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Fighting against Malaria Design and Discovery of New Anti-malarial Agents

Malaria

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Fighting against Malaria Design and Discovery of New Anti-malarial Agents

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    1. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Fighting against Malaria Design and Discovery of New Anti-malarial Agents

    2. Malaria….a Global Problem Approximately, 40% of the world’s population, mostly those living in the world’s poorest countries, are at risk of malaria.

    3. Distribution and Resistance Inappropriate use of antimalarial drugs in the past century contributed to widespread resistance in the malaria parasite to drugs such as chloroquine Over the past decade, a new group of antimalarials – known as artemisinin-based combination therapies (ACTs) – has brought new hope in the fight against malaria

    4. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    5. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Currently used antimalarials

    6. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Drugs and drug combinations in advanced stages of clinical studies Piperaquine/Dihydroartemisinin: Euartekin® ACT: bisquinoline + artemisinine Pyronaridine/Artsunate: Pyramax® (MMV) ACT: Mannich-base + artemisinine Tafenoquine: WR 238605 Activity against blood and liver stages and sporontocidal activity A clinical trial on long-term prophylaxis has been suspended due to vortex keratopathy

    7. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Dropouts Artemisone: second generation semi-synthetic artemisinine OZ-277: synthetic peroxide Clinical development has been discontinued since bioavailability in malaria patients was only one third of the values obtained with healthy volunteers GW844520: 4-(1H)-pyridone Development discontinued due to unexpected cardiotoxicity in dogs

    8. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Novel molecular targets in P. falciparum

    9. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Hemoglobin digestion by proteases Release of toxic free heme Spontaneous oxidation of Iron(II)-heme to Iron(III) heme and production of ROS Crystallization of free heme to hemozoin

    10. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    11. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    12. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    13. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Development of a new class of rapidly and orally acting antimalarial drugs, easy to synthesize by low-cost synthetic strategies and structurally different from known antimalarials Low potential of inducing resistance under drug pressure

    14. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Background: relevant aspects of Plasmodium biology Established drugs: structures targets resistance New drugs to kill resistant Pf:

    15. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Natural Products - Artemisinins

    16. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Plakortin: the main metabolite from Plakortis simplex Plakortin is a C18 polybutyryl-polyketide containing a 1,2-dioxane group Secondary metabolite from bacteria - around 25% of the organic extract

    17. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 9,10-Dihydroplakortin as Hit Compound

    18. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Investigation of the Mechanism of Action

    19. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Analysis of Conformational Behaviour: Steric and Electronic Parameters Plakortin: conformational preference of the 1,2-dioxane ring

    20. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Mechanism of Action: Generation of a Reactive Radical

    21. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Hypothesis of Mechanism of Action

    22. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    23. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    24. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Development of Novel Endoperoxides Total synthesis of the natural compounds Development of simplified analogues Synthesis of basic chained endoperoxides Synthesis of hybrid compounds

    25. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Retrosynthetic Analysis (1)

    26. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Retrosynthetic Analysis (2)

    27. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Synthesis of Alcohol (S)-1 Scheme 1

    28. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Synthesis of Intermediate 10a via Route A Scheme 2

    29. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Synthesis of Intermediate 10b via Route B Scheme 3

    30. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Synthesis of the Endoperoxide Ring Scheme 4

    31. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Synthesis of 9,10-Dihydroplakortin Scheme 5

    32. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    33. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 An Innovative Pharmacophore Towards Potent, Orally Active Antimalarial Agents

    34. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    35. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 CLT: an Old Antifungal Drug with Poor Bioavailability

    36. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    37. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    38. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 CLT: an Old Antifungal Drug with Antimalarial Activity

    39. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    40. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

    41. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 An Hypothesis for CLT Mechanism of Action… Imidazole can mediate the transfer of electrons through its ? system by forming transient oxidized or reduced radicals The triphenylmethyl system is able to form and stabilize a radical

    42. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 From CLT to Novel Antimalarials The “Chloroquine Trick”

    43. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Design Strategy to Novel Antimalarials Based on CLT Scaffold

    44. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Structure-Activity Relationships

    45. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Structure-Activity Relationships

    46. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 General Synthesis of Triarylmethyl Analogues

    47. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Electron withdrawing vs Electron donating groups

    48. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Heme-complexing Groups and Protonatability

    49. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Heterocyclic Derivatives - 1

    50. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Heterocyclic Derivatives - 2

    51. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 The Methyne Carbon Asymmetry Issue

    52. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 NF990 and NF1041 Inhibit b-Hematin Formation in vitro

    53. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 CLT Analogues are Selectively Toxic for Plasmodium

    54. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 In vivo Antimalarial Activity

    55. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Stepforward…NF990/CQ Hybrids

    56. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 General Synthesis of Benzydril Hybrid Compounds

    57. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 Multisite Iron Interaction Properties The Key Role of m-Cl

    58. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 From NF990 to NF1058: a 4-Aminoquinoline/CLT Hybrid

    59. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009 NF1058 and NF1066 – In vivo Activity

    60. ICS - UNIDO “Advanced Design and Development of Potential Drugs against Malaria” Trieste, 12 March 2009

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