Drug screening for activity against protozoan parasites

• Forschungsstelle: TPH
• Projektnummer: 3.03
• Projekttitel Englisch: Drug screening for activity against protozoan parasites

Schlüsselwörter (Englisch)

Parasitic protozoa, drug discovery, in vitro screening, mouse models, new drugs, TDR/WHO, COST programme, EU programme, Drugs for Neglected Diseases initiative (DNDi).

Kurzbeschreibung (Englisch)

Drugs for diseases caused by protozoan parasites (malaria, sleeping sickness, leishmaniasis, Chagas disease) are old, toxic and ineffective due to development of drug resistance. New drugs are urgently needed but pharmaceutical industry world-wide is not pursuing R&D for new medicaments for those diseases. Our institute established a Screening Center for para-sitic diseases 10 years ago. The Center offers in vitro and in vivo screening of natural and synthetic compounds as well as animal models for malaria and African trypanosomes.We collaborate with various partners from university institutes and private companies. A main partner is the TDR/WHO Genomics and Discovery Research Group which has access to chemical libraries of pharmaceutical companies and the 'Drugs for Neglected Diseases initiative' institution. For both institutions we carry out screening and drug evaluation work. Our group is also involved in the COST B22 programme (Antiparasitic Chemotherapy) offering screening for antiparasitic activity. A further collaboration is within the EU program 'dUTPase as a drug target against malaria parasites'.

Projektziele (Englisch)

The overall objective of the project is to find new lead compounds for malaria, African sleeping sickness, leishmaniasisi or Chagas disease which can become content of a drug discovery or lead optimization project to be submitted to foundations such as MMV, Gates or DNDi (Drugs for Neglected Diseases initiative). Specific objectives are:

1) to screen new molecules (natural compounds, synthetic compounds target oriented or from chemical libraries) in vitro for antiparasitic activity and for cytotoxicity.

2) To evaluate in vitro active molecules in rodent models for in vivo efficacy

3) To identify new lead compounds for optimization programs eventually leading to clinical candidates

Abstract (Englisch)

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Publikationen / Ergebnisse (Englisch)

Jones, S.M., Urch, J.E., Brun, R., Harwood, J.L., Berry, C., Gilbert, I.H. Analogues of
thiolactomycin as potential anti-malarial and anti-trypanosomal agents. Bioorg Med Chem. 12(4):683-92 (2004).

Dardonville, C. & Brun, R. Bisguanidine, bis(2-aminoimidazoline), and polyamine derivatives as potent and selective chemotherapeutic agents against Trypanosoma brucei rhodesiense. Synthesis and in vitro evaluation. J. Med. Chem. 47, 2296-2307 (2004).

Dardonville, C. Rinaldi, E., Barrett, M.P., Brun, R., Gilbert, I.H. & Hanau, S. Selective
inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high energy intermediate and transition state analogues. J. Med. Chem. 47(13), 3427-3437 (2004).

Sperandeo, N.R., Brinon, M.C. & Brun R. Synthesis, antiprotozoal and cytotoxic activities of new N-(3,4-dimethyl-5-isoxazolyl)-1,2-naphthoquinone-4-amino derivatives. Farmaco 59(6):431-5 (2004).

Bringmann, G., Dreyer, M., Faber, J.H., Dalsgaard, P.W., Staerk, D., Jaroszewski, J.W., Ndangalasi, H., Mbago, F., Brun, R. & Christensen, S.B. Ancistrotanzanine C and Related 5,1'- and 7,3'-Coupled Naphthylisoquinoline Alkaloids from Ancistrocladus tanzaniensis. J. Nat. Prod. 67(5):743-748 (2004).

Stewart, M.L., Bueno, G.J., Baliani, A., Klenke, B., Brun, R., Brock, J.M., Gilbert, I.H. &
Barrett, M.P. Trypanocidal activity of melamine-based nitroheterocycles. Antimicrob. Agents Chemother. 48(5):1733-8 (2004).

Khabnadideh S, Pez D, Musso A, Brun R, Ruiz Pérez LM, González-Pacanowska D
and Gilbert IH. Design, Synthesis and Evaluation of 2,4-Diaminoquinazolines as Inhibitors of Trypanosomal and Leishmanial Dihydrofolate Reductase. Bioorg. Med. Chem. 13(7):2637-2649 (2005).

Whittingham JL, Leal I, Nguyen C, Kasinathan G, Bell E, Jones AF, Berry C, Benito
A, Turkenburg JP, Dodson EJ, Perez LM, Wilkinson AJ, Johansson NG, Brun R, Gilbert IH, Pacanowska DG, Wilson KS. dUTPase as a Platform for Antimalarial Drug Design: Structural Basis for the Selectivity of a Class of Nucleoside Inhibitors. Structure (Camb). 13(2), 329-338 (2005).

Takasu K, Shimogama T, Saiin C, Kim HS, Wataya Y, Brun R, Ihara M. Synthesis
and evaluation of beta-carbolinium cations as new antimalarial agents based on pi-delocalized lipophilic cation (DLC) hypothesis. Chem Pharm Bull (Tokyo). 53(6), 653-61 (2005).

Bringmann G, Dreyer M, Kopff H, Rischer H, Wohlfarth M, Hadi HA, Brun R, Meimberg H, Heubl G. ent-Dioncophylleine A and related dehydrogenated naphthylisoquinoline alkaloids, the first Asian dioncophyllaceae-type alkaloids, from the "new"plant species Ancistrocladus benomensis. J Nat Prod. 68(5), 686-90 (2005).

Tasdemir D, Brun R, Perozzo R, Donmez AA. Evaluation of antiprotozoal and plasmodial enoyl-ACP reductase inhibition potential of turkish medicinal plants. Phytother Res. 19(2), 162-166 (2005).
Baliani A, Bueno GJ, Stewart ML, Yardley V, Brun R, Barrett MP, Gilbert IH. Design and Synthesis of a Series of Melamine-based Nitroheterocycles with Activity against Trypanosomatid Parasites. J Med Chem. 48(17):5570-5579 (2005).

Nguyen C, Kasinathan G, Leal-Cortijo I, Musso-Buendia A, Kaiser M, Brun R, Ruiz-Perez LM, Johansson NG, Gonzalez-Pacanowska D, Gilbert IH. Deoxyuridine Triphosphate Nucleotidohydrolase as a Potential Antiparasitic Drug Target. J Med Chem. 48(19):5942-5954 (2005).

Jones SM, Urch JE, Kaiser M, Brun R, Harwood JL, Berry C, Gilbert IH. Analogues of Thiolactomycin as Potential Antimalarial Agents. J Med Chem. 48(19):5932-5941 (2005).

George TG, Johnsamuel J, Delfin DA, Yakovich A, Mukherjee M, Phelps MA, Dalton JT, Sackett DL, Kaiser M, Brun R, Werbovetz KA. Antikinetoplastid antimitotic activity and metabolic stability of dinitroaniline sulfonamides and benzamides. Bioorg Med Chem. 14(16), 5699-710 (2006).

Tasdemir D, Kaiser M, Brun R, Yardley V, Schmidt TJ, Tosun F, Ruedi P. Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: in vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies. Antimicrob Agents Chemother. 50(4),1352-64 (2006).

Dardonville C, Barrett MP, Brun R, Kaiser M, Tanious F, Wilson WD. DNA Binding Affinity of Bisguanidine and Bis(2-aminoimidazoline) Derivatives with in Vivo Antitrypanosomal Activity. J Med Chem. 49(12), 3748-3752 (2006).

Takasu K, Pudhom K, Kaiser M, Brun R, Ihara M. Synthesis and antimalarial efficacy of aza-fused rhodacyanines in vitro and in the P. berghei mouse model. J Med Chem. 49(15), 4795-8 (2006).

Calderon AI, Romero LI, Ortega-Barria E, Brun R, Correa MA, Gupta MP. Evaluation of larvicidal and in vitro antiparasitic activities of plants in a biodiversity plot in the Altos de Campana National Park, Panama. Pharmaceut Biol 44(7), 1-16 (2006).


Pez, D., Leal, I., Zuccotta, F., Boussard, C., Brun, R., Croft, S.L., Yardley, V., Ruiz Perez, L.M., Pacanowska, D.G. & Gilbert, I.H. 2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Bioorg. Med. Chem. 11, 4693-4711 (2003).

Klenke, B., Barrett, M.P., Brun, R. & Gilbert, I.H. Antiplasmodial activity of a series of 1,3,5-triazine-substituted polyamines. J. Antimicrob. Chemother. 52 (2):290-293 (2003).

Dardonville, C., Rinaldi, E., Hanau, S., Barrett, M.P., Brun, R. & Gilbert, I.H. Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis. Bioorg. Med. Chem. 11, 3205-3214 (2003).

Sperandeo, N. & Brun, R. Synthesis and biological evaluation of pyrazolyl-Naphtho-quinones as new potential antiprotozoal agents. ChemBioChem 4, 69-72 (2003).

Chowdhury, S.F., Guerrero, R.H., Brun, R., Ruiz-Perez, L.M., Gonzalez Pacanowska, D.& Gilbert, I.H. Synthesis and Testing of 5-Benzyl-2,4-diaminopyrimidines as Potential Inhibitors of Leishmanial and Trypanosomal Dihydrofolate Reductase. J. Enzyme Inhib. Med. Chem. 17, 293-302 (2002).

Griesbeck, A.G., El-Idreesy, T.T., Fiege, M. & Brun, R. Synthesis of anti-malaria active 1,2,4-trioxanes via photooxygenation of a chiral allylic alcohol. Organic Letters, 4, 4193-4195 (2002).

Bringmann, G., Menche, D., Kraus, J., Mühlbacher, J., Peters, K., Peters, E.-M., Brun, R., Bezabih, M. & Abegaz, B.M. Atropo-enantioselective total synthesis of knipholone and related antiplasmodial phenylanthraquinones. J. Org. Chem. 67, 5595-610 (2002).

Klenke, B., Stewart, M., Barrett, M.P., Brun, R. & Gilbert, I. Synthesis andbiological evaluation of s-triazine substituted polyamines as potential new anti-trypanosomal drugs. J. Med. Chem. 44, 3440-3452 (2001).