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Cover
Title
Copyright
Contents
Contributors
Chapter 1 - History of malaria and its treatment
1.1 - Introduction
1.2 - Malaria in antiquity
1.3 - Malaria and natural selection
1.4 - From the Dark Ages onward
1.5 - Jesuit's bark
1.6 - Isolation of the active principle
1.7 - Quinine toxicity and pharmacokinetics
1.8 - Discovery of the parasite
1.9 - Mosquito-malaria hypothesis
1.10 - Completing the life cycle
1.11 - Malaria control
1.12 - World War I
1.13 - Spread of vectors
1.14 - Synthetic drugs and insecticides up to the World War II
1.14.1 - Synthetic drugs
1.14.2 - Insecticides
1.15 - Quinine synthesis
1.16 - The problems of malaria during the World War II
1.17 - Post-war eradication campaigns
1.18 - Postwar drug development in the 1940s and 1950s
1.19 - Drug resistance and the search for novel antimalarial agents
1.20 - Artemisinin
1.21 - Rolling back malaria
1.22 - The way forward
References
Chapter 2 - Knowing one's enemy: the Plasmodium parasite
2.1 - Introduction
2.2 - Taxonomy
2.3 - The parasite
2.3.1 - Plasmodium falciparum
2.3.2 - Plasmodium vivax
2.3.3 - Plasmodium ovale
2.3.4 - Plasmodium malariae
2.3.5 - Plasmodium knowlesi
2.4 - Plasmodium genome and genetics
2.5 - The Plasmodium life cycle
2.5.1 - The liver stage of Plasmodium infection
2.5.2 - The blood stage of Plasmodium infection
2.5.3 - Sexual stages
2.6 - Drugs used to treat malaria
2.6.1 - Quinolines and naphthoquinones
2.6.2 - Acryl alcohols
2.6.3 - Antifolates
2.6.4 - Antibiotics
2.6.5 - Artemisinin and derivatives
2.7 - Evolution and spread of drug resistance
2.8 - Mechanism of resistance in P. falciparum
2.8.1 - Resistance mechanisms to chloroquine
2.8.2 - Resistance mechanisms to antifolates.
2.8.3 - Resistance to atovaquone
2.8.4 - Resistance mechanisms to antibiotics
2.8.5 - Resistance mechanisms to artemisinin and its derivatives
2.8.6 - Strains of Plasmodium falciparum with drug resistance
2.9 - Drug targets in Plasmodium and their rationale
2.9.1 - Introduction
2.9.2 - Targets for current antimalarial drugs
2.9.3 - Rational selection of novel antimalarial targets
2.9.4 - Drug discovery screening strategies for target identification
2.9.4.1 - Whole cell screening
2.9.4.2 - Rational design approach
2.9.4.3 - Systems biology
2.10 - Emerging targets for antimalarial drug development
2.10.1 - Proteases
2.10.2 - The apicoplast as a target
2.10.2.1 - The fatty acid pathway
2.10.2.2 - Isoprenoid biosynthesis
2.10.3 - The parasite mitochondria as a target
2.10.4 - Targeting lipid metabolic pathways
2.10.5 - Targeting protein kinases
2.10.6 - Targeting the proteasome of Plasmodium
2.10.7 - Miscellaneous targets
References
Chapter 3 - The cinchona alkaloids and the aminoquinolines
3.1 - Introduction
3.2 - 4-Aminoquinolines and related quinoline antimalarials
3.2.1 - Introduction
3.2.2 - The mechanism of action of 4-aminoquinolines
3.2.3 - Structure-activity relationships of the 4-aminoquinolines
3.2.4 - Resistance to chloroquine
3.2.5 - Molecular modifications of 4-AQs that overcome resistance and reduce toxicity
3.2.6 - The pharmacokinetics of 4-aminoquinolines
3.3 - 8-Aminoquinolines
3.3.1 - Introduction
3.3.2 - Mechanism of action of 8-aminoquinolines
3.3.3 - Pharmacokinetics of 8-aminoquinolines
3.3.4 - Structure-activity relationships of 8-aminoquinolines
3.4 - Quinoline methanols
3.4.1 - Quinine and quinidine
3.4.2 - Mefloquine and lumefantrine
3.4.3 - Mechanism of action of quinoline methanols.
3.4.4 - Pharmacokinetics of quinoline methanols
3.4.5 - Structure-activity relationships for quinoline methanols
3.5 - Conclusions
References
Chapter 4 - Artemisinin and artemisinin-related agents
4.1 - Introduction
4.2 - Artemisinin and its first generation semi-synthetic derivatives
4.3 - The mechanism of action of the artemisinins
4.3.1 - Bioactivation by ferrous iron to give carbon-centered radicals
4.3.2 - The ferrous iron activator
4.3.3 - Alkylation of heme
4.3.4 - Alkylation of parasite proteins
4.3.5 - Lipid peroxidation
4.3.6 - Alternative targets and modes of action, including non-ferrous activation of artemisinins
4.4 - Structure-activity relationships and the development of new endoperoxide-containing antimalarial drug candidates
4.4.1 - Semi-synthetic artemisinins
4.4.2 - Synthetic 1,2,4-trioxanes
4.4.3 - "Simple" endoperoxides (1,2-dioxanes and 1,2-dioxolanes)
4.4.4 - 1,2,4-Trioxolanes and 1,2,4,5-tetraoxanes
4.5 - Conclusions
References
Chapter 5 - Agents acting on pyrimidine metabolism
5.1 - The folate biosynthesis pathway
5.2 - Inhibitors of dihydrofolate reductase-the development of proguanil (ICI4888)
5.2.1 - Catalytic reduction of DHF to THF
5.2.2 - Discovery of ICI2666
5.2.3 - Structure-activity relationship studies on ICI2666
5.2.3.1 - The 2-anilino ring and bridge
5.2.3.2 - Replacement of the 2-anilino ring
5.2.4 - Modifications to the pyrimidine ring
5.2.4.1 - Substitution at positions 5 and 6
5.2.4.2 - Modifications to position 4
5.2.4.3 - Replacement of the pyrimidine ring
5.2.5 - Biguanide derivatives of ICI2666
5.2.5.1 - Discovery of proguanil (ICI4888)
5.2.5.2 - SAR surrounding proguanil (ICI4888)-the phenyl ring
5.2.5.3 - SAR surrounding proguanil (ICI4888)-replacement of the phenyl ring.
5.2.5.4 - SAR surrounding ICI4888-modifications to the biguanide linker
5.2.6 - Clinical trials and drug metabolism studies
5.3 - Inhibitors of dihydrofolate reductase-the development of pyrimethamine
5.3.1 - The discovery of BW148-22 and SAR studies
5.3.2 - 5-Benzyl derivatives and SAR
5.3.3 - SAR studies on 5-phenyl derivatives
5.3.4 - Clinical evaluation of pyrimethamine
5.4 - Inhibitors of dihydrofolate reductase-the battle against resistance
5.4.1 - N-Benzyloxydihydrotriazines
5.4.2 - Development of WR99210 and associated prodrugs
5.4.3 - Biguanide prodrugs-in vitro metabolism studies
5.5 - Inhibitors of dihydrofolate reductase-structural basis for resistance
5.5.1 - Binding of pyrimethamine and WR99210 to the PfDHFR-TS enzyme
5.5.2 - Proposed binding of cycloguanil to the PfDHFR-TS enzyme
5.5.3 - The A16V/S108T double mutant enzyme
5.6 - Inhibitors of dihydrofolate reductase-overcoming drug resistance
5.6.1 - 3'-Substituted derivatives of pyrimethamine
5.6.2 - Hybrids of pyrimethamine and WR99210
5.6.3 - C2 monosubstituted derivatives of cycloguanil
5.7 - Antifolate agents acting on dihydropteroate synthase
5.7.1 - Introduction
5.7.2 - SAR studies surrounding sulfanilamide
5.7.3 - Clinical trials and synergism with DHFR inhibitors
5.7.4 - Point mutations leading to DHPS resistance
5.7.5 - Homology model of PfDHPS active site
5.7.6 - Sulfones-discovery of dapsone
5.7.7 - Derivatives of dapsone
5.8 - Antifolate agents acting on serine hydroxymethyltransferase
5.8.1 - Introduction
5.8.2 - Pyrazolopyran inhibitors of SHMT
5.8.3 - Binding mode of the pyrazolopyran (+)-181
5.8.4 - Metabolism studies and SAR optimization
5.8.5 - Further metabolism studies and development of structure (±)-216
5.9 - Summary
References.
Chapter 6 - Antimalarial agents acting on hemoglobin degradation
6.1 - Introduction
6.2 - Plasmepsins and falcipains
6.3 - Falcilysin
6.4 - Dipeptidyl aminopeptidases
6.4.1 - Introduction
6.4.2 - DPAP inhibitors
6.5 - Aminopeptidases
6.6 - Plasmodium falciparum M1 alanyl-aminopeptidase
6.6.1 - Introduction
6.6.2 - Mechanism of action of PfA-M1
6.6.3 - Inhibitors of Pf A-M1
6.6.3.1 - Bestatin and analogs
6.6.3.2 - Hydroxamates
6.6.3.3 - Carboxylates
6.6.3.4 - Dual target inhibitors
6.7 - Plasmodium falciparum M17 leucyl-aminopeptidase
6.7.1 - Introduction
6.7.2 - Structure and properties of PfA-M17
6.7.3 - Inhibitors of leucyl aminopeptidase
6.7.3.1 - Bestatin and analogs
6.7.3.2 - Phosphonates
6.8 - Dual-target inhibitors of PfA-M1 and PfA-M17
6.8.1 - Hydroxamates
6.8.2 - Phosphinates
6.8.3 - Phosphonates
6.8.4 - Imidazoles
6.9 - Plasmodium falciparum M18 aspartyl aminopeptidase
6.10 - Plasmodium falciparum prolyl aminopeptidase
6.11 - Methionine aminopeptidases
6.11.1 - Methionine aminopeptidase 1b
6.11.2 - Methionine aminopeptidase 2
6.12 - Conclusion
References
Chapter 7 - Plasmepsins as targets for antimalarial agents
7.1 - Introduction
7.2 - Testing procedures
7.3 - Characteristics of plasmepsins
7.4 - Structure of plasmepsins
7.5 - Mechanism of action
7.6 - Peptidomimetic agents as reversible inhibitors
7.6.1 - Introduction
7.6.2 - Peptidomimetic inhibitors containing a statine transition state isostere
7.6.3 - Peptidomimetic inhibitors containing a hydroxyethylene transition state isostere within a diamine core
7.6.4 - Peptidomimetic inhibitors containing a norstatine or a reversed statine
7.6.5 - Peptidomimetic inhibitors containing an allophenylnorstatine core.
7.6.6 - Peptidomimetic inhibitors containing an extended statine core.
Title
Copyright
Contents
Contributors
Chapter 1 - History of malaria and its treatment
1.1 - Introduction
1.2 - Malaria in antiquity
1.3 - Malaria and natural selection
1.4 - From the Dark Ages onward
1.5 - Jesuit's bark
1.6 - Isolation of the active principle
1.7 - Quinine toxicity and pharmacokinetics
1.8 - Discovery of the parasite
1.9 - Mosquito-malaria hypothesis
1.10 - Completing the life cycle
1.11 - Malaria control
1.12 - World War I
1.13 - Spread of vectors
1.14 - Synthetic drugs and insecticides up to the World War II
1.14.1 - Synthetic drugs
1.14.2 - Insecticides
1.15 - Quinine synthesis
1.16 - The problems of malaria during the World War II
1.17 - Post-war eradication campaigns
1.18 - Postwar drug development in the 1940s and 1950s
1.19 - Drug resistance and the search for novel antimalarial agents
1.20 - Artemisinin
1.21 - Rolling back malaria
1.22 - The way forward
References
Chapter 2 - Knowing one's enemy: the Plasmodium parasite
2.1 - Introduction
2.2 - Taxonomy
2.3 - The parasite
2.3.1 - Plasmodium falciparum
2.3.2 - Plasmodium vivax
2.3.3 - Plasmodium ovale
2.3.4 - Plasmodium malariae
2.3.5 - Plasmodium knowlesi
2.4 - Plasmodium genome and genetics
2.5 - The Plasmodium life cycle
2.5.1 - The liver stage of Plasmodium infection
2.5.2 - The blood stage of Plasmodium infection
2.5.3 - Sexual stages
2.6 - Drugs used to treat malaria
2.6.1 - Quinolines and naphthoquinones
2.6.2 - Acryl alcohols
2.6.3 - Antifolates
2.6.4 - Antibiotics
2.6.5 - Artemisinin and derivatives
2.7 - Evolution and spread of drug resistance
2.8 - Mechanism of resistance in P. falciparum
2.8.1 - Resistance mechanisms to chloroquine
2.8.2 - Resistance mechanisms to antifolates.
2.8.3 - Resistance to atovaquone
2.8.4 - Resistance mechanisms to antibiotics
2.8.5 - Resistance mechanisms to artemisinin and its derivatives
2.8.6 - Strains of Plasmodium falciparum with drug resistance
2.9 - Drug targets in Plasmodium and their rationale
2.9.1 - Introduction
2.9.2 - Targets for current antimalarial drugs
2.9.3 - Rational selection of novel antimalarial targets
2.9.4 - Drug discovery screening strategies for target identification
2.9.4.1 - Whole cell screening
2.9.4.2 - Rational design approach
2.9.4.3 - Systems biology
2.10 - Emerging targets for antimalarial drug development
2.10.1 - Proteases
2.10.2 - The apicoplast as a target
2.10.2.1 - The fatty acid pathway
2.10.2.2 - Isoprenoid biosynthesis
2.10.3 - The parasite mitochondria as a target
2.10.4 - Targeting lipid metabolic pathways
2.10.5 - Targeting protein kinases
2.10.6 - Targeting the proteasome of Plasmodium
2.10.7 - Miscellaneous targets
References
Chapter 3 - The cinchona alkaloids and the aminoquinolines
3.1 - Introduction
3.2 - 4-Aminoquinolines and related quinoline antimalarials
3.2.1 - Introduction
3.2.2 - The mechanism of action of 4-aminoquinolines
3.2.3 - Structure-activity relationships of the 4-aminoquinolines
3.2.4 - Resistance to chloroquine
3.2.5 - Molecular modifications of 4-AQs that overcome resistance and reduce toxicity
3.2.6 - The pharmacokinetics of 4-aminoquinolines
3.3 - 8-Aminoquinolines
3.3.1 - Introduction
3.3.2 - Mechanism of action of 8-aminoquinolines
3.3.3 - Pharmacokinetics of 8-aminoquinolines
3.3.4 - Structure-activity relationships of 8-aminoquinolines
3.4 - Quinoline methanols
3.4.1 - Quinine and quinidine
3.4.2 - Mefloquine and lumefantrine
3.4.3 - Mechanism of action of quinoline methanols.
3.4.4 - Pharmacokinetics of quinoline methanols
3.4.5 - Structure-activity relationships for quinoline methanols
3.5 - Conclusions
References
Chapter 4 - Artemisinin and artemisinin-related agents
4.1 - Introduction
4.2 - Artemisinin and its first generation semi-synthetic derivatives
4.3 - The mechanism of action of the artemisinins
4.3.1 - Bioactivation by ferrous iron to give carbon-centered radicals
4.3.2 - The ferrous iron activator
4.3.3 - Alkylation of heme
4.3.4 - Alkylation of parasite proteins
4.3.5 - Lipid peroxidation
4.3.6 - Alternative targets and modes of action, including non-ferrous activation of artemisinins
4.4 - Structure-activity relationships and the development of new endoperoxide-containing antimalarial drug candidates
4.4.1 - Semi-synthetic artemisinins
4.4.2 - Synthetic 1,2,4-trioxanes
4.4.3 - "Simple" endoperoxides (1,2-dioxanes and 1,2-dioxolanes)
4.4.4 - 1,2,4-Trioxolanes and 1,2,4,5-tetraoxanes
4.5 - Conclusions
References
Chapter 5 - Agents acting on pyrimidine metabolism
5.1 - The folate biosynthesis pathway
5.2 - Inhibitors of dihydrofolate reductase-the development of proguanil (ICI4888)
5.2.1 - Catalytic reduction of DHF to THF
5.2.2 - Discovery of ICI2666
5.2.3 - Structure-activity relationship studies on ICI2666
5.2.3.1 - The 2-anilino ring and bridge
5.2.3.2 - Replacement of the 2-anilino ring
5.2.4 - Modifications to the pyrimidine ring
5.2.4.1 - Substitution at positions 5 and 6
5.2.4.2 - Modifications to position 4
5.2.4.3 - Replacement of the pyrimidine ring
5.2.5 - Biguanide derivatives of ICI2666
5.2.5.1 - Discovery of proguanil (ICI4888)
5.2.5.2 - SAR surrounding proguanil (ICI4888)-the phenyl ring
5.2.5.3 - SAR surrounding proguanil (ICI4888)-replacement of the phenyl ring.
5.2.5.4 - SAR surrounding ICI4888-modifications to the biguanide linker
5.2.6 - Clinical trials and drug metabolism studies
5.3 - Inhibitors of dihydrofolate reductase-the development of pyrimethamine
5.3.1 - The discovery of BW148-22 and SAR studies
5.3.2 - 5-Benzyl derivatives and SAR
5.3.3 - SAR studies on 5-phenyl derivatives
5.3.4 - Clinical evaluation of pyrimethamine
5.4 - Inhibitors of dihydrofolate reductase-the battle against resistance
5.4.1 - N-Benzyloxydihydrotriazines
5.4.2 - Development of WR99210 and associated prodrugs
5.4.3 - Biguanide prodrugs-in vitro metabolism studies
5.5 - Inhibitors of dihydrofolate reductase-structural basis for resistance
5.5.1 - Binding of pyrimethamine and WR99210 to the PfDHFR-TS enzyme
5.5.2 - Proposed binding of cycloguanil to the PfDHFR-TS enzyme
5.5.3 - The A16V/S108T double mutant enzyme
5.6 - Inhibitors of dihydrofolate reductase-overcoming drug resistance
5.6.1 - 3'-Substituted derivatives of pyrimethamine
5.6.2 - Hybrids of pyrimethamine and WR99210
5.6.3 - C2 monosubstituted derivatives of cycloguanil
5.7 - Antifolate agents acting on dihydropteroate synthase
5.7.1 - Introduction
5.7.2 - SAR studies surrounding sulfanilamide
5.7.3 - Clinical trials and synergism with DHFR inhibitors
5.7.4 - Point mutations leading to DHPS resistance
5.7.5 - Homology model of PfDHPS active site
5.7.6 - Sulfones-discovery of dapsone
5.7.7 - Derivatives of dapsone
5.8 - Antifolate agents acting on serine hydroxymethyltransferase
5.8.1 - Introduction
5.8.2 - Pyrazolopyran inhibitors of SHMT
5.8.3 - Binding mode of the pyrazolopyran (+)-181
5.8.4 - Metabolism studies and SAR optimization
5.8.5 - Further metabolism studies and development of structure (±)-216
5.9 - Summary
References.
Chapter 6 - Antimalarial agents acting on hemoglobin degradation
6.1 - Introduction
6.2 - Plasmepsins and falcipains
6.3 - Falcilysin
6.4 - Dipeptidyl aminopeptidases
6.4.1 - Introduction
6.4.2 - DPAP inhibitors
6.5 - Aminopeptidases
6.6 - Plasmodium falciparum M1 alanyl-aminopeptidase
6.6.1 - Introduction
6.6.2 - Mechanism of action of PfA-M1
6.6.3 - Inhibitors of Pf A-M1
6.6.3.1 - Bestatin and analogs
6.6.3.2 - Hydroxamates
6.6.3.3 - Carboxylates
6.6.3.4 - Dual target inhibitors
6.7 - Plasmodium falciparum M17 leucyl-aminopeptidase
6.7.1 - Introduction
6.7.2 - Structure and properties of PfA-M17
6.7.3 - Inhibitors of leucyl aminopeptidase
6.7.3.1 - Bestatin and analogs
6.7.3.2 - Phosphonates
6.8 - Dual-target inhibitors of PfA-M1 and PfA-M17
6.8.1 - Hydroxamates
6.8.2 - Phosphinates
6.8.3 - Phosphonates
6.8.4 - Imidazoles
6.9 - Plasmodium falciparum M18 aspartyl aminopeptidase
6.10 - Plasmodium falciparum prolyl aminopeptidase
6.11 - Methionine aminopeptidases
6.11.1 - Methionine aminopeptidase 1b
6.11.2 - Methionine aminopeptidase 2
6.12 - Conclusion
References
Chapter 7 - Plasmepsins as targets for antimalarial agents
7.1 - Introduction
7.2 - Testing procedures
7.3 - Characteristics of plasmepsins
7.4 - Structure of plasmepsins
7.5 - Mechanism of action
7.6 - Peptidomimetic agents as reversible inhibitors
7.6.1 - Introduction
7.6.2 - Peptidomimetic inhibitors containing a statine transition state isostere
7.6.3 - Peptidomimetic inhibitors containing a hydroxyethylene transition state isostere within a diamine core
7.6.4 - Peptidomimetic inhibitors containing a norstatine or a reversed statine
7.6.5 - Peptidomimetic inhibitors containing an allophenylnorstatine core.
7.6.6 - Peptidomimetic inhibitors containing an extended statine core.