CN: 32-1845/R
ISSN: 2095-6975
YAO Ling, WU Ling-Ling, LI Qian, HU Qin-Mei, ZHANG Shu-Yuan, LIU Kang, JIANG Jian-Qin. Novel berberine derivatives: Design, synthesis, antimicrobial effects, and molecular docking studies[J]. 中国天然药物英文, 2018, 16(10): 774-781

Novel berberine derivatives: Design, synthesis, antimicrobial effects, and molecular docking studies

YAO Ling, WU Ling-Ling, LI Qian, HU Qin-Mei, ZHANG Shu-Yuan, LIU Kang, JIANG Jian-Qin
School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
A series of berberine derivatives were synthesized by introducing substituted benzyl groups at C-9. All these synthesized compounds (4a-4m) were screened for their in vitro antibacterial activity against four Gram-positive bacteria and four Gram-negative bacteria and evaluated for their antifungal activity against three pathogenic fungal strains. All these compounds displayed good antibacterial and antifungal activities, compared to reference drugs including Ciprofloxacin and Fluconazole; Compounds 4f, 4g, and 4l showed the highest antibacterial and antifungal activities. Moreover, all the synthesized compounds were docked into topoisomerase Ⅱ-DNA complex, which is a crucial drug target for the treatment of microbial infections. Docking results showed that H-bond, π-π stacked, π-cationic, and π-anionic interactions were responsible for the strong binding of the compounds with the target protein-DNA complex.
关键词:    Antimicrobial drugs    Berberine derivatives    Molecular docking    Topoisomerase II DNA gyrase    SAR   
收稿日期: 2018-05-28
JIANG Jian-Qin,Tel:13913982651,;LIU Kang,Tel:13912979427,
PDF(1840 KB) Free
YAO Ling 在本刊中的所有文章
WU Ling-Ling 在本刊中的所有文章
LI Qian 在本刊中的所有文章
HU Qin-Mei 在本刊中的所有文章
ZHANG Shu-Yuan 在本刊中的所有文章
LIU Kang 在本刊中的所有文章
JIANG Jian-Qin 在本刊中的所有文章
[1] GBD Mortality, Collaborators COD. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013:a systematic analysis for the Global Burden of Disease Study 2013[J]. Lancet, 2015, 385(9963):117-171.
[2] Fridkin SK, Gaynes RP. Antimicrobial resistance in inten-sive care units[J]. Lancet Infect Dis, 2014, 14(1):303-316.
[3] Bhutta ZA, Salam RA, Das JK, et al. Tackling the existing burden of infectious diseases in the developing world:existing gaps and the way forward[J]. Infec Dis Poverty, 2014, 3(1):28.
[4] Fisher MC, Henk DA, Briggs CJ, et al. Emerging fungal threats to animal, plant and ecosystem health[J]. Nature, 2012, 484(7393):186-194.
[5] Kang CI, Song JH. Antimicrobial resistance in Asia:Cur-rent epidemiology and clinical implications[J]. J Infect Chemother, 2013, 45(1):22-31.
[6] Spellberg B, Blaser M, Guidos RJ, et al. Policy Paper. Combating antimicrobial resistance:policy recommendations to save lives[J]. Clin Infect Dis, 2011, 52(suppl_5):S397-S420.
[7] Eber MR, Laxminarayan R, Perencevich EN, et al. Clinical and economic outcomes attributable to health care-associated sepsis and pneumonia[J]. JAMA Inter Med, 2010, 170(4):347-353.
[8] Livermore DM. Discovery research:the scientific chal-lenge of finding new antibiotics[J]. J Antimicrob Chemother, 2011, 66(9):1941-1944.
[9] Khosa C, Patel K, Abdiyeva K, et al. Proceedings from the CIH LMU 5th infectious diseases symposium 2016 "Drug Resistant Tuberculosis:Old Disease-New Challenge"[J]. BMC Proceedings, 2017, 11(Suppl 10):0-6.
[10] Eidem TM, Lounsbury N, Emery JF, et al. Small-Molecule inhibitors of Staphylococcus aureus RnpA-Mediated RNA turnover and tRNA processing[J]. Antimicrob Agents Ch, 2015, 59(4):2016-2028.
[11] Wiskirchen DE. Antimicrobial research and the develop-ment pipeline[J]. J Am Pharm Assoc, 2012, 52(1):8-9.
[12] Das K, Tiwari RKS, Shrivastava DK. Techniques for evaluation of medicinal plant products as antimicrobial agents:current methods and future trends[J]. J Med Plants Res, 2010, 4(2):104-111.
[13] Affuso F, Mercurio V, Fazio V, et al. Cardiovascular and metabolic effects of berberine[J]. World J Cardiol, 2010, 2(4):71-77.
[14] Derosa G, Maffioli P. Alkaloids in the nature:pharmacol-ogical applications in clinical practice of berberine and mate tea[J]. Curr Top Med Chem, 2014, 14(2):200-206.
[15] Liu CS, Zheng YR, Zhang YF, et al. Research progress on berberine with a special focus on its oral bioavailability[J]. Fitoterapia, 2016, 109(2):274.
[16] El-Salam MA, Mekky H, El-Naggar EMB, et al. Hepatoprotective properties and biotransformation of berberine and berberrubine by cell suspension cultures of Dodonaea viscosa, and Ocimum basilicum[J]. S Afr J Bot, 2015, 97(2015):191-195.
[17] Caliceti C, Franco P, Spinozzi S, et al. Berberine:new insights from pharmacological aspects to clinical evidences in the management of metabolic disorders[J]. Curr Med Chem, 2016, 23(14):1460-1476.
[18] Ortiz LM, Lombardi P, Tillhon M, et al. Berberine, an epiphany against cancer[J]. Molecules, 2014, 19(8):12349-12367.
[19] Pang B, Zhao LH, Zhou Q, et al. Application of berberine on treating type 2 diabetes mellitus[J]. Int J Endocrinol, 2015, 2015(3):905749-905759.
[20] Boberek J M, Stach J, Good L. Genetic evidence for inhi-bition of bacterial division protein FtsZ by berberine[J]. PLos One, 2010, 5(10):e13745.
[21] Bandyopadhyay S, Patra PH, Mahanti A, et al. Potential antibacterial activity of berberine against multi drug resistant enterovirulent Escherichia coli isolated from yaks (Poephagus grunniens) with haemorrhagic diarrhoea[J]. Asian Pac J Trop Med, 2013, 6(4):315-319.
[22] Cecil CE, Davis JM, Cech NB, et al. Inhibition of H1N1 influenza A virus growth and induction of inflammatory mediators by the isoquinoline alkaloid berberine and extracts of goldenseal (Hydrastis canadensis)[J]. Int Immunopharmacol, 2011, 11(11):1706-1714.
[23] Battu SK, Repka MA, Maddineni S, et al. Physicochemical characterization of berberine chloride:a perspective in the development of a solution dosage form for oral delivery[J]. Aaps Pharmscitech, 2010, 11(3):1466-1475.
[24] Zhang Y, Cui YL, Gao LN, et al. Effects of β-cyclodextrin on the intestinal absorption of berberine hydrochloride, a P-glycoprotein substrate[J]. Int J Biol Macromol, 2013, 59(5):363-371.
[25] Chen Z, Ye X, Yi J, et al. Synthesis of 9-O-glycosyl-berberine derivatives and bioavailability evaluation[J]. Med Chem Res, 2012, 21(8):1641-1646.
[26] Wang X, Wang N, Li H, et al. Up-Regulation of PAI-1 and down-regulation of uPA are involved in suppression of invasiveness and motility of hepatocellular carcinoma cells by a natural compound berberine[J]. Int J Mol Sci, 2016, 17(4):577.
[27] Park KD, Lee JH, Kim SH, et al. Synthesis of 13-(substituted benzyl) berberine and berberrubine derivatives as antifungal agents[J]. Bioorg Med Chem Lett, 2006, 16(15):3913-3916.
[28] Samosorn S, Tanwirat B, Muhamad N, et al. Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group[J]. Bioorg Med Chem Lett, 2009, 17(11):3866-3872.
[29] Li YH, Fu HG, Su F, et al. Synthesis and structure-activity relationship of 8-substituted protoberberine derivatives as a novel class of antitubercular agents[J]. Chem Cent J, 2013, 7(1):117.
[30] Lo CY, Hsu LC, Chen MS, et al. Synthesis and anticancer activity of a novel series of 9-O-substituted berberine derivatives:a lipophilic substitute role[J]. Bioorg Med Chem Lett, 2013, 23(1):305-309.
[31] Zhang S, Wang X, Yin W, et al. Synthesis and hypoglyce-mic activity of 9-O-(lipophilic group substituted) berberine derivatives[J]. Bioorg Med Chem Lett, 2016, 26(19):4799-4803.
[32] Iwasa K, Nanba H, Lee DU, et al. Structure-activity relationships of protoberberines having antimicrobial activity[J]. Planta Med, 1998, 64(8):748-751.
[33] Peng L, Shuai K, Yin Z, et al. Antibacterial activity and mechanism of berberine against Streptococcus agalactiae[J]. Int J Clin Exp Pathol, 2014, 8(5):5217-5223.
[34] Kim SA, Kwon Y, Kim JH, et al. Induction of topoisom-erase Ⅱ-mediated DNA cleavage by a protoberberine alkaloid, berberrubine[J]. Biochemistry, 1998, 37(46):16316.
[35] Cockerill FR. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically:Approved Standard[M]. Clinical and Laboratory Standards Institute, 2012, M07-A9, 32(2):18-19.
[36] Wayne P. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard[J]. Nccls Document, 2010, 27(1):21-23.
[37] Bax BD, Chan PF, Eggleston DS, et al. Type ⅡA topoisomerase inhibition by a new class of antibacterial agents[J]. Nature, 2010, 466(7309):935-940.