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Development of New Drugs for the Treatment of Malaria

Final Report Summary - ANTIMAL (Development of new drugs for the treatment of malaria)

The ultimate aim of the ANTIMAL project was to generate novel antimalarial drugs with potential for use in humans, specifically to progress candidate molecules to the 'first time into humans' stage of drug development. To achieve this goal, leading groups of malaria researchers from Europe and Africa with expertise in malaria biology, chemotherapy and drug development gathered to exploit new scientific and political opportunities to secure the development of a portfolio of viable antimalarial drugs. These new chemical entities would be ultimately commercially attractive to industrial partners and through the generation of Public private partnerships (PPPs) they would result in affordable new antimalarial drugs registered to internationally recognised standards.

The main areas of focus of ANTIMAL were the following: novel quinolines, novel peroxides, drugs targeting lipid metabolism, drugs directed against other targets (kinases, pyrimidine metabolism, hexose transporters, bisarylureas, chalcones) and post-candidate development. The project brought together European research institutes of established international reputation in the field of malaria biology and chemotherapy and their affiliated research groups in malaria-endemic areas. Through ANTIMALs programme of jointly executed research, 28 European research groups supported the network's goals to generate viable lead drug molecules in collaboration with seven industrial partners including six Small and medium-sized enterprises (SMEs) and ten partners from malaria endemic countries.

The principal objectives of the project were the following:
1. Bring together a critical mass of researchers from leading institutions.
2. The integration of leading European malaria drugs research centres through a coherent, multidisciplinary and focused programme of research.
3. Provide a vehicle for exploitation of the basic science knowledge generated by European research on malaria drugs and in particular by establishing a 'virtual' pharmaceutical development organisation within Europe for malaria drugs.
4. Establish in the European landscape of malaria research the essential link to provide antimalarial candidate products for clinical evaluation as the essential link between basic science as undertaken by the BIOMALPAR Network of Excellence (NoE) and the more advanced clinical evaluation as undertaken by the European and Developing Countries Clinical Trials Partnership (EDCTP).
5. Generate a series of novel drugs to phase-one clinical trials with the potential for safe, effective and affordable treatment of malaria within endemic countries.
6. Contribute to the training of the next generation of malaria researchers.
7. Contribute to building advanced research capacities in malaria-endemic countries in Sub-Saharan Africa.

The experimental results are grouped into the following five clusters:

- Novel aminoquinolines
The work performed in this cluster main focused the aminoquinoline core, the blood stage P. falciparum malaria and the liver stage parasites. The quinolones were used as proof-of-concept molecules for establishing in silico and in vitro antimalarial DMPK expertise in South Africa and Zimbabwe. During the ANTIMAL project more than 300 novel compounds were synthesised and evaluated for antimalarial activity in vitro and in vivo.

- Novel peroxides
The work performed focused on novel peroxide monotherapies and on peroxide hybrids. A series of lead molecules was generated based on an achiral tetraoxane template to avoid issues of chirality. Furthermore, isolation and structural characterisation of a novel class of endoperoxide from the marine sponge Plakortis simplex was performed. Both projects generated molecules with activity against drug sensitive and resistant parasites and several of the lead molecules showed advantages over existing peroxides. The first of the hybrid projects exploited the reductive cleavage of the peroxide ring to generate a second antimalarial selectively within the parasite while the second hybrid project linked a peroxide template with a quinoline template to aid targeting within the parasite.

- Lipid targets
A series of molecules from bisquaternary ammonium salts was generated which produced a candidate drug molecule that entered clinical trials in man. Moreover, a series of bis-alkylamidine and bis-alkylguanidine drugs, which can mimic the choline structure, was designed and synthesised. For these drugs, the cationic head was also separated by lipophilic alkyl chains. A prodrug approach was validated for bis-alkylamidines. Symmetrical and asymmetrical bis-benzamidine compounds were designed and synthesised and tested. During the ANTIMAL project more than 150 novel compounds were synthesised and evaluated for antimalarial activity in vitro and in vivo as part of this cluster.

- Other targets
The work performed in this cluster laid focus on potential protein kinase targets, especially on the 4-methyl-5-beta-hydroxyethylthiazole (UON) target, on the characterisation of potential targets in pyrimidine metabolism, on novel bisarylureas, as well as on the development of a high-throughput screening assay for the hexose transporter PfHT and also a library of more than 1000 chalcones was synthesised and evaluated against plasmodium falciparum.

- Post-candidate development
The work performed in this cluster focused on a single molecule, FR900098, a novel fosmidomycin derivative targeting isoprenoid biosynthesis. Moreover, a standardised service was provided to the consortium for the in vitro and in vivo testing of molecules and also in vivo experiments in order to evaluate the therapeutic potential of drug combinations.

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