Accessibility / Report Error

Synthesis and antibacterial activity of a series novel 5,7-diisoprenyloxyflavone derivatives

Abstract

In the present study, a series of novel 5,7-diisoprenyloxyflavone derivatives were designed, synthesized, and evaluated for their antibacterial activity. Most of these compounds displayed significant antibacterial effects against Gram-positive bacteria, especially against strains of multidrug-resistant clinical isolates. Compounds 4c, 4g, 4i, 4j, 4k, 4l, 4n, 4q and 4t showed high levels of antimicrobial activity against Staphylococcus aureus RN4220 with minimum inhibitory concentrations of 4.0-20 µM. Compound 4k showed the most potent activity among these compounds against all multidrug-resistant clinical isolates tested. Unfortunately, none of the compounds were active against Gram-negative bacteria at the doses of 24-164 µM.

Keywords:
Flavonoids; Synthesis; Isoprenyloxyflavones; Antibacterial activity


INTRODUCTION

According to the World Health Organization (WHO), infectious diseases are responsible for a significant proportion of deaths worldwide, with antimicrobial agents considered “miracle drugs” that are the leading weapons in the treatment of infectious diseases. However, owing to the development of antimicrobial resistance and the appearance of drug-resistant strains among community-acquired infections, there is evidence of the rapid global spread of resistant clinical isolates, with many current clinically efficacious antimicrobial agents becoming less effective. Therefore, the treatment of bacterial infections remains an important and challenging therapeutic problem (Chen et al., 2010Chen ZH, Zheng CJ, Sun LP, Piao HR. Synthesis of new chalcone derivatives containing a rhodanine-3-acetic acid moiety with potential anti-bacterial activity. Eur J Med Chem. 2010;45(12):5739-5743.). Ongoing drug discovery is necessary for identifying effective, safe, and affordable cures for an expanding spectrum of human ailments. As the treatment of these diseases has serious safety and efficacy issues, the exploration of new antibacterial agents is highly desirable.

Malaria caused by protozoan parasites of the genus plasmodium is a major cause of mortality and morbidity, especially in tropical countries. More than three billion people worldwide have been affected by this deadly disease (Verlinden, Louw, Birkholtz, 2016Verlinden BK, Louw A, Birkholtz LM. Resisting resistance: is there a solution for malaria? Expert Opin Drug Discov. 2016;11(4):395-406.). The increasing resistance of malarial parasites to available drugs is a major reason for these large statistics, despite many reports on the antimalarial efficacy of flavonoids (Friedman, 2007Friedman M. Overview of antibacterial, antitoxin, antiviral, and antifungal activities of tea flavonoids and teas. Mol Nutr Food Res. 2007;51(1):116-134.; Kozyra et al., 2015Kozyra M, Biernasiuk A, Malm A, Chowaniec M. Chemical compositions and antibacterial activity of extracts obtained from the inflorescences of Cirsium canum (L.) all. Nat Prod Res. 2015;29(21):2059-2063.). The development of novel antimicrobial drugs is still in demand owing to increasing incidence of infection caused by the rapid development of microbial resistance to most known antibiotics.

Flavonoids are natural products found throughout nature that have broad physiological activities, low toxicity, and few side effects (Harborne, Williams, 2000Harbme JB, Williams CA. Advances in flavonoid research since 1992. Phytochem. 2000;55(6):481-504.). Flavonoids are a diverse class of polyphenolic phytochemicals found in various vegetables and fruits, and provide color, aroma, flavor, and nutritional and health benefits (Karakaya, Sedef, 1999Karakaya S, Sedef NEL. Quercetin, luteolin, apigenin and kaempferol contents of some foods. Food Chem. 1999;66(3):289-292.). Many flavonoids extracted from plants have been reported to show various biological effects, including anticancer, antioxidant, antibacterial, anti-inflammatory, and antidepressant effects (Ahmed, Khan, Saeed, 2015Ahmed D, Khan MM, Saeed R. Comparative analysis of phenolics, flavonoids, and antioxidant and antibacterial potential of methanolic, hexanic and aqueous extracts from adiantum caudatum leaves. Antioxidants (Basel). 2015;4(2):394-409.; Xie et al., 2014Xie C, Peng Z, Zhao SL, Pan CY, Guan LP, Sun XY. Synthesis of 2´-hydroxy-4´- isoprenyloxychalcone derivatives with potential antidepressant-like activity. Med Chem. 2014;10(8):789-799.; Kulbacka et al., 2016Kulbacka J, Pucek A, Kotulska M, Dubińska-magiera M, Rossowska J, Rols MP, Wilk KA. Electroporation and lipid nanoparticles with cyanine IR-780 and flavonoids as efficient vectors to enhanced drug delivery in colon cancer. Bioelectrochem. 2016;110:19-31.; Yao et al., 2014Yao Y, Lin G , Xie Y, Ma P, Li G, Meng Q, Wu T. Preformulation studies of myricetin: a natural antioxidant flavonoid. Pharmazie. 2014;69(1):19-26.; Keshari et al., 2016Keshari AK, Kumar G, Kushwaha PS, Bhardwaj M, Kumar P, Rawat A, Kumar D, Prakash A, Ghosh B, Saha S. Isolated flavonoids from Ficus racemosa stem bark possess antidiabetic, hypolipidemic and protective effects in albino Wistar rats. J Ethnopharmacol. 2016;181:252-262.). Apigenin (5,7,4´-trihydroxyflavonoid; Figure 1), a bioflavonoid widely found in citrus fruits, has been found to exert a variety of pharmacological effects, including antibacterial, anticancer, and antiproliferative effects (Banerjee et al., 2015Banerjee K, Banerjee S, Das S, Mandal M. Probing the potential of apigenin liposomes in enhancing bacterial membrane perturbation and integrity loss. J Colloid Interf Sci. 2015;453:48-59.; Liu et al., 2013Liu R, Zhang H, Yuan M, Zhou J, Tu Q, Liu JJ, Wang J. Synthesis and biological evaluation of apigenin derivatives as antibacterial and antiproliferative agents. Molecules. 2013;18(9):11496-11511.; Eumkeb, Chukrathok, 2013Eumkeb G, Chukrathok S. Synergistic activity and mechanism of action of ceftazidime and apigenin combination against ceftazidime-resistant Enterobacter cloacae. Phytomedicine. 2013;20(3-4):262-269.; Choi et al., 2010Choi AY, Choi JH, Lee JY, Yoon KS, Choe W, Ha J, Yeo EJ, Kang I. Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. Neurochem Int. 2010;57(2):143-152.; Turktekin et al., 2011Turktekin M, Konac E, Onen HI, Alp E, Yilmaz A, Menevse S. Evaluation of the effects of the flavonoid apigenin on apoptotic pathway gene expression on the colon cancer cell line (HT29). J Med Food. 2011;14(10):1107-1117.; Ruivo et al., 2015Ruivo J, Francisco C, Oliveira R, Figueiras A. The main potentialities of resveratrol for drug delivery systems. Braz J Pharm Sci. 2015;51(3):499-513.). The prenyl moiety is widely found in many drugs and natural products (Zhao et al., 2011Zhao LM, Jin HS, Wan LJ, Zhang LM. General and highly a-regioselective zinc-mediated prenylation of aldehydes and ketones. J Org Chem. 2011;76(6):1831-1837.; Winans et al., 1999Winans KA, King DA, Rao VR, Bertozzi CR. A Chemically synthesized version of the insect antibacterial glycopeptide, diptericin, disrupts bacterial membrane integrity. Biochem. 1999;38(36):11700-11710.). Prenylation has been reported to produce flavonoids with enhanced antibacterial, antioxidant, anti-inflammatory, larvicidal, cytotoxicity, and estrogenic activities (Rao et al., 2009Rao GV, Swamy BN, Chandregowda V, Reddy GC. Synthesis of (+/-) Abyssinone I and related compounds:Their anti-oxidant and cytotoxic activities. Eur J Med Chem. 2009;44(5):2239-2245.; Vogel et al., 2008Vogel S, Ohmayer S, Brunner G, Heilmann J. Natural and non-natural prenylate chalcones: synthesis, cytotoxicity and anti-oxidative activity. Bioorg Med Chem. 2008;16(8):4286-4293.; Vogel et al., 2010Vogel S, Barbic M, Jürgenliemk G, Heilmann J. Synthesis, cytotoxicity, anti- oxidative and anti-inflammatory activity of chalcones and influence of A-ring modifications on the pharmacological effect. Eur J Med Chem. 2010;45(6):2206-2213.). It has been proposed that prenyl moieties can make a compound more lipophilic, leading to a high affinity with cell membranes (Chen et al., 2014Chen X, Mukwaya E, Wong MS, Zhang Y. A systematic review on biological activities of prenylated flavonoids. Pharm Biol. 2014;52(5):655-660 .; Marín, Máñez, 2013Marín M, Máñez S. Recent trends in the pharmacological activity of isoprenyl phenolics. Curr Med Chem. 2013;20(2):272-279.; Coelho et al., 1992Coelho AL, Vasconcellos MLAA, Simas ABC, Rabi JA, Costa PRR. A convenient synthesis of (±)-4-Prenylpterocarpin. Synthesis. 1992;10:914-916.).

FIGURE 1
The structure of apigenin and general structure of compounds 4a-4t.

To obtain new compounds with better antibacterial effects, and as part of our ongoing research on structure-based design using apigenin as the lead compound, the introduction of a prenyloxy group on the A-ring of apigenin was used to prepare a series of 20 novel 5,7-diisoprenyloxyflavone derivatives (4a-4t; Scheme-1). These compounds were synthesized, characterized, and screened for their antibacterial activities. The synthesized of 5,7-diisoprenyloxyflavone derivatives (4a-4t) and antibacterial effects are not reported and is the originality compounds.

SCHEME1
Synthesis routes of target compounds 4a-4t.

MATERIAL AND METHODS

Chemistry

Melting points were determined in open capillary tubes and were uncorrected. IR spectra were recorded on a FT-IR1730 (Bruker, Switzerland) using KBr pellets. 1H-NMR and 13C-NMR spectra were measured on an AV-300 spectrometer (Bruker, Switzerland), with all chemical shifts given in ppm relative to tetramethylsilane standard. High-resolution mass spectrometry (HRMS) was performed on an MALDI-TOF/TOF mass spectrometer (Bruker Daltonik, Bremen, Germany). Major chemicals were purchased from Aldrich Chemical Corporation (Shanghai, China), and all chemicals were of analytical grade. Compounds 1a-1t, 2a-2t and 3a-3t were synthesized to refer to previously published literature (Guan et al., 2013Guan LP, Zhao DH, Chang Y, Sun Y, Ding XL, Jiang JF. Design, synthesis and antidepressant activity evaluation 2′-hydroxy-4′,6′-diisoprenyloxychalcone derivatives. Med Chem Res. 2013;22(11):5218-5226.; Xie et al., 2014Xie C, Peng Z, Zhao SL, Pan CY, Guan LP, Sun XY. Synthesis of 2´-hydroxy-4´- isoprenyloxychalcone derivatives with potential antidepressant-like activity. Med Chem. 2014;10(8):789-799..).

General procedure for the preparation of compounds (4a-4t)

To a stirred solution of compounds 3a-3t (0.4 mmol) in DMSO (30 mL) in a 100-mL round-bottomed flask was added I2 (0.4 mmol). The mixture was then stirred at 100-130 °C for 3-5 h to achieve reaction completion (as monitored by TLC) (Kim et al., 2007Kim S, Sohn DW, Kim YC, Kim SA, Lee SK, Kim HS. Fine tuning of a reported synthetic route for biologically active flavonoid, baicalein. Arch Pharm Res. 2007;30(1):18-21.). The reaction mixture was then poured into ice-water to produce a yellow precipitate, which was collected and recrystallized from ethanol to afford corresponding products 4a-4t. The yields and IR, 1H-NMR, 13C-NMR, and mass spectral data for each compound are provided below.

5,7-Diisoprenyloxyflavone (4a)

Yield: 79.3%; mp 74-76 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.63 (s, 3H, -CH3), 1.66 (s, 3H, -CH3), 1.72 (s, 3H, -CH3), 1.76 (s, 3H, -CH3), 4.42 (d, 2H, -CH2), 4.57 (d, 2H, -CH2), 5.38 (t, 1H, =CH), 5.49 (t, 1H, =CH), 6.09-6.12 (m, 2H, -C6H2), 6.81 (s, 1H, =CH), 7.16-7.38 (m, 5H, -C6H5); 13C-NMR (DMSO-d6, 75 MHz): δ 19.7, 20.1, 25.7, 26.0, 45.7, 45.9, 98.1, 99.7, 104.0, 105.3, 123.7, 124.0, 126.7, 127.0, 128.3, 128.9, 129.3, 130.7, 132.5, 132.8, 160.4, 163.3, 164.2, 168.7, 182.8; IR (KBr) cm-1: 2931, 1678, 1221, 970; ESI-HRMS calcd. for C25H26O4+ ([M+H]+): 391.183, found: 391.1820.

2’-Fluoro-5,7-diisoprenyloxyflavone (4b)

Yield: 61.2%; mp 92-94 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.62 (s, 3H, -CH3), 1.65 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 1.74 (s, 3H, -CH3), 4.47 (d, 2H, -CH2), 4.61 (d, 2H, -CH2), 5.40 (t, 1H, =CH), 5.47 (t, 1H, =CH), 6.05-6.11 (m, 2H, -C6H2), 6.67 (s, 1H, =CH), 6.98-7.32 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.9, 20.3, 25.5, 25.9, 45.5, 45.8, 97.8, 98.9, 103.7, 104.8, 116.4, 121.8, 123.6, 123.8, 124.7, 128.7, 129.6, 132.6, 132.7, 158.9, 162.7, 163.8, 168.5, 182.6; IR (KBr) cm-1: 2934, 1676, 1220, 972; ESI-HRMS calcd. for C25H25FO4+ ([M+H]+): 408.1737, found: 408.1742.

3’-Fluoro-5,7-diisoprenyloxyflavone (4c)

Yield: 59%; mp 98-100 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.66 (s, 3H, -CH3), 1.69 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 4.44 (d, 2H, -CH2), 4.69 (d, 2H, -CH2), 5.47 (t, 1H, =CH), 5.65 (t, 1H, =CH), 6.06-6.14 (m, 2H, -C6H2), 6.67 (s, 1H, =CH), 6.82-7.28 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.2, 19.7, 25.1, 25.5, 65.8, 66.0, 99.1, 100.1, 103.9, 105.3, 111.8, 115.1, 122.8, 123.4, 123.7, 130.4, 132.4, 132.8, 133.0, 159.6, 162.3, 162.7, 163.6, 168.4, 183.1; IR (KBr) cm-1: 2932, 1676, 1222, 970; ESI-HRMS calcd. for C25H25FO4+ ([M+H]+): 408.1737, found: 408.1730.

4’-Fluoro-5,7-diisoprenyloxyflavone (4d)

Yield: 73.3%; mp 97-99 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.66 (s, 3H, -CH3), 1.69 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.72 (s, 3H, -CH3), 4.63 (d, 2H, -CH2), 4.66 (d, 2H, -CH2), 5.43 (t, 1H, =CH), 5.45 (t, 1H, =CH), 6.03-6.12 (m, 2H, -C6H2), 6.73 (s, 1H, =CH), 6.90-7.29 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): 19.2, 19.4, 25.2, 25.4, 45.1, 45.3, 96.8, 97.9, 103.5, 104.7, 115.2, 115.7, 123.3, 123.5, 126.5, 128.3, 128.5, 159.4, 162.2, 162.5, 163.5, 168.4, 182.4; IR (KBr) cm-1: 2932, 1672, 1221, 971; ESI-HRMS calcd. for C25H25FO4+ ([M+H]+): 408.1737, found: 408.1746.

2’-Chloro-5,7-diisoprenyloxyflavone (4e)

Yield: 74.1%, mp 105-107 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.67 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 4.58 (d, 2H, -CH2), 4.61 (d, 2H, -CH2), 5.42 (t, 1H, =CH), 5.47 (t, 1H, =CH), 6.03-6.10 (m, 2H, -C6H2), 6.65 (s, 1H, =CH), 7.06-7.28 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.3, 19.6, 25.3, 25.6, 45.3, 45.5, 97.5, 98.6, 103.6, 104.5, 123.5, 123.8, 126.6, 127.4, 128.7, 129.5, 131.2, 131.9, 132.4, 132.6, 159.2, 162.6, 163.7, 168.5, 182.5; IR (KBr) cm-1: 2943, 1676, 1220, 973; ESI-HRMS calcd. for C25H25ClO4+ ([M+H]+): 425.1441, found: 425.1430.

3’-Chloro-5,7-diisoprenyloxyflavone (4f)

Yield: 77%; mp 119-121 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.69 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.74 (s, 3H, -CH3), 1.75 (s, 3H, -CH3), 4.50 (d, 2H, -CH2), 4.54 (d, 2H, -CH2), 5.40 (t, 1H, =CH), 5.44 (t, 1H, =CH), 6.02-6.11 (m, 2H, -C6H2), 6.68 (s, 1H, =CH), 7.14-7.34 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.6, 19.9, 25.4, 25.8, 65.5, 65.8, 98.9, 99.4, 103.3, 104.8, 123.7, 123.9, 124.5, 126.7, 128.3, 130.7, 131.6, 132.5, 132.8, 134.5, 160.2, 162.4, 163.6, 169.1, 182.9; IR (KBr) cm-1: 2940, 1677, 1222, 970; ESI-HRMS calcd. for C25H25ClO4+ ([M+H]+): 425.1441, found: 425.1451.

4’-Chloro-5,7-diisoprenyloxyflavone (4g)

Yield: 81%; mp 117-119 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.65 (s, 3H, -CH3), 1.67 (s, 3H, -CH3), 1.72 (s, 3H, -CH3), 1.74 (s, 3H, -CH3), 4.62 (d, 2H, -CH2), 4.64 (d, 2H, -CH2), 5.40 (t, 1H, =CH), 5.43 (t, 1H, =CH), 6.05-6.12 (m, 2H, -C6H2), 6.81 (s, 1H, =CH), 7.21-7.26 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 20.1, 20.3, 25.4, 25.7, 65.6, 65.8, 99.2, 100.1, 103.8, 104.7, 123.7, 124.0, 127.3, 127.8, 128.2, 128.5, 129.2, 132.2, 132.5, 133.7, 159.6, 162.4, 163.5, 168.7, 182.9; IR (KBr) cm-1: 2943, 1676, 1220, 973; ESI-HRMS calcd. for C25H25ClO4+ ([M+H]+): 425.1441, found: 425.1449.

2’-Bromo-5,7-diisoprenyloxyflavone (4h)

Yield: 69%; mp 120-122 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.68 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 1.75 (s, 3H, -CH3), 4.48 (d, 2H, -CH2), 4.50 (d, 2H, -CH2), 5.42 (t, 1H, =CH), 5.47 (t, 1H, =CH), 6.05-6.13 (m, 2H, -C6H2), 6.77 (s, 1H, =CH), 7.06-7.41 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.2, 19.7, 25.4, 25.6, 65.3, 65.5, 98.4, 99.2, 103.1, 104.4, 118.3, 123.6, 123.9, 127.1, 128.6, 130.4, 131.6, 132.3, 132.5, 138.4, 159.4, 162.7, 164.1, 168.5, 182.6; IR (KBr) cm-1: 2936, 1674, 1220, 968; ESI-HRMS calcd. for C25H25BrO4+ ([M+H]+): 469.0936, found: 469.0915.

3’-Bromo-5,7-diisoprenyloxyflavone (4i)

Yield: 70%; mp 114-117 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.67 (s, 3H, -CH3), 1.69 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.72 (s, 3H, -CH3), 4.56 (d, 2H, -CH2), 4.59 (d, 2H, -CH2), 5.40 (t, 1H, =CH), 5.43 (t, 1H, =CH), 6.03-6.11 (m, 2H, -C6H2), 6.79 (s, 1H, =CH), 7.12-7.50 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.3, 19.5, 25.5, 25.7, 64.8, 65.0, 96.4, 97.7, 103.3, 104.5, 122.8, 123.8, 124.0, 125.7, 129.1, 130.2, 130.5, 131.9, 132.3, 132.5, 162.4, 163.3, 163.9, 168.5, 182.6; IR (KBr) cm-1: 2941, 1677, 1222, 972; ESI-HRMS calcd. for C25H26O4+ ([M+H]+): 469.0936, found: 469.0943.

4’-Bromo-5,7-diisoprenyloxyflavone (4j)

Yield: 78.5%, mp 122-124 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.65 (s, 3H, -CH3), 1.68 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 4.62 (d, 2H, -CH2), 4.65 (d, 2H, -CH2), 5.39 (t, 1H, =CH), 5.42 (t, 1H, =CH), 6.04-6.13 (m, 2H, -C6H2), 6.76 (s, 1H, =CH), 7.21-7.42 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.6, 19.8, 25.4, 25.7, 66.1, 66.5, 96.8, 97.9, 103.7, 104.6, 122.4, 123.4, 123.7, 128.1, 128.4, 129.9, 131.3, 131.4, 132.3, 132.5, 160.0, 162.7, 163.8, 168.6, 182.5; IR (KBr) cm-1: 2941, 1678, 1222, 972; ESI-HRMS calcd. for C25H26O4+ ([M+H]+): 469.0936, found: 469.0921.

2’,4’-Dichloro-5,7-diisoprenyloxyflavone (4k)

Yield: 78.4%, mp 107-108 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.67 (s, 3H, -CH3), 1.69 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 1.75 (s, 3H, -CH3), 4.48 (d, 2H, -CH2), 4.50 (d, 2H, -CH2), 5.42 (t, 1H, =CH), 5.45 (t, 1H, =CH), 6.05-6.11 (m, 2H, -C6H2), 6.78 (s, 1H, =CH), 7.10-7.28 (m, 3H, -C6H3); 13C-NMR (DMSO-d6, 75 MHz): δ 19.6, 19.8, 25.5, 25.8, 65.5, 65.7, 96.4, 97.8, 103.7, 104.5, 123.5, 123.8, 127.1, 129.3, 129.6, 130.4, 132.4, 132.7, 132.9, 159.7, 162.3, 163.8, 168.5, 182.5; IR (KBr) cm-1: 2941, 1676, 1221, 968; ESI-HRMS calcd. for C25H24Cl2O4+ ([M+H]+): 459.1052, found: 459.1041.

4’-Nitro-5,7-diisoprenyloxyflavone (4l)

Yield: 60%, mp 91-93 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.69 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 1.76 (s, 3H, -CH3), 4.62 (d, 2H, -CH2), 4.67 (d, 2H, -CH2), 5.39 (t, 1H, =CH), 5.43 (t, 1H, =CH), 6.05-6.11 (m, 2H, -C6H2), 7.02 (s, 1H, =CH), 7.76-8.43 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.5, 19.7, 25.5, 25.7, 65.5, 65.8, 98.7, 99.9, 103.8, 104.3, 121.3, 121.5, 123.5, 123.7, 127.6, 127.9, 132.4, 132.7, 136.5, 148.8, 160.2, 162.5, 163.7, 168.4, 182.5; IR (KBr) cm-1: 2941, 1676, 1221, 972; ESI-HRMS calcd. for C25H25NO6+ ([M+H]+): 436.1682, found: 436.1669.

2’-Methyl-5,7-diisoprenyloxyflavone (4m)

Yield: 74.4%, mp 96-98 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.69 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 2.40 (s, 3H, -CH3), 4.45 (d, 2H, -CH2), 4.47 (d, 2H, -CH2), 5.41 (t, 1H, =CH), 5.43 (t, 1H, =CH), 6.03-6.12 (m, 2H, -C6H2), 6.56 (s, 1H, =CH), 7.03-7.21 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 18.4, 19.5, 19.7, 25.3, 25.6, 65.5, 65.7, 97.5, 98.7, 103.5, 104.6, 123.3, 123.5, 125.7, 126.5, 127.3, 128.7, 129.3, 132.2, 132.5, 159.8, 162.7, 163.8, 168.5, 182.6; IR (KBr) cm-1: 2939, 1676, 1221, 971; ESI-HRMS calcd. for C26H28O4+ ([M+H]+): 405.1988, found: 405.1968.

3’-Methyl-5,7-diisoprenyloxyflavone (4n)

Yield: 76%, mp 101-104 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.69 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.72 (s, 3H, -CH3), 1.75 (s, 3H, -CH3), 2.39 (s, 3H, -CH3), 4.42 (d, 2H, -CH2), 4.44 (d, 2H, -CH2), 5.40 (t, 1H, =CH), 5.42 (t, 1H, =CH), 6.03-6.12 (m, 2H, -C6H2), 6.73 (s, 1H, =CH), 6.95-7.13 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.8, 20.1, 24.3, 25.5, 25.8, 65.6, 65.9, 98.9, 100.2, 103.3, 104.5, 123.3, 123.7, 123.9, 126.2, 128.3, 128.8, 130.3, 132.5, 132.7, 138.7, 159.7, 162.5, 163.6, 168.8, 182.4; IR (KBr) cm-1: 2942, 1677, 1222, 970; ESI-HRMS calcd. for C26H28O4+ ([M+H]+): 405.1988, found: 405.1971.

4’-Methyl-5,7-diisoprenyloxyflavone (4o)

Yield: 85.6%, mp 113-115 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.67 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 1.74 (s, 3H, -CH3), 2.38 (s, 3H, -CH3), 4.51 (d, 2H, -CH2), 4.53 (d, 2H, -CH2), 5.40 (t, 1H, =CH), 5.42 (t, 1H, =CH), 6.05-6.13 (m, 2H, -C6H2), 6.75 (s, 1H, =CH), 7.01-7.19 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.7, 19.9, 24.1, 25.5, 25.8, 65.6, 65.9, 98.8, 99.6, 103.4, 104.5, 123.6, 123.8, 126.2, 126.4, 127.5, 129.2, 129.3, 132.4, 132.7, 137.6, 159.9, 162.8, 163.5, 168.6, 182.4; IR (KBr) cm-1: 2941, 1676, 1220, 970; ESI-HRMS calcd. for C26H28O4+ ([M+H]+): 405.1988, found: 405.1990.

2’-Methoxy-5,7-diisoprenyloxyflavone (4p)

Yield: 68.4%, mp 80-83 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.68 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.72 (s, 3H, -CH3), 1.74 (s, 3H, -CH3), 3.74 (s, 3H, -O CH3), 4.63 (d, 2H, -CH2), 4.65 (d, 2H, -CH2), 5.41 (t, 1H, =CH), 5.44 (t, 1H, =CH), 6.04-6.11 (m, 2H, -C6H2), 6.73 (s, 1H, =CH), 6.73-7.20 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.7, 20.0, 25.6, 25.8, 56.5, 65.1, 65.4, 96.7, 98.9, 103.3, 104.6, 110.7, 114.4, 121.3, 123.4, 123.6, 127.2, 129.6, 132.6, 132.7, 159.7, 162.0, 163.4, 168.4, 182.6; IR (KBr) cm-1: 2943, 1678, 1221, 970; ESI-HRMS calcd. for C26H28O5+ ([M+H]+): 421.1937, found: 421.1921.

3’-Methoxy-5,7-diisoprenyloxyflavone (4q)

Yield: 65.2 %, mp. 77-79 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.66 (s, 3H, -CH3), 1.67 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 3.71 (s, 3H, -O CH3), 4.45 (d, 2H, -CH2), 4.48 (d, 2H, -CH2), 5.39 (t, 1H, =CH), 5.43 (t, 1H, =CH), 6.06-6.12 (m, 2H, -C6H2), 6.59 (s, 1H, =CH), 6.71-7.19 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.8, 20.1, 25.6, 25.8, 56.0, 64.9, 65.4, 98.8, 100.1, 103.2, 104.3, 110.3 113.5, 118.5, 123.5, 123.6, 129.8, 131.4, 132.5, 132.8, 159.8, 162.5, 163.8, 168.3, 182.6; IR (KBr) cm-1: 2942, 1677, 1220, 971; ESI-HRMS calcd. for C26H28O5+ ([M+H]+): 421.1937, found: 421.1921.

4’-Methoxy-5,7-diisoprenyloxyflavone (4r)

Yield: 81.1%, mp 88-90 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.69 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.72 (s, 3H, -CH3), 3.71 (s, 3H, -O CH3), 4.50 (d, 2H, -CH2), 4.52 (d, 2H, -CH2), 5.39 (t, 1H, =CH), 5.42 (t, 1H, =CH), 6.02-6.10 (m, 2H, -C6H2), 6.69 (s, 1H, =CH), 6.67-7.13 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.4, 20.3, 25.4, 25.6, 55.9, 65.8, 60.2, 97.8, 99.9, 103.4, 104.5, 114.7, 114.9, 122.7, 123.3, 123.5, 127.4, 127.6, 132.4, 132.7, 160.1, 162.3, 163.6, 168.5, 182.4; IR (KBr) cm-1: 2941, 1675, 1221, 969; ESI-HRMS calcd. for C26H28O5+ ([M+H]+): 421.1937, found: 421.1942.

4’-Dimethylamine-5,7-diisoprenyloxyflavone (4s)

Yield: 63%, mp 83-85 °C; 1H-NMR (DMSO-d6, 300 MHz): δ 1.68 (s, 3H, -CH3), 1.69 (s, 3H, -CH3), 1.70 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 2.80, 2.89 (s, 6H, -N(CH3)2), 4.61 (d, 2H, -CH2), 4.63 (d, 2H, -CH2), 5.40 (t, 1H, =CH), 5.42 (t, 1H, =CH), 6.03-6.11 (m, 2H, -C6H2), 6.76 (s, 1H, =CH), 6.60-7.16 (m, 4H, -C6H4); 13C-NMR (DMSO-d6, 75 MHz): δ 19.8, 20.2, 25.4, 25.7, 40.5, 40.8, 65.4, 65.6, 97.8, 99.6, 103.4, 104.5, 114.3, 114.5, 119.3, 123.3, 123.4, 127.1, 127.4, 132.4, 132.5, 148.4, 160.0, 162.5, 163.4, 168.4, 182.5; IR (KBr) cm-1: 2940, 1676, 1220, 970; ESI-HRMS calcd. for C27H31NO4+ ([M+H]+): 434.2253, found: 434.2243.

3-Methoxy-4’-hydroxy-5,7-diisoprenyloxyflavone (4t)

Yield: 73.4%; obtained as an oil; 1H-NMR (DMSO-d6, 300 MHz): δ 1.67 (s, 3H, -CH3), 1.69 (s, 3H, -CH3), 1.71 (s, 3H, -CH3), 1.73 (s, 3H, -CH3), 3.75 (s, 3H, -OCH3), 4.60 (d, 2H, -CH2), 4.63 (d, 2H, -CH2), 5.41 (t, 1H, =CH), 5.44 (t, 1H, =CH), 6.03-6.12 (m, 2H, -C6H2), 6.73 (s, 1H, =CH), 6.53-6.79 (m, 3H, -C6H3), 9.12 (s, 1H, -OH); 13C-NMR (DMSO-d6, 75 MHz): δ 19.7, 19.9, 25.7, 25.9, 56.8, 65.6, 65.8, 98.9, 99.9, 103.6, 104.3, 113.4, 115.4, 120.3, 123.4, 123.7, 124.6, 132.5, 132.7, 145.7, 150.1, 159.7, 162.2, 163.5, 168.5, 182.3; IR (KBr) cm-1: 3250, 2942, 1678, 1221, 970; ESI-HRMS calcd. for C26H28O6+ ([M+H]+): 437.1886, found: 437.1864.

Evaluation of the antibacterial activity in vitro

The microorganisms used in the present study were S. aureus (S. aureus KCTC 503, S. aureus RN4220, and S. aureus KCTC 209), S. mutans (S. mutans KCTC 3289 and S. mutans KCTC 3065), and Escherichia coli (E. coli 1924 and E. coli 1356). The strains of multidrug-resistant clinical isolates used were multidrug-resistant S. aureus (MRSA CCARM 3167 and MRSA CCARM 3506) and quinolone-resistant S. aureus (QRSA CCARM 3505 and QRSA CCARM 3519). Clinical isolates were collected from various patients hospitalized in several clinics (Hosseinkhani et al., 2016Hosseinkhani F, Jabalameli F, Banar M, Abdellahi N, Taherikalani M, Leeuwen WB, Emaneini M. Monoterpene isolated from the essential oil of trachyspermum ammi is cytotoxic to multidrug-resistant pseudomonas aeruginosa and staphylococcus aureus strains. Rev Soc Bras Med Trop. 2016;49(2):172-176 .; Fan, Reichling, Wink, 2013Fan X, Reichling J, Wink M. Antibacterial activity of the recombinant antimicrobial peptide Ib-AMP4 from Impatiens balsamina and its synergy with other antimicrobial agents against drug resistant bacteria. Pharmazie. 2013;68(7):628-630.; Sharma et al., 2011Sharma PK, Chandak N, Kumar P, Sharma C, Aneja KR. Synthesis and biological evaluation of some 4-functionalized-pyrazoles as antimicrobial agents. Eur J Med Chem. 2011;46(4):1425-1432.).

A twofold serial dilution technique (Song et al., 2013Song MX, Zheng CJ, Deng XQ, Wang Q, Hou SP, Liu TT, Xing XL, Piao HR. Synthesis and bioactivity evaluation of rhodanine derivatives as potential anti-bacterial agents. Eur J Med Chem. 2012;54:403-412.) was used to determine the minimum inhibitory concentrations (MICs) of the compounds against susceptible microorganisms in the preliminary test (Gram-positive and Gram-negative bacteria) and against strains of clinical isolates of multidrug-resistant Gram-positive bacteria. The compounds dissolved in DMSO and two-fold diluted at concentrations from 200 µg/mL to 0.1 µg/mL, and they were added to culture media (Brain heart infusion for S. mutans and Mueller-Hinton agar for other bacteria) to obtain final concentrations of 0.5-64 µg/mL. The final amount of bacteria applied was 105 CFU/mL. MIC values were determined after incubation at 37 °C for 20 h. The lowest concentration of the test substance that completely inhibited microorganism growth was recorded as the MIC (expressed in µM). Norfloxacin was used as the drug standard. All experiments were conducted in triplicate.

RESULTS AND DISCUSSION

Chemistry

The target compounds were obtained as outlined in Scheme 1. Compounds 1a-1t were synthesized from the Claisen-Schmidt condensation of commercially available 2,4,6-trihydroxyacetophenone (protected as methoxymethyl ethers) with different substituted aromatic aldehydes in aqueous ethanolic sodium hydroxide (Zhen et al., 2016Zhen XH, Quan YC, Peng Z, Han Y, Zheng ZJ, Guan LP. Design, synthesis, and potential antidepressant-like activity of 7-prenyloxy-2,3-dihydroflavanone derivatives. Chem Biol Drug Des. 2016;87(6):858-866.). Intermediates 1a-1t were then treated with 3 M HCl in methanol to yield 2,4,6-trihydroxychalcones derivatives 2a-2t (Xie et al., 2014Xie C, Peng Z, Zhao SL, Pan CY, Guan LP, Sun XY. Synthesis of 2´-hydroxy-4´- isoprenyloxychalcone derivatives with potential antidepressant-like activity. Med Chem. 2014;10(8):789-799.). Subsequent substitution with prenyl bromide in acetone under reflux in the presence of anhydrous K2CO3 afforded compounds 3a-3t (Wang et al., 2015Wang HM, Zhang L, Liu J, Yang ZL, Zhao HY,Yang Y, Shen D, Lu K, Fan ZC, Yao QW, Zhang YM, Teng YO, Peng Y. Synthesis and anticancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs. Eur J Med Chem. 2015;92:439-448.). 5,7-Diisoprenyloxyflavone derivatives 4a-4t were obtained in good yields by treating 3a-3t with I2 in DMSO. The chemical structures of the target compounds were characterized by IR, 1H-NMR, 13C-NMR, and high-resolution mass spectroscopy. The IR spectra of the newly synthesized 5,7-diisoprenyloxyflavone derivatives 4a-4t showed absorption stretching bands at 2931-2943 cm-1 and 1672-1678 cm-1 stretching (1220-1222 cm-1) corresponding to (-CH3), (C=O) and (C-O-C) group, respectively. IR spectrum of compound 4t showed absorption bands at 3250 cm-1 corresponding to stretching absorption of -OH group. The characteristic feature in the 1H-NMR spectrum of compound 2t is the appearance of two triplet peaks at 5.41 and 5.44 ppm which represented the prenyl protons in (CH=C-) group. Furthermore, two singlet peaks at 6.73 ppm and 9.12 ppm related to flavone ring 3-C protons in (CH=) group and at phenyl ring 4´-C protons in (-OH) group were observed. 1H-NMR spectra showed the =CH protons of the group at 6.56-7.02 ppm, The characteristic feature in the 13C-NMR spectrum of compound 2t displayed four signals peakes in (-CH3) group (19.7 ppm, 19.9 ppm, 25.7 ppm, 25.9 ppm), while showed C=O signals at 182.3 ppm. The structure of 2t was further verified by mass spectroscopy that showed a molecular ion peak [M+H]+ at ESI-HRMS 437.1864 (55.4%) in accordance with the molecular formula C26H28O6.

Antibacterial activity

In this study, antibacterial activity was determined from the MIC with different strains in vitro, including multidrug-resistant clinical isolates. Norfloxacin was used as a positive control for bacteria. As shown in Table I, compounds 4a-4t did not exhibit antibacterial activity against Gram-negative strains at a dose of 24-164 µM in vitro, but some compounds displayed potent antibacterial activity against Gram-positive strains. Nine compounds gave MIC values of 4.4-19 µM. Compounds 4c, 4g, 4i, 4j, 4k, 4l, 4n, 4q and 4t were highly active against S. aureus (S. aureus RN4220, S. aureus KCTC 503, and S. aureus KCTC 209) and Streptococcus mutans KCTC (S. mutans KCTC 3065 and S. mutans KCTC 3289) strains, with MIC values of 4.4-19 µM, but were less active than standard drug norfloxacin. The synthesized derivatives showed significant antibacterial effects against S. aureus, with 2,4-Cl2 substituted compound 4k giving a MIC value of 4.4 µM, which was similarly active to standard drug norfloxacin.

TABLE I
Inhibitory activity of compounds 4a-4t expressed as MIC (µM)

By analyzing the activities of synthesized compounds 4a-4t, the following structure activity relationships were observed. Eight electron-donor compounds including o-CH3, m-CH3, p-CH3, o-OCH3, m-OCH3, p-OCH3, p-N(CH3)2, and 3-OCH3-4-OH on the substituent of phenyl ring, were designed and synthesized. Pharmacological test results showed that their activities were lower than those of halogen-substituted derivatives of phenyl ring, with activities in the order 3-OCH3-4-OH > m-OCH3 > m-CH3> H > o-CH3, p-CH3 > o-OCH3, p-OCH3, p-N(CH3)2. For different position methyl and methoxy groups on the substituent of phenyl ring influenced the antibacterial effects with activities in the order m-CH3 > o-CH3, p-CH3, and m-OCH3 > o-OCH3, p-OCH3. Furthermore, the position of electron-withdrawing (F, Cl, and Br) groups on the B ring (of phenyl ring) significantly influenced the antibacterial activity, with activities in the order m-F > p-F > o-F for fluoro-substituted compounds of phenyl ring, and p-Br > m-Br > o-Br for bromo-substituted compounds of phenyl ring. In comparison, the chloro-substituted derivatives of phenyl ring showed activities in the order 2,4-dichloro > p-Cl > m-Cl > o-Cl. Therefore, compounds 4c, 4g, and 4j bearing m-F, p-Cl, and p-Br substituents of phenyl ring, respectively, showed better activities, while those bearing o-F, o-Cl, and o-Br substituents of phenyl ring (4b, 4e, and 4f, respectively) were inactive for all microorganisms, even at doses of 24-151 µM. Compound 4k (MIC = 4.4 µM) was 30-fold more potent than apigenin (MIC = 118.5 µM). It has been proposed that the prenyl moiety on A ring makes compounds more lipophilic, which leads to a higher affinity with cell membranes, with prenylation shown to afford flavonoids with enhanced antibacterial activities (Ei-Bassuony, Abouzid, 2010Ei-Bassuony A, Abouzid S. A new prenylated flavanoid with antibacterial activity from propolis collected in Egypt. Nat Prod Commun. 2010;5(1):43-45.; Yu et al., 2015Yu Q, Ravu RR, Xu QM, Ganji S, Jacob MR, Khan SI, Yu BY, Li XC. Antibacterial prenylated acylphloroglucinols from psorothamnus fremontii. J Nat Prod. 2015;78(11):2748-2753 .).

Activity against clinical isolates of multidrug-resistant Gram-positive bacteria

The most active compounds, 4c, 4g, 4i, 4j, 4k, 4l, 4n, 4q and 4t, were also evaluated for antibacterial effects against clinical isolates of multidrug-resistant Gram-positive bacteria (Table II). These derivatives were found to be highly active against these clinical isolates, giving MIC values of 4.0-20 µM. Compound 4k was more potent than norfloxacin against most microorganisms tested, giving an MIC value of 4.0 µM. This suggested that the introduction of two halogen atoms of phenyl ring and a prenyl moiety on A ring into the hybrid compound played an important role in improving the antibacterial properties (Chen et al., 2014Chen X, Mukwaya E, Wong MS, Zhang Y. A systematic review on biological activities of prenylated flavonoids. Pharm Biol. 2014;52(5):655-660 .; Marín, Máñez, 2013Marín M, Máñez S. Recent trends in the pharmacological activity of isoprenyl phenolics. Curr Med Chem. 2013;20(2):272-279.). Therefore, compound 4k should be used as the lead compound for further design and investigations.

TABLE II
MIC values (in µM) against clinical isolates of multidrug-resistant Gram-positive bacterial strains

CONCLUSION

We synthesized a series of novel 5,7-diisoprenyl oxyflavone derivatives and evaluated their antibacterial effects against Gram-positive and Gram-negative bacteria.

Compounds 4c, 4g, 4i, 4j, 4k, 4l, 4n, 4q and 4t were highly active against S. aureus and S. mutans KCTC, giving MIC values of 4.0-20 µM, and also showed high activities against clinical isolates of multidrug-resistant Gram-positive bacteria, with MIC values of 4.0-20 µM. In particular, compound 4k was more potent than norfloxacin against most microorganisms tested, giving a better MIC value of 4.0 µM. This indicated that hybrid compounds possessing flavone and prenyl moieties might possess improved antibacterial properties. These results indicate that the further design and development of such compounds will be of interest in future research.

ACKNOWLEDGEMENTS

This work was supported by the Science and Technology Program Project of Zhoushan City of China (No. 2016C41005) and the National Natural Science Foundation of China (No. 81560149) and 13th Five-Year Key Projects of Jilin Provincial Education Department of China (No. JJKH2016261H). We also thank Simon Partridge, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

REFERENCES

  • Ahmed D, Khan MM, Saeed R. Comparative analysis of phenolics, flavonoids, and antioxidant and antibacterial potential of methanolic, hexanic and aqueous extracts from adiantum caudatum leaves. Antioxidants (Basel). 2015;4(2):394-409.
  • Banerjee K, Banerjee S, Das S, Mandal M. Probing the potential of apigenin liposomes in enhancing bacterial membrane perturbation and integrity loss. J Colloid Interf Sci. 2015;453:48-59.
  • Chen ZH, Zheng CJ, Sun LP, Piao HR. Synthesis of new chalcone derivatives containing a rhodanine-3-acetic acid moiety with potential anti-bacterial activity. Eur J Med Chem. 2010;45(12):5739-5743.
  • Chen X, Mukwaya E, Wong MS, Zhang Y. A systematic review on biological activities of prenylated flavonoids. Pharm Biol. 2014;52(5):655-660 .
  • Choi AY, Choi JH, Lee JY, Yoon KS, Choe W, Ha J, Yeo EJ, Kang I. Apigenin protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis. Neurochem Int. 2010;57(2):143-152.
  • Coelho AL, Vasconcellos MLAA, Simas ABC, Rabi JA, Costa PRR. A convenient synthesis of (±)-4-Prenylpterocarpin. Synthesis. 1992;10:914-916.
  • Ei-Bassuony A, Abouzid S. A new prenylated flavanoid with antibacterial activity from propolis collected in Egypt. Nat Prod Commun. 2010;5(1):43-45.
  • Eumkeb G, Chukrathok S. Synergistic activity and mechanism of action of ceftazidime and apigenin combination against ceftazidime-resistant Enterobacter cloacae. Phytomedicine. 2013;20(3-4):262-269.
  • Fan X, Reichling J, Wink M. Antibacterial activity of the recombinant antimicrobial peptide Ib-AMP4 from Impatiens balsamina and its synergy with other antimicrobial agents against drug resistant bacteria. Pharmazie. 2013;68(7):628-630.
  • Friedman M. Overview of antibacterial, antitoxin, antiviral, and antifungal activities of tea flavonoids and teas. Mol Nutr Food Res. 2007;51(1):116-134.
  • Guan LP, Zhao DH, Chang Y, Sun Y, Ding XL, Jiang JF. Design, synthesis and antidepressant activity evaluation 2′-hydroxy-4′,6′-diisoprenyloxychalcone derivatives. Med Chem Res. 2013;22(11):5218-5226.
  • Harbme JB, Williams CA. Advances in flavonoid research since 1992. Phytochem. 2000;55(6):481-504.
  • Hosseinkhani F, Jabalameli F, Banar M, Abdellahi N, Taherikalani M, Leeuwen WB, Emaneini M. Monoterpene isolated from the essential oil of trachyspermum ammi is cytotoxic to multidrug-resistant pseudomonas aeruginosa and staphylococcus aureus strains. Rev Soc Bras Med Trop. 2016;49(2):172-176 .
  • Karakaya S, Sedef NEL. Quercetin, luteolin, apigenin and kaempferol contents of some foods. Food Chem. 1999;66(3):289-292.
  • Keshari AK, Kumar G, Kushwaha PS, Bhardwaj M, Kumar P, Rawat A, Kumar D, Prakash A, Ghosh B, Saha S. Isolated flavonoids from Ficus racemosa stem bark possess antidiabetic, hypolipidemic and protective effects in albino Wistar rats. J Ethnopharmacol. 2016;181:252-262.
  • Kim S, Sohn DW, Kim YC, Kim SA, Lee SK, Kim HS. Fine tuning of a reported synthetic route for biologically active flavonoid, baicalein. Arch Pharm Res. 2007;30(1):18-21.
  • Kozyra M, Biernasiuk A, Malm A, Chowaniec M. Chemical compositions and antibacterial activity of extracts obtained from the inflorescences of Cirsium canum (L.) all. Nat Prod Res. 2015;29(21):2059-2063.
  • Kulbacka J, Pucek A, Kotulska M, Dubińska-magiera M, Rossowska J, Rols MP, Wilk KA. Electroporation and lipid nanoparticles with cyanine IR-780 and flavonoids as efficient vectors to enhanced drug delivery in colon cancer. Bioelectrochem. 2016;110:19-31.
  • Liu R, Zhang H, Yuan M, Zhou J, Tu Q, Liu JJ, Wang J. Synthesis and biological evaluation of apigenin derivatives as antibacterial and antiproliferative agents. Molecules. 2013;18(9):11496-11511.
  • Marín M, Máñez S. Recent trends in the pharmacological activity of isoprenyl phenolics. Curr Med Chem. 2013;20(2):272-279.
  • Rao GV, Swamy BN, Chandregowda V, Reddy GC. Synthesis of (+/-) Abyssinone I and related compounds:Their anti-oxidant and cytotoxic activities. Eur J Med Chem. 2009;44(5):2239-2245.
  • Ruivo J, Francisco C, Oliveira R, Figueiras A. The main potentialities of resveratrol for drug delivery systems. Braz J Pharm Sci. 2015;51(3):499-513.
  • Sharma PK, Chandak N, Kumar P, Sharma C, Aneja KR. Synthesis and biological evaluation of some 4-functionalized-pyrazoles as antimicrobial agents. Eur J Med Chem. 2011;46(4):1425-1432.
  • Song MX, Zheng CJ, Deng XQ, Wang Q, Hou SP, Liu TT, Xing XL, Piao HR. Synthesis and bioactivity evaluation of rhodanine derivatives as potential anti-bacterial agents. Eur J Med Chem. 2012;54:403-412.
  • Turktekin M, Konac E, Onen HI, Alp E, Yilmaz A, Menevse S. Evaluation of the effects of the flavonoid apigenin on apoptotic pathway gene expression on the colon cancer cell line (HT29). J Med Food. 2011;14(10):1107-1117.
  • Verlinden BK, Louw A, Birkholtz LM. Resisting resistance: is there a solution for malaria? Expert Opin Drug Discov. 2016;11(4):395-406.
  • Vogel S, Ohmayer S, Brunner G, Heilmann J. Natural and non-natural prenylate chalcones: synthesis, cytotoxicity and anti-oxidative activity. Bioorg Med Chem. 2008;16(8):4286-4293.
  • Vogel S, Barbic M, Jürgenliemk G, Heilmann J. Synthesis, cytotoxicity, anti- oxidative and anti-inflammatory activity of chalcones and influence of A-ring modifications on the pharmacological effect. Eur J Med Chem. 2010;45(6):2206-2213.
  • Winans KA, King DA, Rao VR, Bertozzi CR. A Chemically synthesized version of the insect antibacterial glycopeptide, diptericin, disrupts bacterial membrane integrity. Biochem. 1999;38(36):11700-11710.
  • Wang HM, Zhang L, Liu J, Yang ZL, Zhao HY,Yang Y, Shen D, Lu K, Fan ZC, Yao QW, Zhang YM, Teng YO, Peng Y. Synthesis and anticancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs. Eur J Med Chem. 2015;92:439-448.
  • Xie C, Peng Z, Zhao SL, Pan CY, Guan LP, Sun XY. Synthesis of 2´-hydroxy-4´- isoprenyloxychalcone derivatives with potential antidepressant-like activity. Med Chem. 2014;10(8):789-799.
  • Yao Y, Lin G , Xie Y, Ma P, Li G, Meng Q, Wu T. Preformulation studies of myricetin: a natural antioxidant flavonoid. Pharmazie. 2014;69(1):19-26.
  • Yu Q, Ravu RR, Xu QM, Ganji S, Jacob MR, Khan SI, Yu BY, Li XC. Antibacterial prenylated acylphloroglucinols from psorothamnus fremontii. J Nat Prod. 2015;78(11):2748-2753 .
  • Zhao LM, Jin HS, Wan LJ, Zhang LM. General and highly a-regioselective zinc-mediated prenylation of aldehydes and ketones. J Org Chem. 2011;76(6):1831-1837.
  • Zhen XH, Quan YC, Peng Z, Han Y, Zheng ZJ, Guan LP. Design, synthesis, and potential antidepressant-like activity of 7-prenyloxy-2,3-dihydroflavanone derivatives. Chem Biol Drug Des. 2016;87(6):858-866.

Publication Dates

  • Publication in this collection
    06 Apr 2020
  • Date of issue
    2020

History

  • Received
    07 Nov 2017
  • Accepted
    23 Oct 2018
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br