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Synthesis and in vitro evaluation of leishmanicidal activity of 7-hydroxy-4-phenylcoumarin derivatives

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Abstract

Eight coumarin derivatives (2–8) were synthesized from 7-hydroxy-4-phenylcoumarin 1 and were evaluated for their in vitro leishmanicidal activity against promastigote and amastigote forms of Leishmania amazonensis, as well their toxicity in murine macrophages. Compounds 4 and 7 showed the most significant results against promastigote forms of L. amazonensis. They were at least three-fold more active than 1 and Compound 4 was as effective as Amphotericin B. Compound 4, a 7-O-prenylated derivative, and 7, a tetra- O -acetyl-β- D -glucopyranosyl derivative, presented IC50 values of 21.35 and 10.03 µM against promastigote and IC50 values of 58.10 and 34.93 µM, respectively against amastigote forms. Furthermore, they do not cause toxicity in mammalian or Leishmania cells in vitro. This study shows that these coumarin derivatives are potential prototypes for the development of novel drugs with leishmanicidal activity.

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References

  • Akendengue B, Ngou-Milama E, Laurens A, Hocquemiller R (1999) Recent advances in the fight against Leishmaniasis with natural products. Parasite 6:3–8

    Article  CAS  PubMed  Google Scholar 

  • Arango V, Robledo S, Séon-Méniel B, Figadère B, Cardona W, Sáez J, Otálvaro F (2010) Coumarins from Galipea panamensis and their activity against Leishmania panamensis. J Nat Prod 73:1012–1014

    Article  CAS  PubMed  Google Scholar 

  • Beattie L, Kaye PM (2011) Leishmania–host interactions: What has imaging taught us?. Cell Microbiol 13:1659–1667

    Article  PubMed  Google Scholar 

  • Bhargava P, Singh R (2012) Developments in diagnosis and antileishmanial drugs. Interdiscip Perspect Infect Dis 2012:626838

    PubMed  PubMed Central  Google Scholar 

  • Brenzan MA, Nakamura CV, Dias Filho BP, Ueda-Nakamura T, Young MCM, Cortez DAGC (2007) Antileishmanial activity of crude extract and coumarin from calophyllum brasiliense leaves against Leishmania amazonensis. Parasitol Res 101:715–722

    Article  PubMed  Google Scholar 

  • Brenzan MA, Nakamura CV, Dias Filho BP, Ueda-Nakamura T, Young MCM, Corrêa AG, Alvim Júnior J, dos Santos AO, Cortez DAGC (2008) Structure–activity relationship of (-) Mammea A/BB derivatives against leishmania amazonensis. Biomed Pharmacother 62:651–658

    Article  CAS  PubMed  Google Scholar 

  • Conchie J, Levvy GA, Marsh CA (1957) Methyl and phenyl glycosides of the common sugars. Adv Carbohydr Chem 12:157–187

    CAS  PubMed  Google Scholar 

  • Cragg GM (1997) Natural products in drug discovery and development. J Nat Prod 60:52–60

    Article  CAS  PubMed  Google Scholar 

  • Croft SL, Olliaro P (2011) Leishmaniasis chemotherapy-challenges and opportunities. Clin Microbiol Infect 17:1478–1483

    Article  CAS  PubMed  Google Scholar 

  • Croft SL, Sundar S, Fairlamb AH (2006) Drug resistance in Leishmaniasis. Clin Microbiol Rev 19:111–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • da Cunha EFF, Sippl W, Ramalho TC, Antunes OAC, de Alencastro RB, Albuquerque MG (2009) 3D-QSAR CoMFA/CoMSIA models based on theoretical active conformers of HOE/BAY-793 analogs derived from HIV-1 protease inhibitor complexes. Eur J Med Chem 44:4344–4352

    Article  PubMed  Google Scholar 

  • El-Ansary SL, Hussein MM, Rahman DEA, Hamed MIAL (2012) Synthesis and docking studies of furobenzopyrones of potential antimicrobial and photochemotherapeutic activities. Life Sci J 9:1114–1125

    Google Scholar 

  • Fidalgo LM, Gille L (2011) Mitochondria and trypanosomatids: Targets and drugs. Pharmaceut Res 28:2758–2770

    Article  CAS  Google Scholar 

  • Garazd YL, Garazd MM, Khilya VP (2005) Modified coumarins. 19. Synthesis of Neoflavone D-Glycopyranosides. Chem Nat Compd 41:663–668

    Article  CAS  Google Scholar 

  • Hohenberg P, Kohn W (1964) Inhomogeneous electron gas. Phys Rev 136:B864–871

    Article  Google Scholar 

  • Hotez PJ, Savioli L, Fenwick A (2012) Neglected tropical diseases of the middle East and North Africa: review of their prevalence, distribution, and opportunities for control ed. Serap Aksoy. PLoS Negl Trop Dis 6:e1475

    Article  PubMed  PubMed Central  Google Scholar 

  • Jorgensen WL, Duffy EM (2000) Prediction of drug solubility from Monte Carlo simulations. Bioorg Med Chem Lett 10:1155–1158

    Article  CAS  PubMed  Google Scholar 

  • Kappagoda S, Singh U, Blackburn BG (2011) Antiparasitic therapy. Mayo Clin Proc 86:561–583

    Article  PubMed  PubMed Central  Google Scholar 

  • Kaye P, Scott P (2011) Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol 9:604–615

    Article  CAS  PubMed  Google Scholar 

  • Kuarm BS, Madhav JV, Rajitha B (2012) Xanthan sulfuric acid: an efficient and recyclable solid acid catalyst for Pechmann condensation. Synth Commun 42:1770–1777

    Article  CAS  Google Scholar 

  • Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2012) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 64(SUPPL):4–17

    Article  Google Scholar 

  • Liu X, Testa B, Fahr A (2011) Lipophilicity and Its relationship with passive drug permeation. Pharmaceut Res 28:962–977

    Article  CAS  Google Scholar 

  • Maciel-Rezende CM, de Almeida L, Costa ED’M, Pires FR, Alves KF, Viegas Junior C, Dias DF, Doriguetto AC, Marques MJ, dos Santos MH (2013) Synthesis and biological evaluation against Leishmania amazonensis of a series of Alkyl-substituted benzophenones. Bioorg Med Chem 21:3114–3119

    Article  CAS  PubMed  Google Scholar 

  • Miertus SE, Scrocco E, Tomasi J (1981) Electrostatic interaction of a solute with a continuum. A direct utilization of AB initio molecular potentials for the prevision of solvent effects. Chem Phys 55:117–129

    Article  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  • Napolitano HB, Silva M, Ellena J, Rodrigues BDG, Almeida ALC, Vieira PC, Oliva G, Thiemann OH (2004) Aurapten, a Coumarin with growth inhibition against Leishmania major promastigotes. Braz J Med Biol Res 37:1847–1852

    Article  CAS  PubMed  Google Scholar 

  • Ndjonka D, Rapado LN, Silber AM, Liebau E, Wrenger C (2013) Natural products as a source for treating neglected parasitic diseases. Int J Mol Sci 14:3395–3439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pereira IO, Marques MJ, Pavan AL, Codonho BS, Barbiéri CL, Beijo LA, Doriguetto AC, D’Martin EC, dos Santos MH (2010) Leishmanicidal activity of benzophenones and extracts from Garcinia Brasiliensis Mart. fruits. Phytomedicine 17:339–345

    Article  CAS  PubMed  Google Scholar 

  • Rizzi E, Dallavalle S, Merlini L, Pratesi G, Zunino F (2006) Short synthesis of cytotoxic 4‐arylcoumarins. Synth Commun 36:1117–1122

    Article  CAS  Google Scholar 

  • Seifert K, Munday J, Syeda T, Croft SL (2011) In vitro interactions between sitamaquine and Amphotericin B, sodium stibogluconate, miltefosine, paromomycin and pentamidine against Leishmania Donovani. J Antimicrob Chemother 66:850–854

    Article  CAS  PubMed  Google Scholar 

  • Singh N, Mishra BB, Bajpai S, Singh RK, Tiwari VK (2014) Natural product based leads to fight against Leishmaniasis. Bioorg Med Chem 22:18–45

    Article  CAS  PubMed  Google Scholar 

  • Subramanyam Raju M, Subba Rao NV (1974) Search for physiologically active compounds. Part XXIV. synthesis of 7, 8-Furano, Pyrono and 3-Methyl-4-Phenylcoumarins. Proc Indian Acad Sci Sect A 79:223–229

    Google Scholar 

  • Tiuman TS, Brenzan MA, Ueda-Nakamura T, Dias Filho BP, Cortez DGC, Nakamura CV (2012) Intramuscular and topical treatment of cutaneous Leishmaniasis lesions in mice infected with Leishmania amazonensis using Coumarin (-) Mammea A/BB. Phytomedicine 19:1196–1199

    Article  CAS  PubMed  Google Scholar 

  • Urzúa A, Echeverría J, Rezende MC, Wilkens M (2008) Antibacterial properties of 3 H-spiro[1-benzofuran-2,1′-cyclohexane] derivatives from Heliotropium Filifolium. Molecules 13:2385–2393

    Article  PubMed  Google Scholar 

  • v. Pechmann H (1884) Neue Bildungsweise Der Cumarine. Synthese Des Daphnetins I. Ber Deut Chem Ges 17:929–936

    Article  Google Scholar 

  • van Assche T, Deschacht M, da Luz RAI, Maes L, Cos P (2011) Leishmania-macrophage interactions: Insights into the redox biology. Free Radic Bio Med 51:337–351

    Article  Google Scholar 

  • van Griensven J, Diro E (2012) Visceral leishmaniasis. Infect Dis Clin N Am 26:309–322

    Article  Google Scholar 

  • Vieira PC, Mafezoli J, Pupo MT, Fernandes JB, da Silva MFGF, de Albuquerque S, Oliva G, Pavão F (2001) Strategies for the isolation and identification of trypanocidal compounds from the rutales. Pure Appl Chem 73:617–622

    Article  CAS  Google Scholar 

  • Yalkowsky SH (1999) Solubility and solubilization in aqueous media, 1st ed. American Chemical Society, Washington, DC

    Google Scholar 

  • Zweckmair T, Becker M, Ahn K, Hettegger H, Kosma P, Rosenaua T, Potthast A (2014) A novel method to analyze the degree of acetylation in biopolymers. J Chromatogr A 1372:212–220

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Rede Mineira de Química (RQ-MG) (CEX-RED-00010-14), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Financiadora de Estudos e Projetos (FINEP), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for the financial support.

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Authors and Affiliations

  1. Laboratório de Fitoquímica e Química Medicinal – LFQM, Universidade Federal de Alfenas, Alfenas-MG, 37130-000, Brazil

    Isael A. Rosa & Claudinei A. Silva

  2. Laboratório de Parasitologia/Biologia Molecular de Microrganismos, Universidade Federal de Alfenas, Alfenas-MG, 37130-000, Brazil

    Letícia de Almeida, Karina F. Alves & Marcos J. Marques

  3. Laboratório de Pesquisa em Química Farmacêutica – LQFar, Faculdade de Ciências Farmacêuticas, Universidade Federal de Alfenas, Alfenas-MG, 37130-000, Brazil

    Antônio M. Fregnan & Diogo T. Carvalho

  4. CIEXA-JAT, Universidade Federal de Goiás, Regional Jataí, Jataí-GO, 75801-615, Brazil

    Claudinei A. Silva

  5. Departamento de Química, Universidade Federal de Lavras, Lavras-MG, 37200-000, Brazil

    Juliana O. S. Giacoppo & Teodorico C. Ramalho

  6. Departamento de Química, Universidade Federal de Viçosa, Viçosa-MG, 36570-000, Brazil

    Marcelo H. dos Santos

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  1. Isael A. Rosa
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  2. Letícia de Almeida
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  3. Karina F. Alves
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  5. Antônio M. Fregnan
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  6. Claudinei A. Silva
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  7. Juliana O. S. Giacoppo
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Correspondence to Claudinei A. Silva or Marcelo H. dos Santos.

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Rosa, I.A., de Almeida, L., Alves, K.F. et al. Synthesis and in vitro evaluation of leishmanicidal activity of 7-hydroxy-4-phenylcoumarin derivatives. Med Chem Res 26, 131–139 (2017). https://doi.org/10.1007/s00044-016-1729-1

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  • DOI: https://doi.org/10.1007/s00044-016-1729-1

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