Generic placeholder image

Medicinal Chemistry

Author(s): Beatriz C. Marques, Mariana B. Santos, Daiane B. Anselmo, Diego A. Monteiro, Eleni Gomes, Marilia F.C. Saiki, Paula Rahal, Pedro L. Rosalen, Janaina C.O. Sardi and Luis O. Regasini*

DOI: 10.2174/1573406415666190724145158

DownloadDownload PDF Flyer Cite As
Methoxychalcones: Effect of Methoxyl Group on the Antifungal, Antibacterial and Antiproliferative Activities

Page: [881 - 891] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Chalcones substituted by methoxyl groups have presented a broad spectrum of bioactivities, including antifungal, antibacterial and antiproliferative effects. However, a clear and unambiguous investigation about the relevance of this substituent on the chalcone framework has not been described.

Objective: The purpose of this work is to assess the antibacterial, antifungal and antiproliferative activities of the two series of seventeen synthesized regioisomeric methoxychalcones. Series I and II were constituted by chalcones substituted by methoxyl groups on rings A (5–12) and B (13–21), respectively. In addition, the library of methoxychalcones was submitted to in silico drug-likeness and pharmacokinetics properties predictions.

Methods: Methoxychalcones were synthesized and their structures were confirmed by NMR spectral data analyses. Evaluations of antimicrobial activity were performed against five species of Candida, two Gram-negative and five Gram-positive species. For antiproliferative activity, methoxychalcones were evaluated against four human tumorigenic cell lines, as well as human non-tumorigenic keratinocytes. Drug-likeness and pharmacokinetics properties were predicted using Molinspiration and PreADMET toolkits.

Results: In general, chalcones of series I are the most potent antifungal, antibacterial and antiproliferative agents. 3’, 4’, 5’-Trimethoxychalcone (12) demonstrated potent antifungal activity against Candida krusei (MIC = 3.9 μg/mL), eight times more potent than fluconazole (reference antifungal drug). 3’-Methoxychalcone (6) displayed anti-Pseudomonas activity (MIC = 7.8 μg/mL). 2’,5’-Dimethoxychalcone (9) displayed potent antiproliferative effect against C-33A (cervix), A-431 (skin) and MCF-7 (breast), with IC50 values ranging from 7.7 to 9.2 μM. Its potency was superior to curcumin (reference antiproliferative compound), which exhibited IC50 values ranging from 10.4 to 19.0 μM.

Conclusion: Our studies corroborated the relevance of methoxychalcones as antifungal, antibacterial and antiproliferative agents. In addition, we elucidated influence of the position and number of methoxyl groups toward bioactivity. In silico predictions indicated good drug-likeness and pharmacokinetics properties to the library of methoxychalcones.

Keywords: Antibacterial, antifungal, antiproliferative, chalcone, methoxyl, drug-likeness.

Graphical Abstract

[1]
Mazu, T.K.; Bricker, B.A.; Flores-Rozas, H.; Ablordeppey, S.Y. The mechanistic targets of antifungal agents: An overview. Mini Rev. Med. Chem., 2016, 16(7), 555-578.
[http://dx.doi.org/10.2174/1389557516666160118112103] [PMID: 26776224]
[2]
Karacaer, Z.; Oncul, O.; Turhan, V.; Gorenek, L.; Ozyurt, M. A surveillance of nosocomial candida infections: epidemiology and influences on mortalty in intensive care units. Pan Afr. Med. J., 2014, 19, 398-406.
[http://dx.doi.org/10.11604/pamj.2014.19.398.4960] [PMID: 25995794]
[3]
Santajit, S.; Indrawattana, N. Mechanisms of antimicrobial resistance in ESKAPE pathogens. BioMed Res. Int., 2016, 20162475067
[http://dx.doi.org/10.1155/2016/2475067] [PMID: 27274985]
[4]
Udwadia, Z.F. MDR, XDR, TDR tuberculosis: ominous progression. Thorax, 2012, 67(4), 286-288.
[http://dx.doi.org/10.1136/thoraxjnl-2012-201663] [PMID: 22427352]
[5]
Das, M.; Manna, K. Chalcone Scaffold in Anticancer Armamentarium: A Molecular Insight. J. Toxicol., 2016, 20167651047
[http://dx.doi.org/10.1155/2016/7651047] [PMID: 26880913]
[6]
Michael, J.T.; John, O.D.; Melissa, M.C.; Ahmedin, J.; Elizabeth, M.W. The global burden of cancer: priorities for prevention. Carcinogenesis, 2010, 31, 100-110.
[7]
Jemal, A.; Bray, F.; Center, M.M.; Ferlay, J.; Ward, E.; Forman, D. Global cancer statistics. CA Cancer J. Clin., 2011, 61(2), 69-90.
[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[8]
Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev., 2017, 117(12), 7762-7810.
[http://dx.doi.org/10.1021/acs.chemrev.7b00020] [PMID: 28488435]
[9]
Rozmer, Z.; Perje’si, P. Naturally occurring chalcones and their biological activities. Phytochem. Rev., 2016, 15, 87-120.
[http://dx.doi.org/10.1007/s11101-014-9387-8]
[10]
Gomes, M.N.; Muratov, E.N.; Pereira, M.; Peixoto, J.C.; Rosseto, L.P.; Cravo, P.V.L.; Andrade, C.H.; Neves, B.J. Chalcone derivatives: Promising starting points for drug design. Molecules, 2017, 22(8), 1210.
[http://dx.doi.org/10.3390/molecules22081210] [PMID: 28757583]
[11]
Dastagir, G.; Rizvi, M.A. Glycyrrhiza glabra L. (Liquorice). Pak. J. Pharm. Sci., 2016, 29(5), 1727-1733.
[PMID: 27731836]
[12]
Maria Pia, G.D.; Sara, F.; Mario, F.; Lorenza, S. Biological effects of licochalcones. Mini Rev. Med. Chem., 2019, 19(8), 647-656.
[http://dx.doi.org/10.2174/1389557518666180601095420] [PMID: 30049263]
[13]
Messier, C.; Grenier, D. Effect of licorice compounds licochalcone A, glabridin and glycyrrhizic acid on growth and virulence properties of Candida albicans. Mycoses, 2011, 54(6), e801-e806.
[http://dx.doi.org/10.1111/j.1439-0507.2011.02028.x] [PMID: 21615543]
[14]
Zhou, T.; Deng, X.; Qiu, J. Antimicrobial activity of licochalcone E against Staphylococcus aureus and its impact on the production of staphylococcal alpha-toxin. J. Microbiol. Biotechnol., 2012, 22(6), 800-805.
[http://dx.doi.org/10.4014/jmb.1112.12020] [PMID: 22573157]
[15]
Ethiraj, K.R.; Aranjani, J.M.; Khan, F.N. Potential cytotoxic and apoptosis inducing agents: synthesis and evaluation of methoxy-substituted chalcones against human lung and cervical cancers. Med. Chem. Res., 2013, 22, 5408-5417.
[http://dx.doi.org/10.1007/s00044-013-0520-9]
[16]
Santos, M.B.; Pinhanelli, V.C.; Garcia, M.A.R.; Silva, G.; Baek, S.J.; França, S.C.; Fachin, A.L.; Marins, M.; Regasini, L.O. Antiproliferative and pro-apoptotic activities of 2′- and 4′-aminochalcones against tumor canine cells. Eur. J. Med. Chem., 2017, 138, 884-889.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.049] [PMID: 28738308]
[17]
Passalacqua, T.G.; Torres, F.A.E.; Nogueira, C.T.; de Almeida, L.; Del Cistia, M.L.; dos Santos, M.B.; Dutra, L.A.; Bolzani, V.S.; Regasini, L.O.; Graminha, M.A.; Marchetto, R.; Zottis, A. The 2′,4′-dihydroxychalcone could be explored to develop new inhibitors against the glycerol-3-phosphate dehydrogenase from Leishmania species. Bioorg. Med. Chem. Lett., 2015, 25(17), 3564-3568.
[http://dx.doi.org/10.1016/j.bmcl.2015.06.085] [PMID: 26169126]
[18]
Wayne, P.A. NCCLS: National Committee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard 2th ed.; CLSI Document M27-A2; National Committee for Clinical Laboratory Standards: Wayne, PA, USA, 2002.
[19]
da Silva, A.R.; de Andrade Neto, J.B.; da Silva, C.R. Campos, Rde.S.; Costa Silva, R.A.; Freitas, D.D.; do Nascimento, F.B.; de Andrade, L.N.; Sampaio, L.S.; Grangeiro, T.B.; Magalhães, H.I.F.; Cavalcanti, B.C.; de Moraes, M.O.; Nobre Júnior, H.V. Berberine antifungal activity in fluconazole-resistant pathogenic yeasts: Action mechanism evaluated by flow cytometry and biofilm growth inhibition in Candida spp. Antimicrob. Agents Chemother., 2016, 60(6), 3551-3557.
[http://dx.doi.org/10.1128/AAC.01846-15] [PMID: 27021328]
[20]
Wayne, P.A. NCCLS: National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard, 9th ed.; CLSI Document M07-A9; National Committee for Clinical Laboratory Standards: Wayne, PA, USA, 2012.
[21]
Issam, A.; Stefan, Z.; Jürgen, R.; Michael, W. Antimicrobial Activities of European Propolis Collected from Various Geographic Origins Alone and in Combination with Antibiotics. Medicines (Basel), 2018, 5, 2.
[http://dx.doi.org/10.3390/medicines5010002]
[22]
Hirsch, E.B.; Zucchi, P.C.; Chen, A.; Raux, B.R.; Kirby, J.E.; McCoy, C.; Eliopoulos, G.M. Susceptibility of multidrug-resistant gram-negative urine isolates to oral antibiotics. Antimicrob. Agents Chemother., 2016, 60(5), 3138-3140.
[http://dx.doi.org/10.1128/AAC.02961-15] [PMID: 26883704]
[23]
Iqbal, B.; Ghildiyal, A. Sahabjada.; Singh, S.; Arshad, M.; Mahdi, A.A.; Tiwari, S. Antiproliferative and apoptotic effect of curcumin and TRAIL (TNF related apoptosis inducing ligand) in chronic myeloid leukaemic cells. J. Clin. Diagn. Res., 2016, 10(4), XC01-XC05.
[http://dx.doi.org/10.7860/JCDR/2016/18507.7579] [PMID: 27190933]
[24]
Campos, G.R.F.; Bittar, C.; Jardim, A.C.G.; Shimizu, J.F.; Batista, M.N.; Paganini, E.R.; Assis, L.R.; Bartlett, C.; Harris, M.; Bolzani, V.D.S.; Regasini, L.O.; Rahal, P. Hepatitis C virus in vitro replication is efficiently inhibited by acridone Fac4. J. Gen. Virol., 2017, 98(7), 1693-1701.
[http://dx.doi.org/10.1099/jgv.0.000808] [PMID: 28699869]
[25]
www.molinspiration.com
[26]
www. preadmet.bmdrc.org
[27]
Karaman, I.; Gezegen, H.; Gürdere, M.B.; Dingil, A.; Ceylan, M. Screening of biological activities of a series of Chalcone derivatives against human pathogenic microorganisms. Chem. Biodivers., 2010, 7(2), 400-408.
[http://dx.doi.org/10.1002/cbdv.200900027] [PMID: 20151389]
[28]
López, S.N.; Castelli, M.V.; Zacchino, S.A.; Domínguez, J.N.; Lobo, G.; Charris-Charris, J.; Cortés, J.C.; Ribas, J.C.; Devia, C.; Rodríguez, A.M.; Enriz, R.D. In vitro antifungal evaluation and structure-activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall. Bioorg. Med. Chem., 2001, 9(8), 1999-2013.
[http://dx.doi.org/10.1016/S0968-0896(01)00116-X] [PMID: 11504637]
[29]
Alam, M.S.; Rahman, S.M.M.; Lee, D-U. Synthesis, Biological Evaluation, Quantitative-SAR and Docking Studies of Novel Chalcone Derivatives as Antibacterial and Antioxidant Agents. Chem. Pap., 2015, 69, 1118-1129.
[http://dx.doi.org/10.1515/chempap-2015-0113]
[30]
Singh, P.; Anand, A.; Kumar, V. Recent developments in biological activities of chalcones: a mini review. Eur. J. Med. Chem., 2014, 85, 758-777.
[http://dx.doi.org/10.1016/j.ejmech.2014.08.033] [PMID: 25137491]
[31]
Matos, M.J.; Vazquez-Rodriguez, S.; Uriarte, E.; Santana, L. Potential pharmacological uses of chalcones: a patent review (from June 2011 - 2014). Expert Opin. Ther. Pat., 2015, 25(3), 351-366.
[http://dx.doi.org/10.1517/13543776.2014.995627] [PMID: 25598152]
[32]
Mahapatra, D.K.; Bharti, S.K.; Asati, V. Chalcone scaffolds as anti-infective agents: structural and molecular target perspectives. Eur. J. Med. Chem., 2015, 101, 496-524.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.052] [PMID: 26188621]
[33]
Costa, A.; Chiaradia-Delatorre, L.D.; dos Santos Bubniak, L.; Mascarello, A.; Marzarotto, M.A.L.; de Moraes, A.C.R.; Stumpf, T.R.; Cordeiro, M.N.S.; Yunes, R.A.; Nunes, R.J. Apoptotic effect of synthetic 2′,4′,5′-trimethoxychalcones in human K562 and jurkat Leukemia Cells. Med. Chem. Res., 2014, 23(10), 4301-4319.
[http://dx.doi.org/10.1007/s00044-014-1002-4]
[34]
Weldon, D.J.; Saulsbury, M.D.; Goh, J.; Rowland, L.; Campbell, P.; Robinson, L.; Miller, C.; Christian, J.; Amis, L.; Taylor, N.; Dill, C.; Davis, W., Jr; Evans, S.L.; Brantley, E. One-pot synthesis of cinnamylideneacetophenones and their in vitro cytotoxicity in breast cancer cells. Bioorg. Med. Chem. Lett., 2014, 24(15), 3381-3384.
[http://dx.doi.org/10.1016/j.bmcl.2014.05.089] [PMID: 24957352]
[35]
Seo, Y.H. Discovery of 2′,4′-dimethoxychalcone as a Hsp90 inhibitor and its effect on iressa-resistant non-small cell lung cancer (NSCLC). Arch. Pharm. Res., 2015, 38(10), 1783-1788.
[http://dx.doi.org/10.1007/s12272-015-0595-6] [PMID: 25855012]
[36]
Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1999, 1(1), 55-68.
[http://dx.doi.org/10.1021/cc9800071] [PMID: 10746014]
[37]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[38]
Veber, D.F.; Johnson, S.R.; Cheng, H.Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[39]
Polkam, N.; Ramaswamy, V.R.; Rayam, P.; Allaka, T.R.; Anantaraju, H.S.; Dharmarajan, S.; Perumal, Y.; Gandamalla, D.; Yellu, N.R.; Balasubramanian, S.; Anireddy, J.S. Synthesis, molecular properties prediction and anticancer, antioxidant evaluation of new edaravone derivatives. Bioorg. Med. Chem. Lett., 2016, 26(10), 2562-2568.
[http://dx.doi.org/10.1016/j.bmcl.2016.03.024] [PMID: 27055942]
[40]
Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem., 2000, 43(20), 3714-3717.
[http://dx.doi.org/10.1021/jm000942e] [PMID: 11020286]
[41]
Selick, H.E.; Beresford, A.P.; Tarbit, M.H. The emerging importance of predictive ADME simulation in drug discovery. Drug Discov. Today, 2002, 7(2), 109-116.
[http://dx.doi.org/10.1016/S1359-6446(01)02100-6] [PMID: 11790621]
[42]
Yee, S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man--fact or myth. Pharm. Res., 1997, 14(6), 763-766.
[http://dx.doi.org/10.1023/A:1012102522787] [PMID: 9210194]
[43]
Ma, X.L.; Chen, C.; Yang, J. Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharmacol. Sin., 2005, 26(4), 500-512.
[http://dx.doi.org/10.1111/j.1745-7254.2005.00068.x] [PMID: 15780201]
[44]
Farrugia, M.K.; Fogha, E.P.; Miah, A.R.; Yednock, J.; Palmer, H.C.; Guilfoose, J. Candida meningitis in an immunocompetent patient detected through (1→3)-beta-d-glucan. Int. J. Infect. Dis., 2016, 51, 25-26.
[http://dx.doi.org/10.1016/j.ijid.2016.08.020] [PMID: 27590564]
[45]
Pai, S.; Bedford, L.; Ruramayi, R.; Aliyu, S.H.; Sule, J.; Maslin, D.; Enoch, D.A. Pseudomonas aeruginosa meningitis/ventriculitis in a UK tertiary referral hospital. QJM, 2016, 109(2), 85-89.
[http://dx.doi.org/10.1093/qjmed/hcv094] [PMID: 25991873]