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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 worlds population, mostly those living in the worlds 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 StepforwardNF990/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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