Discovery of novel agents with dual trypanocidal and fungicidal activity to treat Chagas’ disease
Project type
Honours and/or PhD
| Supervisor(s) | Division | |
| (Primary) | Chemical Biology | .(JavaScript must be enabled to view this email address) |
Dr Brad Sleebs (Co-supervisor) |
Chemical Biology | .(JavaScript must be enabled to view this email address) |
Details of project
Building on our increasing interest in the discovery of novel compounds that could form the basis of treatments of a variety of parasitic diseases, such as malaria, leishmaniasis, Chagas’ disease and Human African trypanosomiasis, this project seeks to discover improved compounds for the treatment of Chagas’ disease.
Chagas’ disease is caused by the protozoan parasite Trypanosoma cruzi, which is found in 18 countries in Latin America. In the 2004 World Health Report, Chagas disease was estimated to cause 14,000 deaths and a disease burden of 0.7 million DALYs annually. There are currently only two significant therapies for Chagas disease, nifurtimox and benznidazole. These drug treatments are ineffective at preventing the development and treatment of chronic Chagas disease and induce a number of adverse effects. Hence, there is an urgent need for the development of new cost effective therapy against T. cruzi with minimal side effects.
We have previously reported on a high-throughput screening campaign conducted to identify inhibitors of trypanothione reductase (TR) that might consequently be toxic to trypanosomatids. This led to the serendipitous discovery of a compound potently active against T. cruzi and highly selective relative to other kinetoplastids such as Leishmania donovani and Trypanosoma brucei. Serendipitous, because activity against trypanothione reductase is far too weak to explain its potent trypanocidal activity.
This led to the further discovery of several other novel trypanocides, which we have recently found to possess potent activity against certain species filamentous fungi of great relevance to human pathogenesis. Some of these compounds are entirely novel and “singletons”, for which we need to establish structure-activity relationships to find the most potent, selective, stable and drug-like compounds that are the best candidates for preclinical development, either as Chaga’s disease treatments, antifungals, or both.
That is the aim of this exciting medicinal chemistry project.
Project references
- Holloway GA, Parisot JP, Novello PM, Watson KG, Armstrong T, Thompson RCA, Street IP and Baell JB. Discovery of novel and potent benzhydryl-tropane trypanocides highly selective for Trypanosoma cruzi. Bioorg. Med. Chem. Lett. 2010 20:1816-1818.
- Lackovic K, Parisot JP, Sleebs N, Baell JB, Debien L, Watson KG, Curtis JM, Handman E, Street IP and Kedzierski L. Inhibitors of Leishmania GDP-Mannose Pyrophosphorylase Identified by High-Throughput Screening of Small Molecule Chemical Library. Antimicrob. Agents Chemother. 2010, 54:1712-1719.
- Nhu D, Duffy S, Avery VM, Hughes AH & Baell JB. 3-Arylamino-6-benzylamino-1,2,4,5-tetrazines with potent antimalarial activity. Bioorg. Med. Chem. Lett. 2010 20:4496-4498.
- Holloway GA, Baell JB, Fairlamb AH, Novello PM, Parisot JP, Richardson J, Watson KG and Street IP. Discovery of 2-iminobenzimidazoles as a new class of Trypanothione Reductase inhibitor by high throughput screening. Bioorg. Med. Chem. Lett. 2007 17:1422-1427.
- Holloway GA, Charman WN, Fairlamb AH, Brun R, Kaiser, M Kostewicz E, Novello PM, Parisot JP, Richardson J, Street IP, Watson KG and Baell JB. Trypanothione reductase high-throughput screening campaign identifies novel classes of inhibitors with anti-parasitic activity. Antimicrob. Agents Chemother. 2009, 53:2824-2833.
Research interests
The Medicinal Chemistry laboratory, part of the Division of Chemical Biology, conducts research aimed at developing new therapeutically useful molecules. Projects in the laboratory currently focus on cancer and parasitic diseases such as malaria, human African trypanosomiasis (sleeping sickness), leishmaniasis, Chagas’ disease and most recently, those arising from fungal infections. Of great relevance to this project, one of only a few compound classes worldwide taken into development as a potential Chagas’ disease treatment was discovered in our laboratories.
The great challenge in cutting edge medicinal chemistry is to take a weakly active compound and to greatly improve potency and selectivity while keeping other aspects such as metabolic stability and aqueous solubility within reasonable parameters. This is one of our principal interests and one in which our group has an outstanding track record.
Selected publications
- Brady RM, Khakham Y, Lessene G & Baell JB. Benzoylureas as removable Cis amide inducers: synthesis of cyclic amides via Ring Closing Metathesis (RCM). Org. Biomol. Chem. 2011, 9:656-658.
- Sleebs BE, Czabotar PE, Fairbrother, WJ, Fairlie WD, Flygare, JA, Huang, DCS, Kersten WJA, Koehler MFT, Lessene G, Lowes K, Parisot JP, Smith BJ, Smith ML, Souers AJ, Street IP, Yang H and Baell, JB. Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma extra long (Bcl-xL) with potent pro-apoptotic cell-based activity. J. Med. Chem. 2011 54: 1914-1926.
- Baell JB. Observations on screening-based research and some concerning trends in the literature. Future Med. Chem. 2010 2:1529–1546.
- Baell JB and Holloway GA. New substructure filters for removal of pan assay interference compounds [PAINS] from screening libraries and for their exclusion in bioassays. J. Med. Chem. 2010 53:2719-2740.
- Ban K, Duffy S, Khakham Y, Avery VM, Hughes AH, Montagnat O, Katneni K, Ryan E & Baell JB. 3-Alkylthio-1,2,4-triazine dimers with potent antimalarial activity. Bioorg. Med. Chem. Lett. 2010 20:6024-6029.
Research theme
Infectious diseases
Scientific discipline
- Chemistry
- Medicinal Chemistry
Keywords
Drug discovery, Neglected Diseases, Parasitic Diseases, American Trypanosomiasis, Chagas’ Disease, Kinetoplastids, Fungicides