., Mei, W.‐L., & Dai, H.‐F. on basis of in vitro and quantum chemistry calculation. Asian Journal of (2014). 2‐(2‐Phenylethyl) chromone derivatives from Chinese agarwood Chemistry, 26(21), 7283. induced by artificial holing. Fitoterapia, 98, 117–123. https://doi.org/ Kohda, C., Yanagawa, Y., & Shimamura, T. (2008). Epigallocatechin gallate 10.1016/j.fitote.2014.07.011 inhibits intracellular survival of Listeria monocytogenes in macrophages. Lopes, L. A. A., dos Santos Rodrigues, J. B., Magnani, M., de Souza, E. L., & Biochemical and Biophysical Research Communications, 365(2), 310–315. de Siqueira‐Júnior, J. P. (2017). Inhibitory effects of flavonoids on bio- Konduru, N. K., Dey, S., Sajid, M., Owais, M., & Ahmed, N. (2013). Synthe- film formation by Staphylococcus aureus that overexpresses efflux – sis and antibacterial and antifungal evaluation of some chalcone based protein genes. Microbial Pathogenesis, 107, 193 197. sulfones and bisulfones. European Journal of Medicinal Chemistry, 59, Luo, J., Kong, J. L., Dong, B. Y., Huang, H., Wang, K., Wu, L. H., … Chen, Y. 23–30. Q. (2016). Baicalein attenuates the quorum sensing‐controlled viru- Kong, N.‐N., Fang, S.‐T., Liu, Y., Wang, J.‐H., Yang, C.‐Y., & Xia, C.‐H. lence factors of Pseudomonas aeruginosa and relieves the (2014). Flavonoids from the halophyte Apocynum venetum and their inflammatory response in p. Aeruginosa‐infected macrophages by antifouling activities against marine biofilm‐derived bacteria. Natural downregulating the MAPK and NFκB signal‐transduction pathways. Product Research, 28(12), 928–931. Drug Design, Development and Therapy, 10, 183–203. Kong, W., Zhao, Y., Xing, X., Ma, X., Sun, X., Yang, M., & Xiao, X. (2015). Makhafola, T. J., Samuel, B. B., Elgorashi, E. E., & Eloff, J. N. (2012). Antibacterial evaluation of flavonoid compounds against E. coli by Ochnaflavone and ochnaflavone 7‐O‐methyl ether two antibacterial microcalorimetry and chemometrics. Applied Microbiology and Biotech- biflavonoids from Ochna pretoriensis (Ochnaceae). Natural Product Com- nology, 99(14), 6049–6058. munications, 7(12), 1601–1604. Kowalski, K., Koceva‐Chyła, A., Szczupak, Ł., Hikisz, P., Bernasińska, J., Mallavadhani, U. V., Sahoo, L., Kumar, K. P., & Murty, U. S. (2014). Synthe- Rajnisz, A., … Therrien, B. (2013). Ferrocenylvinyl‐flavones: Synthesis, sis and antimicrobial screening of some novel chalcones and flavanones structure, anticancer and antibacterial activity studies. Journal of Organ- substituted with higher alkyl chains. Medicinal Chemistry Research, ometallic Chemistry, 741, 153–161. 23(6), 2900–2908. Koysomboon, S., Van Altena, I., Kato, S., & Chantrapromma, K. (2006). Manner, S., Skogman, M., Goeres, D., Vuorela, P., & Fallarero, A. (2013). Antimycobacterial flavonoids from Derris indica. Phytochemistry, Systematic exploration of natural and synthetic flavonoids for the inhi- 67(10), 1034–1040. bition of Staphylococcus aureus biofilms. International Journal of Molecular Sciences, 14(10), 19434–19451. Kuete, V., Fozing, D., Kapche, W., Mbaveng, A., Kuiate, J., Ngadjui, B., & Abegaz, B. (2009). Antimicrobial activity of the methanolic extract Maresso, A. W., & Schneewind, O. (2008). Sortase as a target of anti‐infec- and compounds from Morus mesozygia stem bark. Journal of tive therapy. Pharmacological Reviews, 60(1), 128–141. – Ethnopharmacology, 124(3), 551 555. Mariani, R., Suganda, A., & Sukandar, E. (2016). Drug‐drug interactions Kuete, V., Simo, I. K., Ngameni, B., Bigoga, J. D., Watchueng, J., Kapguep, R. between griseofulvin and a new prenylated chalcone from elatostema N., … Beng, V. P. (2007). Antimicrobial activity of the methanolic parasiticum and its antibacterial activity nortriptyline at binding sites extract, fractions and four flavonoids from the twigs of Dorstenia of bovine serum albumin. Pharmacology, 1,1–6. angusticornis Engl.(Moraceae). Journal of Ethnopharmacology, 112(2), Martín‐Rodríguez, A. J., Ticona, J. C., Jiménez, I. A., Flores, N., Fernández, J. – 271 277. J., & Bazzocchi, I. L. (2015). Flavonoids from Piper delineatum modulate Kumar, S., & Pandey, A. K. (2013). Chemistry and biological activities of quorum‐sensing‐regulated phenotypes in Vibrio harveyi. Phytochemis- flavonoids: An overview. The Scientific World Journal, 2013, 16. try, 117,98–106. Kunthalert, D., Baothong, S., Khetkam, P., Chokchaisiri, S., & Suksamrarn, A. Mazimba, O., Masesane, I. B., & Majinda, R. R. (2012). A flavanone and (2014). A chalcone with potent inhibiting activity against biofilm forma- antimicrobial activities of the constituents of extracts from Mundulea tion by nontypeable Haemophilus influenzae. Microbiology and sericea. Natural Product Research, 26(19), 1817–1823. – Immunology, 58(10), 581 589. Mbaveng, A. T., Ngameni, B., Kuete, V., Simo, I. K., Ambassa, P., Roy, R., … Lechner, D., Gibbons, S., & Bucar, F. (2008). Modulation of isoniazid sus- Abegaz, B. M. (2008). Antimicrobial activity of the crude extracts and ceptibility by flavonoids in Mycobacterium. Phytochemistry Letters, five flavonoids from the twigs of Dorstenia barteri (Moraceae). Journal 1(2), 71–75. of Ethnopharmacology, 116(3), 483–489. Lee, G.‐S., Kim, E.‐S., Cho, S.‐I., Kim, J.‐H., Choi, G., Ju, Y.‐S., … Kim, H.‐J. Mbaveng, A. T., Sandjo, L. P., Tankeo, S. B., Ndifor, A. R., Pantaleon, A., (2010). Antibacterial and synergistic activity of prenylated chalcone Nagdjui, B. T., & Kuete, V. (2015). Antibacterial activity of nineteen isolated from the roots of Sophora flavescens. Journal of Korean Society selected natural products against multi‐drug resistant Gram‐negative for Applied Biological Chemistry, 53(3), 290–296. phenotypes. Springer Plus, 4(1), 823. Lee, J.‐H., Park, J.‐H., Cho, H. S., Joo, S. W., Cho, M. H., & Lee, J. (2013). Moon, S. H., Lee, J. H., Kim, K.‐T., Park, Y.‐S., Nah, S.‐Y., Ahn, D. U., & Anti‐biofilm activities of quercetin and tannic acid against Staphylococ- Paik, H.‐D. (2013). Antimicrobial effect of 7‐O‐butylnaringenin, a cus aureus. Biofouling, 29(5), 491–499. novel flavonoid, and various natural flavonoids against Helicobacter 26 FARHADI ET AL.

pylori strains. International Journal of Environmental Research and Public against methicillin resistant Staphylococcus aureus (MRSA). Medicinal Health, 10(11), 5459–5469. Chemistry Research, 25(10), 2214–2219. Mun, S.‐H., Joung, D.‐K., Kim, S.‐B., Park, S.‐J., Seo, Y.‐S., Gong, R., … Kang, Rahman, M. M., Gibbons, S., & Gray, A. I. (2007). Isoflavanones from O.‐H. (2014). The mechanism of antimicrobial activity of Uraria picta and their antimicrobial activity. Phytochemistry, 68(12), sophoraflavanone B against methicillin‐resistant Staphylococcus aureus. 1692–1697. – Foodborne Pathogens and Disease, 11(3), 234 239. Rajendran, N., Subramaniam, S., Christena, L. R., Muthuraman, M. S., Mun, S.‐H., Kang, O.‐H., Joung, D.‐K., Kim, S.‐B., Seo, Y.‐S., Choi, J.‐G., … Subramanian, N. S., Pemiah, B., & Sivasubramanian, A. (2016). Antimi- Han, S.‐H. (2013). Combination therapy of sophoraflavanone B against crobial flavonoids isolated from Indian medicinal plant Scutellaria MRSA: In vitro synergy testing. Alternative Medicine, 2013,7. oblonga inhibit biofilms formed by common food pathogens. Natural – Mun, S. H., Lee, Y. S., Han, S. H., Lee, S. W., Cha, S. W., Kim, S. B., … Kwon, Product Research, 30(17), 2002 2006. D. Y. (2015). In vitro potential effect of morin in the combination with Randhawa, H. K., Hundal, K. K., Ahirrao, P. N., Jachak, S. M., & Nandanwar, β‐lactam antibiotics against methicillin‐resistant Staphylococcus aureus. H. S. (2016). Efflux pump inhibitory activity of flavonoids isolated from Foodborne Pathogens and Disease, 12(6), 545–550. Alpinia calcarata against methicillin‐resistant Staphylococcus aureus. – Musa, N., Musa, N., Ibrahim, W. N., Shariat, M. Z. A., Zamani, A. I., Abdullah, Biologia, 71(5), 484 493. M. R., … Soh, A. S. A. (2011). Methanolic activities of selected weeds on Rashed, K., Ćirić, A., Glamočlija, J., & Soković, M. (2014). Antibacterial and bacteria isolated from Macrobrachium rosenbergii larvae. The Thai Jour- antifungal activities of methanol extract and phenolic compounds from nal of Veterinary Medicine, 41(4), 535. Diospyros virginiana L. Industrial Crops and Products, 59, 210–215. Navarro‐Martínez, M. D., Navarro‐Perán, E., Cabezas‐Herrera, J., Ruiz‐ Rattanachaikunsopon, P., & Phumkhachorn, P. (2007). Bacteriostatic effect Gómez, J., García‐Cánovas, F., & Rodríguez‐López, J. N. (2005). of flavonoids isolated from leaves of Psidium guajava on fish pathogens. Antifolate activity of epigallocatechin gallate against Stenotrophomonas Fitoterapia, 78(6), 434–436. – maltophilia. Antimicrobial Agents and Chemotherapy, 49(7), 2914 2920. Rigano, D., Formisano, C., Basile, A., Lavitola, A., Senatore, F., Rosselli, S., & Navrátilová, A., Nešuta, O., Vančatová, I., Čížek, A., Varela‐M, R. E., Lopez‐ Bruno, M. (2007). Antibacterial activity of flavonoids and Aban, J., … Žemličková, H. (2016). C‐Geranylated flavonoids from Pau- phenylpropanoids from Marrubium globosum ssp. libanoticum. lownia tomentosa fruits with antimicrobial potential and synergistic Phytotherapy Research, 21(4), 395–397. – activity with antibiotics. Pharmaceutical Biology, 54(8), 1398 1407. Ruddock, P. S., Charland, M., Ramirez, S., Lopez, A., Neil Towers, G. H., Nenaah, G. (2013). Antimicrobial activity of Calotropis procera Ait. Arnason, J. T., … Dillon, J. A. (2011). Antimicrobial activity of flavonoids (Asclepiadaceae) and isolation of four flavonoid glycosides as the active from Piper lanceaefolium and other Colombian medicinal plants against constituents. World Journal of Microbiology and Biotechnology, 29(7), antibiotic susceptible and resistant strains of Neisseria gonorrhoeae. 1255–1262. Sexually Transmitted Diseases, 38(2), 82–88. Novak, Z., Chlebek, J., Opletal, L., Jiros, P., Macakova, K., Kunes, J., & Rukachaisirikul, T., Innok, P., Aroonrerk, N., Boonamnuaylap, W., Cahlikova, L. (2012). Corylucinine, a new alkaloid from Corydalis cava Limrangsun, S., Boonyon, C., … Suksamrarn, A. (2007). Antibacterial (Fumariaceae), and its cholinesterase activity. Natural Product Commu- pterocarpans from Erythrina subumbrans. Journal of Ethnopharmacology, nications, 7(7), 859–860. 110(1), 171–175. Oh, I., Yang, W.‐Y., Chung, S.‐C., Kim, T.‐Y., Oh, K.‐B., & Shin, J. (2011). In Salah, N. B., Casabianca, H., Jannet, H. B., Chenavas, S., Sanglar, C., Fildier, vitro sortase A inhibitory and antimicrobial activity of flavonoids iso- A., & Bouzouita, N. (2015). Phytochemical and biological investigation lated from the roots of Sophora flavescens. Archives of Pharmacal of two Diplotaxis species growing in Tunisia: D. virgata & D. erucoides. Research, 34(2), 217–222. Molecules, 20(10), 18128–18143. Okwu, D. E., & Nnamdi, F. U. (2011). Two novel flavonoids from Bryophyl- Salar Bashi, D., Bazzaz, B. S. F., Sahebkar, A., Karimkhani, M., & Ahmadi, A. lum pinnatum and their antimicrobial Activity. Journal of Chemical and (2012). Investigation of optimal extraction, antioxidant, and antimicro- Pharmaceutical Research, 3(2), 1–10. bial activities of Achillea biebersteinii and A. wilhelmsii. Pharm. O – Omosa, L. K., Amugune, B., Ndunda, B., Milugo, T. K., Heydenreich, M., Biologico, 52(9), 1168 1176. Yenesew, A., & Midiwo, J. O. (2014). Antimicrobial flavonoids and Seleem, D., Pardi, V., & Murata, R. M. (2017). Review of flavonoids: A diterpenoids from Dodonaea angustifolia. South African Journal of diverse group of natural compounds with anti‐Candida albicans activity Botany, 91,58–62. in vitro. Archives of Oral Biology, 76,76–83. Omosa, L. K., Midiwo, J. O., Mbaveng, A. T., Tankeo, S. B., Seukep, J. A., Selvakumar, N., Kumar, G. S., Azhagan, A. M., Rajulu, G. G., Sharma, S., Voukeng, I. K., … Omolle, R. A. (2016). Antibacterial activities and struc- Kumar, M. S., … Trehan, S. (2007). Synthesis, SAR and antibacterial ture–activity relationships of a panel of 48 compounds from Kenyan studies on novel chalcone oxazolidinone hybrids. Journal of Medicinal plants against multidrug resistant phenotypes. Springer Plus, 5(1), 1–15. Chemistry, 42(4), 538–543. Orabi, M. A., Aoyama, H., Kuroda, T., & Hatano, T. (2014). Structures of Shahzadi, I., & Shah, M. M. (2015). Acylated flavonol glycosides from two new flavonoids and effects of licorice phenolics on vancomycin‐ Tagetes minuta with antibacterial activity. Microbial Pathogenesis, 6. – resistant Enterococcus species. Molecules, 19(4), 3883 3897. Shi, L. Z., & Czuprynski, C. J. (2009). Beta‐naphthoflavone causes an AhR‐ Orhan, D. D., Özçelik, B., Özgen, S., & Ergun, F. (2010). Antibacterial, anti- independent inhibition of invasion and intracellular multiplication of fungal, and antiviral activities of some flavonoids. Microbiological Listeria monocytogenes in murine hepatocytes. Microbial Pathogenesis, Research, 165(6), 496–504. 47(5), 258–266. Patel, N. B., & Patel, M. D. (2017). Synthesis and evaluation of antibacterial Siriwong, S., Teethaisong, Y., Thumanu, K., Dunkhunthod, B., & Eumkeb, G. and antifungal activities of 4‐thiazolidinones and 2‐azetidinones deriv- (2016). The synergy and mode of action of quercetin plus amoxicillin atives from chalcone. Medicinal Chemistry Research,1–12. against amoxicillin‐resistant Staphylococcus epidermidis. BMC Pharma- Patra, A. K. (2012). An overview of antimicrobial properties of different cology and Toxicology, 17(1), 39. classes of phytochemicals. In Dietary phytochemicals and microbes Šmejkal, K., Chudík, S., Kloucek, P., Marek, R., Cvacka, J., Urbanová, M., … (pp. 1–32). Dordrecht: Springer. Holubová, P. (2008). Antibacterial C‐geranylflavonoids from Paulownia – Prabu, G., Gnanamani, A., & Sadulla, S. (2006). Guaijaverin—A plant flavo- tomentosa fruits. Journal of Natural Products, 71(4), 706 709. noid as potential antiplaque agent against Streptococcus mutans. Stompor, M., & Żarowska, B. (2016). Antimicrobial activity of xanthohumol Journal of Applied Microbiology, 101(2), 487–495. and its selected structural analogues. Molecules, 21(5), 608. Qiu, F., Meng, L., Chen, J., Jin, H., & Jiang, L. (2016). In vitro activity of five Taiwo, B. J., & Igbeneghu, O. A. (2014). Antioxidant and antibacterial activ- flavones from Scutellaria baicalensisin combination with Cefazolin ities of flavonoid glycosides from Ficus exasperata Vahl‐Holl (moraceae) FARHADI ET AL. 27

leaves. African Journal of Traditional, Complementary, and Alternative Wang, S., Wang, C., Gao, L., Cai, H., Zhou, Y., Yang, Y., … Muhammad, I. Medicines, 11(3), 97–101. (2017). Rutin inhibits Streptococcus suis biofilm formation by affecting CPS biosynthesis. Frontiers in Pharmacology, 8, 379. Tajuddeen, N., Sallau, M. S., Musa, A. M., Yahaya, S. M., Habila, J. D., & Ismail, A. M. (2016). A novel antimicrobial flavonoid from the stem bark Wang, S. Y., Sun, Z. L., Liu, T., Gibbons, S., Zhang, W. J., & Qing, M. (2014). of Commiphora pedunculata (Kotschy & Peyr.) Engl. Natural Product Flavonoids from Sophora moorcroftiana and their synergistic antibacte- Research, 30(10), 1109–1115. rial effects on MRSA. Phytotherapy Research, 28(7), 1071–1076. Tajuddeen, N., Sani Sallau, M., Muhammad Musa, A., James Habila, D., & Wen, L., Wu, D., Jiang, Y., Prasad, K. N., Lin, S., Jiang, G., … Yang, B. (2014). Yahaya, S. M. (2014). Flavonoids with antimicrobial activity from the Identification of flavonoids in litchi (Litchi chinensis Sonn.) leaf and eval- stem bark of Commiphora pedunculata (Kotschy & Peyr.) Engl. Natural uation of anticancer activities. Journal of Functional Foods, 6, 555–563. Product Research, 28(21), 1915–1918. Woźnicka, E., Kuźniar, A., Nowak, D., Nykiel, E., Kopacz, M., Gruszecka, J., Tamba, Y., Ohba, S., Kubota, M., Yoshioka, H., Yoshioka, H., & Yamazaki, M. & Golec, K. (2013). Comparative study on the antibacterial activity of (2007). Single GUV method reveals interaction of tea catechin (−)‐epi- some flavonoids and their sulfonic derivatives. Acta Poloniae – gallocatechin gallate with lipid membranes. Biophysical Journal, 92(9), Pharmaceutica, 70(3), 567 571. 3178–3194. Wu, D., Kong, Y., Han, C., Chen, J., Hu, L., Jiang, H., & Shen, X. (2008). D‐Alanine: D‐alanine ligase as a new target for the flavonoids Tan, C. X., Schrader, K. K., Khan, I. A., & Rimando, A. M. (2015). Activities of quercetin and apigenin. International Journal of Antimicrobial Agents, wogonin analogs and other flavones against Flavobacterium columnare. 32(5), 421–426. Chemistry & Biodiversity, 12(2), 259–272. https://doi.org/10.1002/ cbdv.201400181 Wu, T., He, M., Zang, X., Zhou, Y., Qiu, T., Pan, S., & Xu, X. (2013). A structure–activity relationship study of flavonoids as inhibitors of E. coli by Tantry, M. A., Dar, J. A., Idris, A., Akbar, S., & Shawl, A. S. (2012). Acylated membrane interaction effect. Biochimica et Biophysica Acta (BBA) ‐ flavonol glycosides from Epimedium elatum, a plant endemic to the Biomembranes, 1828(11), 2751–2756. Western Himalayas. Fitoterapia, 83(4), 665–670. Xiao, H. T., Peng, J., Liang, Y., Yang, J., Bai, X., Hao, X. Y., … Sun, Q. Y. Tebou, P., Tamokou, J.‐d.‐D., Ngnokam, D., Voutquenne‐Nazabadioko, L., (2011). Acetylcholinesterase inhibitors from Corydalis yanhusuo. Natu- Kuiate, J.‐R., & Bag, P. (2017). Flavonoids from Maytenus buchananii ral Product Research, 25(15), 1418–1422. as potential cholera chemotherapeutic agents. South African Journal of ‐ ‐ ‐ ‐ … Botany, 109,58–65. Xiao, Z. P., Peng, Z. Y., Dong, J. J., He, J., Ouyang, H., Feng, Y. T., Xiang, Y.‐P. (2013). Synthesis, structure–activity relationship analysis and ‐ ‐ ‐ ‐ ‐ ‐ Tran, T. D., Do, T. H., Tran, N. C., Ngo, T. D., Tran, C. D., & Thai, K. M. kinetics study of reductive derivatives of flavonoids as Helicobacter (2012). Synthesis and anti Methicillin resistant Staphylococcus aureus pylori urease inhibitors. European Journal of Medicinal Chemistry, 63, ‐ activity of substituted chalcones alone and in combination with non 685–695. beta‐lactam antibiotics. Bioorganic & Medicinal Chemistry Letters, ‐ ‐ ‐ ‐ ‐ 22(14), 4555–4560. Xiao, Z. P., Shi, D. H., Li, H. Q., Zhang, L. N., Xu, C., & Zhu, H. L. (2007). Polyphenols based on isoflavones as inhibitors of Helicobacter pylori Tran, T.‐D., Nguyen, T.‐T.‐N., Do, T.‐H., Huynh, T.‐N.‐P., Tran, C.‐D., & Thai, urease. Bioorganic & Medicinal Chemistry Letters, 15(11), 3703–3710. K.‐M. (2012). Synthesis and antibacterial activity of some heterocyclic Xiao, Z.‐P., Wang, X.‐D., Wang, P.‐F., Zhou, Y., Zhang, J.‐W., Zhang, L., … chalcone analogues alone and in combination with antibiotics. Molecules, Lin, X.‐Y. (2014). Design, synthesis, and evaluation of novel fluoroquin- 17(6), 6684–6696. olone–flavonoid hybrids as potent antibiotics against drug‐resistant Tsuchiya, H., & Iinuma, M. (2000). Reduction of membrane fluidity by anti- microorganisms. European Journal of Medicinal Chemistry, 80,92–100. bacterial sophoraflavanone G isolated from Sophora exigua. Xiao, Z.‐P., Wei, W., Liu, Q., Wang, P.‐F., Luo, X., Chen, F.‐Y., … Zhu, H.‐L. Phytomedicine, 7(2), 161–165. (2017). C‐7 modified flavonoids as novel tyrosyl‐tRNA synthetase Ulanowska, K., Majchrzyk, A., Moskot, M., Jakóbkiewicz‐Banecka, J., & inhibitors. RSC Advances, 7(11), 6193–6201. ę W grzyn, G. (2007). Assessment of antibacterial effects of flavonoids Xie, Y., Yang, W., Tang, F., Chen, X., & Ren, L. (2015). Antibacterial activi- by estimation of generation times in liquid bacterial cultures. Biologia, ties of flavonoids: Structure‐activity relationship and mechanism. – 62(2), 132 135. Current Medicinal Chemistry, 22(1), 132–149. ȩ Ulanowska, K., Tkaczyk, A., Konopa, G., & W grzyn, G. (2006). Differential Yang, W.‐Y., Won, T. H., Ahn, C.‐H., Lee, S.‐H., Yang, H.‐C., Shin, J., & Oh, antibacterial activity of genistein arising from global inhibition of DNA, K.‐B. (2015). Streptococcus mutans sortase A inhibitory metabolites RNA and protein synthesis in some bacterial strains. Archives of Micro- from the flowers of Sophora japonica. Bioorganic & Medicinal Chemistry – biology, 184(5), 271 278. Letters, 25(7), 1394–1397. Ustün, O., Ozçelik, B., Akyön, Y., Abbasoglu, U., & Yesilada, E. (2006). Zainuri, D. A., Arshad, S., Khalib, N. C., Razak, I. A., Pillai, R. R., Sulaiman, S. Flavonoids with anti‐Helicobacter pylori activity from Cistus laurifolius F., … Armaković, S. J. (2017). Synthesis, XRD crystal structure, spectro- leaves. Journal of Ethnopharmacology, 108(3), 457–461. scopic characterization (FT‐IR, 1 H and 13 C NMR), DFT studies, Vasavi, H. S., Arun, A. B., & Rekha, P. D. (2014). Anti‐quorum sensing activ- chemical reactivity and bond dissociation energy studies using molecu- ity of Psidium guajava L. flavonoids against Chromobacterium violaceum lar dynamics simulations and evaluation of antimicrobial and ‐ ‐ ‐ and Pseudomonas aeruginosa PAO1. Microbiology and Immunology, antioxidant activities of a novel chalcone derivative,(E) 1 (4 ‐ ‐ ‐ ‐ ‐ ‐ ‐ 58(5), 286–293. bromophenyl) 3 (4 iodophenyl) prop 2 en 1 one. Journal of Molecular Structure, 1128, 520–533. Venugopala, K. N., Rashmi, V., & Odhav, B. (2013). Review on natural cou- Zampini, I., Villena, J., Salva, S., Herrera, M., Isla, M., & Alvarez, S. (2012). marin lead compounds for their pharmacological activity. BioMed Research International, 2013, 963248. Potentiality of standardized extract and isolated flavonoids from Zuccagnia punctata for the treatment of respiratory infections by Wan, C.‐X., Luo, J.‐G., Ren, X.‐P., & Kong, L.‐Y. (2015). Interconverting Streptococcus pneumoniae: In vitro and in vivo studies. Journal of flavonostilbenes with antibacterial activity from Sophora alopecuroides. Ethnopharmacology, 140(2), 287–292. https://doi.org/10.1016/j. Phytochemistry, 116, 290–297. jep.2012.01.019 Wang, L., Yang, R., Yuan, B., Liu, Y., & Liu, C. (2015). The antiviral and anti- Zeng, Z., Qian, L., Cao, L., Tan, H., Huang, Y., Xue, X., … Zhou, S. (2008). Vir- microbial activities of licorice, a widely‐used Chinese herb. Acta tual screening for novel quorum sensing inhibitors to eradicate biofilm Pharmaceutica Sinica B, 5(4), 310–315. formation of Pseudomonas aeruginosa. Applied Microbiology and Biotech- Wang, Q., Wang, H., & Xie, M. (2010). Antibacterial mechanism of soybean nology, 79(1), 119. isoflavone on Staphylococcus aureus. Archives of Microbiology, 192(11), Zhang, L., Kong, Y., Wu, D., Zhang, H., Wu, J., Chen, J., … Shen, X. (2008). 893–898. Three flavonoids targeting the β‐hydroxyacyl‐acyl carrier protein 28 FARHADI ET AL.

dehydratase from Helicobacter pylori: Crystal structure characterization – with enzymatic inhibition assay. Protein Science, 17(11), 1971 1978. How to cite this article: Farhadi F, Khameneh B, Iranshahi M, Zhong, L., Zhou, L., Zhou, Y., Chen, Y., Sui, P., Wang, J., & Wang, M. (2012). Iranshahy M. Antibacterial activity of flavonoids and their Antimicrobial flavonoids from the twigs of Populus nigra× Populus – deltoides. Natural Product Research, 26(4), 307–313. structure activity relationship: An update review. Phytotherapy – Zou, Z., Xu, P., Wu, C., Zhu, W., Zhu, G., He, X., … Zeng, W. (2016). Research. 2018;1 28. https://doi.org/10.1002/ptr.6208 Carboxymethyl flavonoids and a chromone with antimicrobial activity from Selaginella moellendorffii Hieron. Fitoterapia, 111, 124–129.

View publication stats