Advertisement

Parasitology Research

, Volume 114, Issue 2, pp 501–512 | Cite as

Anti-trypanosomal activities and structural chemical properties of selected compound classes

  • Alicia Ponte-SucreEmail author
  • Heike Bruhn
  • Tanja Schirmeister
  • Alexander Cecil
  • Christian R. Albert
  • Christian Buechold
  • Maximilian Tischer
  • Susanne Schlesinger
  • Tim Goebel
  • Antje Fuß
  • Daniela Mathein
  • Benjamin Merget
  • Christoph A. Sotriffer
  • August Stich
  • Georg Krohne
  • Markus Engstler
  • Gerhard Bringmann
  • Ulrike HolzgrabeEmail author
Original Paper

Abstract

Potent compounds do not necessarily make the best drugs in the market. Consequently, with the aim to describe tools that may be fundamental for refining the screening of candidates for animal and preclinical studies and further development, molecules of different structural classes synthesized within the frame of a broad screening platform were evaluated for their trypanocidal activities, cytotoxicities against murine macrophages J774.1 and selectivity indices, as well as for their ligand efficiencies and structural chemical properties. To advance into their modes of action, we also describe the morphological and ultrastructural changes exerted by selected members of each compound class on the parasite Trypanosoma brucei. Our data suggest that the potential organelles targeted are either the flagellar pocket (compound 77, N-Arylpyridinium salt; 15, amino acid derivative with piperazine moieties), the endoplasmic reticulum membrane systems (37, bisquaternary bisnaphthalimide; 77, N-Arylpyridinium salt; 68, piperidine derivative), or mitochondria and kinetoplasts (88, N-Arylpyridinium salt; 68, piperidine derivative). Amino acid derivatives with fumaric acid and piperazine moieties (4, 15) weakly inhibiting cysteine proteases seem to preferentially target acidic compartments. Our results suggest that ligand efficiency indices may be helpful to learn about the relationship between potency and chemical characteristics of the compounds. Interestingly, the correlations found between the physico-chemical parameters of the selected compounds and those of commercial molecules that target specific organelles indicate that our rationale might be helpful to drive compound design toward high activities and acceptable pharmacokinetic properties for all compound families.

Keywords

Compound design Drug potency Drug targets Electron microscopy Ligand efficiency Trypanosoma brucei 

Notes

Acknowledgments

This work was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG Collaborative Research Center 630, “Recognition, Preparation, and Functional Analysis of Agents against Infectious Diseases”; projects A1, A2, A4, B8, C7, Z1, and QM). We thank Daniela Bunsen and Claudia Gehrig from the University of Würzburg, (Core Unit for Electron Microscopy) and Martina Schultheis, Elena Katzowitsch, and Svetlana Sologub (Institute for Molecular Infection Biology, University of Würzburg) for the technical assistance. APS had the support of the Alexander von Humboldt Foundation, Germany.

Supplementary material

436_2014_4210_MOESM1_ESM.xlsx (80 kb)
Supplementary Material Table 1 (XLSX 80 kb)
436_2014_4210_Fig5_ESM.gif (539 kb)
Supplementary Material Figure 1

A: Methyl triphenyl phosphonium; B: Mitotracker; C: Lysotracker; D: Chloroquine; E: Acridine Orange (GIF 539 kb)

436_2014_4210_MOESM2_ESM.tif (2.3 mb)
High resolution image (TIFF 2329 kb)
436_2014_4210_Fig6_ESM.gif (177 kb)
Supplementary Material Figure 2

Ultrastructural changes induced by compounds in T. brucei after 48 h of incubation at IC50. Images were captured with a Zeiss EM10 transmission electron microscope at 100 Kv at 7 000-12 500 fold amplification and scanned images were processed using Adobe Photoshop. The most obvious alterations in compound-treated cells were as follows: marked flagellar pocket changes (g, q, r); dilated kinetoplasts and mitochondria (d, e, f, h, j, n); an elevated amount of dark vesicles (d, g, i, l, o, s); the appearance of membrane-whorl-like structures (c, i, o) and distorted endoplasmic reticulum (i, o, q); appearance of translucent vacuoles resembling lysosomes (f, m, q) and appearance of two flagella inside the flagellar pocket (m) as compared with control cells. Note the usual appearance of mitochondria, nuclei and flagellar pocket in control and DMSO-treated cells (a, and b, respectively). Autophagic vesicles (AV); endoplasmic reticulum (ER); flagellum (F); flagellar pocket (FP); glycosomes (G); kinetoplast (K); lysosomes (L); mitochondria(M); membrane-whorl-like structures (MWS); nuclei (N); dark vesicles (V). (GIF 177 kb)

436_2014_4210_MOESM3_ESM.tif (156 kb)
High resolution image (TIFF 156 kb)

References

  1. Anderson RG, Orci L (1988) A view of acidic intracellular compartments. J Cell Biol 106:539–543PubMedCrossRefGoogle Scholar
  2. Balaban AT, Boulton AJ (1969) 2,4,6-Trimethylpyrylium tetrafluoroborate. Org Synth 49:121–122CrossRefGoogle Scholar
  3. Bender W, Staudt M, Trankle C, Mohr K, Holzgrabe U (2000) Probing the size of a hydrophobic binding pocket within the allosteric site of muscarinic acetylcholine M2-receptors. Life Sci 66:1675–1682PubMedCrossRefGoogle Scholar
  4. Braña MF, Ramos A (2001) Naphthalimides as anti-cancer agents: synthesis and biological activity. Curr Med Chem Anticancer Agents 1:237–255PubMedCrossRefGoogle Scholar
  5. Breuning A, Degel B, Schulz F, Büchold C, Stempka M, Machon U et al (2010) Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids. J Med Chem 53:1951–1963PubMedCrossRefGoogle Scholar
  6. Bringmann G, Hoerr V, Holzgrabe U, Stich A (2003) Antitrypanosomal naphthylisoquinoline alkaloids and related compounds. Pharmazie 58:343–346PubMedGoogle Scholar
  7. Brun R, Blum J, Chappuis F, Burri C (2010) Human African trypanosomiasis. Lancet 375:148–159PubMedCrossRefGoogle Scholar
  8. Buechold C, Hemberger Y, Heindl C, Welker A, Degel B, Pfeuffer T, Staib P, Schneider S, Rosenthal PJ, Gut J, Morschhaeuser J, Bringmann G, Schirmeister T et al (2011) New cis-configured aziridine-2-carboxylates as aspartic acid protease inhibitors. Chem Med Chem 6:141–152CrossRefGoogle Scholar
  9. De Duve C, De Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F (1974) Lysosomotropic agents. Biochem Pharmacol 24:2495–2531CrossRefGoogle Scholar
  10. Efremov RG, Chugunov AO, Pyrkov TV, Priestle JP, Arseniev AS, Jacoby E (2007) Molecular lipophilicity in protein modeling and drug design. Curr Med Chem 14:393–415PubMedCrossRefGoogle Scholar
  11. Field MC, Allen CL, Dhir V, Goulding D, Hall BS, Morgan GW et al (2004) New approaches to the microscopic imaging of Trypanosoma brucei. Microsc Microanal 10:621–636PubMedCrossRefGoogle Scholar
  12. Goebel T, Ulmer D, Projahn H, Klöckner J, Heller E, Glaser M et al (2008) In search of novel agents for therapy of tropical diseases and human immunodeficiency virus. J Med Chem 51:238–250PubMedCrossRefGoogle Scholar
  13. Griffiths G, Hoflack B, Simons K, Mellman I, Kornfeld S (1988) The mannose 6-phosphate receptor and the biogenesis of lysosomes. Cell 52:329–341PubMedCrossRefGoogle Scholar
  14. Hou T, Wang J, Zhang W, Xu X (2007) ADME evaluation in drug discovery. 6. Can oral bioavailability in humans be effectively predicted by simple molecular property-based rules? J Chem Inf Model 47:460–463PubMedCrossRefGoogle Scholar
  15. Leeson P, Springthorpe B (2007) The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov 6:881–890PubMedCrossRefGoogle Scholar
  16. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26PubMedCrossRefGoogle Scholar
  17. Mellman I, Fuchs R, Helenins A (1986) Acidification of the endocytic and exocytic pathways. Annu Rev Biochem 55:663–700PubMedCrossRefGoogle Scholar
  18. Milletti F, Storchi L, Sforna G, Cruciani G (2007) New and original pKa prediction method using grid molecular interaction fields. J Chem Inform Model 47:2172–2181CrossRefGoogle Scholar
  19. Muth M, Hoerr V, Glaser M, Ponte-Sucre A, Moll H, Stich A, Holzgrabe U (2007) Antitrypanosomal activity of quaternary naphthalimide derivatives. Bioorg Med Chem Lett 17:1590–1593PubMedCrossRefGoogle Scholar
  20. O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR (2011) Open Babel: an open chemical toolbox. J Chem Inform 3:1–14Google Scholar
  21. Okabe K, Inada N, Gota C, Harada Y, Funatsu T, Uchiyama S (2012) Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy. Nat Commun 3:705PubMedCentralPubMedCrossRefGoogle Scholar
  22. Ponte-Sucre A, Faber JH, Gulder T, Kajahn I, Pedersen SE, Schultheis M, Bringmann G, Moll H (2007) Activities of naphthylisoquinoline alkaloids and synthetic analogs against Leishmania major. Antimicrob Agents Chemother 51:188–194PubMedCentralPubMedCrossRefGoogle Scholar
  23. Ponte-Sucre A, Gulder T, Wegehaupt A, Albert C, Rikanović C, Schaeflein L et al (2009) Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N, C-coupled arylisoquinolinium salts. J Med Chem 52:626–636PubMedCrossRefGoogle Scholar
  24. Ponte-Sucre A, Gulder TA, Vollmers G, Bringmann G, Moll H (2010) Alterations to the structure of Leishmania major induced by N-arylisoquinolines correlate with compound accumulation and disposition. J Med Microbiol 59:69–75PubMedCrossRefGoogle Scholar
  25. Ponte-Sucre A, Díaz E, Padrón-Nieves M (2012) Quantitative structure-activity analysis of leishmanicidal compounds. In Ramalho TC, Freitas MP, and da Cunha EFF, editors. Chemoinformatics: Directions toward combating neglected diseases. Bentham Science Publishers; p. 33–49Google Scholar
  26. Rippert AJ, Hansen HJ (1995) Synthesis of 4,6,8-trisubstituted methyl azulene-2-carboxylates. Helv Chim Acta 78:238–241CrossRefGoogle Scholar
  27. R Core Team (2013) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org/.
  28. Sami SM, Dorr RT, Alberts DS, Sólyom AM, Remers WA (2000) Analogues of amonafide and azonafide with novel ring systems. J Med Chem 43:3067–3073PubMedCrossRefGoogle Scholar
  29. Scory S, Stierhof YD, Caffrey CR, Steverding D (2000) The cysteine proteinase inhibitor Z-Phe-Ala-CHN2 alters cell morphology and cell division activity of Trypanosoma brucei bloodstream forms in vivo. Kinetoplastid Biol Dis 6:2CrossRefGoogle Scholar
  30. Scott ID, Nicholls DG (1980) Energy transduction in intact synaptosomes. Influence of plasma-membrane depolarization on the respiration and membrane potential of internal mitochondria determined in situ. Biochem J 186:21–33PubMedCentralPubMedGoogle Scholar
  31. Shelley JC, Cholleti A, Frye LL, Greenwood JR, Timlin MR, Uchimaya M (2007) Epik: a software program for pK a prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des 21:681–691PubMedCrossRefGoogle Scholar
  32. Smith TK, Bûtikofer P (2010) Lipid metabolism in Trypanosoma brucei. Mol Biochem Parasitol 172:66–79PubMedCentralPubMedCrossRefGoogle Scholar
  33. Steverding D, Tyler KM (2005) Novel antitrypanosomal agents. Expert Opin Investig Drugs 14:939–955PubMedCrossRefGoogle Scholar
  34. Stich A, Ponte-Sucre A, Holzgrabe U (2013) Do we need new drugs against human African trypanosomiasis? Lancet Infect Dis 13:733–734PubMedCrossRefGoogle Scholar
  35. Tetko IV, Gasteiger J, Todeschini R, Mauri A, Livingstone D, Ertl P et al (2005) Virtual computational chemistry laboratory—design and description. J Comput Aided Mol Des 19:453–463PubMedCrossRefGoogle Scholar
  36. Tischer M, Sologub L, Pradel G, Holzgrabe U (2010) The bisnaphthalimides as new active lead compounds against Plasmodium falciparum. Bioorg Med Chem 18:2998–3003PubMedCrossRefGoogle Scholar
  37. Verkman AS (2004) Drug discovery in academia. Am J Physiol Cell Physiol 286:C465–C474PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Alicia Ponte-Sucre
    • 1
    Email author
  • Heike Bruhn
    • 2
  • Tanja Schirmeister
    • 3
    • 4
  • Alexander Cecil
    • 5
  • Christian R. Albert
    • 6
  • Christian Buechold
    • 3
  • Maximilian Tischer
    • 3
  • Susanne Schlesinger
    • 7
  • Tim Goebel
    • 3
  • Antje Fuß
    • 7
  • Daniela Mathein
    • 7
  • Benjamin Merget
    • 3
  • Christoph A. Sotriffer
    • 3
  • August Stich
    • 7
  • Georg Krohne
    • 8
  • Markus Engstler
    • 9
  • Gerhard Bringmann
    • 6
  • Ulrike Holzgrabe
    • 3
    Email author
  1. 1.Laboratory of Molecular Physiology, Institute of Experimental Medicine, School of Medicine Luis Razetti, Faculty of MedicineUniversidad Central de VenezuelaCaracasVenezuela
  2. 2.Institute of Molecular Infection BiologyUniversity of WürzburgWürzburgGermany
  3. 3.Institute of Pharmacy and Food ChemistryUniversity of WürzburgWürzburgGermany
  4. 4.Institute of Pharmacy and BiochemistryUniversity of MainzMainzGermany
  5. 5.Department of BioinformaticsUniversity of WürzburgWürzburgGermany
  6. 6.Institute of Organic ChemistryUniversity of WürzburgWürzburgGermany
  7. 7.Department of Tropical MedicineInstitute of Medical MissionWürzburgGermany
  8. 8.Division of Electron MicroscopyBiocenter of the University of WürzburgWürzburgGermany
  9. 9.Department of Cell and Developmental BiologyUniversity of WürzburgWürzburgGermany

Personalised recommendations