Sonderforschungsbereich 630

    Project Part B3

    Identification and characterization of leishmanicidal compounds

    Prof. Dr. Heidrun Moll, Dr. Uta Schurigt

    Institute for Molecular Infection Biology

    Chemotherapy of leishmaniasis, an infectious disease caused by protozoan parasites, is mainly based on antimony compounds. However, their toxicity causes serious side effects that often result in patients deserting the treatment. Moreover, resistance to antimonials is frequent and can reach 50-65 % of the treated cases in some areas of the world. Second-line drugs are also toxic and require close clinical control. Finally, current anti-leishmanial treatments remain extremely expensive for countries in which the disease is endemic. These issues emphasize the urgent need for affordable alternative drugs against leishmaniasis.
    Schemes to develop novel leishmanicidal drugs include the analysis of naturally occurring plant-derived compounds such as naphthylisoquinoline alkaloids, isolated from African tropical lianas. They were shown to have anti-plasmodial and anti-trypanosomal activity and, therefore, are interesting drug candidates to be used against Leishmania. Another promising strategy is the targeting of parasite cysteine proteases which are essential for their growth, differentiation and pathogenicity.
    To identify new leishmanicidal compounds for potential clinical use, we compared the cytotoxic effects of naphthylisoquinoline alkaloids and cysteine protease inhibitors against Leishmania major and its major host cells, macrophages and dendritic cells. Treatment of L. major promastigotes, the extracellular parasite form, with specific naphthylisoquinoline alkaloids and cysteine protease inhibitors resulted in a dose-dependent inhibition of parasite growth with IC50 values in the low micromolar range. Both types of compounds decreased the infection rate of peritoneal macrophages at concentrations that were 8- to 500-fold lower and, thus, had an even more potent effect on intracellular Leishmania amastigotes. Cysteine protease inhibitors were less toxic against host cells than naphthylisoquinoline alkaloids. Furthermore, cysteine protease inhibitors, but not naphthylisoquinoline alkaloids, were able to modulate the cytokine secretion and nitric oxide production by host macrophages. Our results suggest that the intracellular form of the parasite is more sensitive to the compounds and demonstrate that cysteine protease inhibitors are promising candidates for further investigation of their leishmanicidal activity.
    Encouraged by these findings, we recently performed structure-activity-relationship (SAR) studies varying several structural parameters of the lead compounds. Three simplified synthetic analogs of the naphthylisoquinoline alkaloids had enhanced activity against L. major and macrophages. The mechanisms might involve both a direct leishmanicidal effect and the modulation of the cytokine activity and nitric oxide production by macrophages. These results suggest that the newly synthesized structurally simplified N,C-coupled arylisoquinolinium salts are very promising candidates to be considered as leishmanicidal pharmacophores.

    Selected, SFB-relevant Publications

    J. Glaser, M. Schultheis, S. Hazra, B. Hazra, H. Moll, U. Schurigt, U. Holzgrabe; Antileishmanial lead structures from nature: analysis of structure-activity relationships of a compound library derived from caffeic Acid bornyl ester. Molecules 2014, 19, 1394-1410. doi:10.3390/molecules19021394

    G. Bringmann, K. Thomale, S. Bischof, C. Schneider, M. Schultheis, T. Schwarz, H. Moll, U. Schurigt; A Novel Leishmania major Amastigote Assay in 96-Well Format for Rapid Drug Screening and its Use for the Discovery and Evaluation of a New Class of Leishmanicidal Quinolinium Salts. Antimicrob Agents Chemother 2013. 57, 3003-30011. doi:10.1128/AAC.02201-12

    S. Ghosh, S. Debnath, S. Hazra, A. Hartung, K. Thomale, M. Schultheis, P. Kapkova, U. Schurigt, H. Moll, U. Holzgrabe, B. Hazra; Valeriana wallichii root extracts and fractions with activity against Leishmania spp. Parasitol Res 2011, 108, 861-871.

    G. Bringmann, B. Hertlein-Amslinger, I. Kajahn, M. Dreyer, R. Brun, H. Moll, A. Stich, K. N. Ioset, W. Schmitz, L. H. Ngoc; Phenolic analogs of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A, from Ancistrocladus cochinchinensis (Ancistrocladaceae), with improved antiprotozoal activities. Phytochemistry 2011, 72, 89-93.

    U. Schurigt, C. Schad, C. Glowa, U. Baum, K. Thomale, J.K. Schnitzer, M. Schultheis, N. Schaschke, T. Schirmeister, H. Moll; Aziridine-2,3-dicarboxylate-based cysteine cathepsin inhibitors induce cell death in Leishmania major associated with accumulation of debris in autophagy-related lysosome-like vacuoles. Antimicrob Agents Chemother 2010, 54, 5028-5041.

    A. Ponte-Sucre, T. Gulder, T.A.M. Gulder, G. Vollmers, G. Bringmann, H. Moll; Alterations to the structure of Leishmania major induced by N-arylisoquinolines correlate with compound accumulation and disposition. J Med Microbiol 2010, 59, 69-75.

    S.M. Pimentel-Elardo, S. Kozytska, T.S. Bugni, C.M. Ireland, H. Moll, U. Hentschel; Anti-parasitic compounds from Streptomyces sp. strains isolated from Mediterranean sponges. Mar Drugs 2010, 8, 373-380.

    G. Bringmann, S.K. Bischof, S. Müller, T. Gulder, C. Winter, A. Stich, H. Moll, M. Kaiser, R. Brun, J. Dreher, K. Baumann; QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids. Eur J Med Chem 2010, 45, 5370-83.

    A. Ponte-Sucre, T. Gulder, A. Wegehaupt, C. Albert, C. Rikanovic, L. Schaeflein, A. Frank, M. Schultheis, M. Unger, U. Holzgrabe, G. Bringmann, H. Moll; Structure-activity relationship and studies on the molecular mechanism of leishmanicidal N,C-coupled arylisoquinolinium salts. J Med Chem 2009, 52, 626-636.

    C.R. Caffrey, D. Steverding, R.K. Swenerton, B. Kelly, D. Walshe, A. Debnath, Y.M. Zhou, P.S. Doyle, A.T. Fafarman, J.A. Zorn, K.M. Land, J. Beauchene, K. Schreiber, H. Moll, A. Ponte-Sucre, T. Schirmeister, A. Saravanamuthu, A.H. Fairlamb, F.E. Cohen, J.H. McKerrow, J.L. Weisman, B.C. May; Bis-acridines as lead anti-parasitic agents: structure activity analysis of a discrete compound library in vitro. Antimicrob Agents Chemother 2007, 51, 2164-2172.

    M. Muth, V. Hoerr, M. Glaser, A. Ponte-Sucre, H. Moll, A. Stich, U. Holzgrabe; Antitrypanosomal activity of quaternary naphthalimide derivatives. Bioorg Med Chem Lett 2007, 17, 1590-1593.

    Ponte-Sucre, A., J. H. Faber, T. Gulder, I. Kajahn, S. E. H. Pedersen, M. Schultheis, G. Bringmann and H. Moll;  Activities of naphthylisoquinoline alkaloids and synthetic analogs against Leishmania major. Antimicrob. Agents Chemother. 2007, 51, 188-194.

    Bringmann, G., I. Kajahn, M. Reichert, S. E. H. Pedersen, J. H. Faber, T. Gulder, R. Brun, S. B. Christensen, A. Ponte-Sucre, H. Moll, G. Heubl and V. Mudogo; Ancistrocladinium A and B, the first N,C-coupled naphthyldihydroisoquinoline alkaloids, from a Congolese Ancistrocladus species. J. Org. Chem. 2006, 7, 9348-9356.

    Ponte-Sucre, A., R. Vicik, M. Schultheis, T. Schirmeister and H. Moll.; Aziridine-2,3-dicarboxylates: Peptidomimetic cysteine protease inhibitors with antileishmanial activity. Antimicrob. Agents Chemother. 2006, 50, 2439-2447.

    Vicik, R., V. Hoerr, M. Glaser, M. Schultheis, E. Hansell, J. H. McKerrow, U. Holzgrabe, C. R. Caffrey, A. Ponte-Sucre, H. Moll, A. Stich and T. Schirmeister; Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents. Bioorg. Med. Chem. Letters 2006, 16, 2753-2757.


    Collaborative Research Center 630
    Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases
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    97074 Würzburg

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