Antimalarial Agents: Design and Mechanism of Action

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 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 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 PfA-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
		7.6.7 - Peptidomimetic inhibitors containing a diamine core
		7.6.8 - Peptidomimetic inhibitors involving symmetrical structures
		7.6.9 - Peptidomimetics with macrocyclic rings
	7.7 - Peptidomimetic inhibitors that form covalent bonds with plasmepsins
		7.7.1 - Reversible inhibitors
		7.7.2 - Irreversible inhibitors
	7.8 - Repurposing HIV-1 protease inhibitors
	7.9 - Repurposing cathepsin D inhibitors
	7.10 - Non-peptide inhibitors
		7.10.1 - Introduction
		7.10.2 - Diphenylureas and thioureas
		7.10.3 - Ethylene diamines and 4-aminopiperidines
			7.10.3.1 - Ethylene diamines
			7.10.3.2 - Piperidines
		7.10.4 - Azanorbornanes
		7.10.5 - Azepines
		7.10.6 - Pyrrolidines
		7.10.7 - α,α-Difluoroketones
		7.10.8 - Aminohydantoins
		7.10.9 - 2-Aminoquinazolin-4(3H)-ones
		7.10.10 - Miscellaneous agents
	7.11 - Inhibitors of plasmepsin V
		7.11.1 - Introduction
		7.11.2 - The importance of protein transport
		7.11.3 - The role of plasmepsin V in protein transport
		7.11.4 - Examples of plasmepsin V inhibitors
	7.12 - Plasmepsins IX and X
	7.13 - Conclusions
	References
Chapter 8 - Falcipains as drug targets in antimalarial therapy
	8.1 - Introduction
	8.2 - Substrate preference of falcipains
	8.3 - Structure of falcipains
	8.4 - Mechanism of enzyme catalysis
	8.5 - Inhibitors of falcipain—introduction
	8.6 - Irreversible peptidomimetic inhibitors of falcipains
		8.6.1 - Introduction
		8.6.2 - Fluoromethyl ketones
		8.6.3 - Vinyl sulfones
		8.6.4 - Agents containing α,β-unsaturated carbonyl groups
			8.6.4.1 - α,β-Unsaturated esters
			8.6.4.2 - α,β-Unsaturated imides
			8.6.4.3 - α,β-unsaturated ketones
		8.6.5 - Epoxides and aziridines as irreversible inhibitors
		8.6.6 - O-Acyl hydroxamates and O-acyl hydroxyureas
	8.7 - Peptidomimetic inhibitors of falcipains that form reversible covalent bonds
		8.7.1 - Introduction
		8.7.2 - Aldehydes and α-ketoamides
		8.7.3 - Nitriles
	8.8 - Conformationally restrained peptidomimetic inhibitors of falcipains
		8.8.1 - Introduction
		8.8.2 - Benzodiazepines
		8.8.3 - Pyridones and pyrimidinones
		8.8.4 - Lactams
	8.9 - Non-peptide inhibitors
		8.9.1 - Chalcones
		8.9.2 - Thiosemicarbazones and isatins
		8.9.3 - Isoquinolines
		8.9.4 - Tetrazoles, triazoles, and quinazolines
		8.9.5 - Phthalimides
		8.9.6 - Aryl nitriles and pyrimidinecarbonitriles
		8.9.7 - Phenothiazinones
		8.9.8 - Thiazoles
		8.9.9 Miscellaneous structures
			8.9.9.1 Structures derived from virtual screening
			8.9.9.2 - Structures derived from natural products
	8.10 - Dual-action agents
		8.10.1 - Dual-action agents involving chalcones
			8.10.1.1 - Dual-action agents involving chalcone and peroxides
			8.10.1.2 - Dual-action agents involving chalcones and quinolines
		8.10.2 - Dual-action agents involving thiosemicarbazones and semicarbazones
			8.10.2.1 - Structures containing 4-aminoquinolines and semicarbazones/thiosemicarbazones
			8.10.2.2 - Structures containing artemisinins and semicarbazones/thiosemicarbazones
		8.10.3 - Dual-action agents involving lactams
		8.10.4 - Miscellaneous hybrids
	8.11 - Other approaches
	8.12 - Conclusion
	References
Chapter 9 - Drug targets in the apicoplast
	9.1 - The apicoplast
	9.2 - Biosynthesis of isoprenes in Plasmodium cells
	9.3 - 1-Deoxy-d-xylulose 5-phosphate reductoisomerase
		9.3.1 - Introduction
		9.3.2 - Mechanism of action
		9.3.3 - Analogs of DOXP
	9.4 - Inhibitors of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR)
		9.4.1 - Fosmidomycin and FR900098
		9.4.2 - Binding interactions of fosmidomycin
		9.4.3 - Issues relating to testing and drug design
		9.4.4 - Analogs of fosmidomycin—modification of the phosphonate group
		9.4.5 - Analogs of fosmidomycin—modification of the hydroxamate group
		9.4.6 - Analogs of fosmidomycin—modification of the linker
		9.4.7 - Analogs of fosmidomycin with linker substituents
		9.4.8 - Further α-substituted analogs of fosmidomycin
		9.4.9 - Reverse fosmidomycin analogs
		9.4.10 - Reversed fosmidomycin analogs with an amide group
		9.4.11 - Phosphonate esters as prodrugs for fosmidomycin analogs
		9.4.12 - Bisphosphonates and phosphonates
	9.5 - 2-C-Methyl-d-erythritol 4-phosphate cytidyltransferase
		9.5.1 - Introduction
		9.5.2 - Binding interactions involving CTP
		9.5.3 - Mechanism of the enzyme-catalyzed reaction
		9.5.4 - Effect of fosmidomycin on IspD
		9.5.5 - Inhibitors of IspD
	9.6 - 4-Diphosphocytidyl-2-C-Methyl-d-erythritol kinase (IspE)
	9.7 - 2-C-Methyl-d-erythritol 2,4-cyclodiphosphate synthase (IspF)
	9.8 - 2C-Methyl-d-erythritol 2,4-cyclodiphosphate reductase (Pf IspG) and 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate re...
	9.9 - Fatty acid biosynthesis
		9.9.1 - Introduction
		9.9.2 - β-Ketoacyl-ACP synthase III
		9.9.3 - Elongation phase
		9.9.4 - 3-Oxoacyl-ACP reductase
		9.9.5 - Inhibitors of β-hydroxyacyl-acyl carrier protein dehydratase
		9.9.6 - Enoyl-acyl carrier protein reductase
			9.9.6.1 - Triclosan and related analogs
			9.9.6.2 - Flavonoids
			9.9.6.3 - Miscellaneous agents
		9.9.7 - Inhibitors of PfFabBF
	9.10 - Other potential targets in the apicoplast
		9.10.1 - Pyruvate dehydrogenase complex
		9.10.2 - Lipoate scavenging and synthesis
			9.10.2.1 - Inhibition of the scavenging process
			9.10.2.2 - Inhibition of de novo lipoate synthesis
		9.10.3 - Other targets related to fatty acid metabolism159
	9.11 - Antibiotics
	9.12 - Conclusions
	References
Chapter 10 - Drugs targeting mitochondrial functions
	10.1 - Introduction
	10.2 - The mitochondrial electron-transport chain of Plasmodium sp. and de novo pyrimidine biosynthesis
	10.3 - The cytochrome bc1 complex
		10.3.1 - Introduction
		10.3.2 - Inhibitors of the cytochrome bc1 complex
			10.3.2.1 - Hydroxynaphthoquinones
			10.3.2.2 - Pyridones
			10.3.2.3 - Acridones
			10.3.2.4 - Quinolones
	10.4 - Dihydroorotate dehydrogenase
		10.4.1 - Introduction
		10.4.2 - Inhibitors of PfDHODH
			10.4.2.1 - Introduction
			10.4.2.2 - Leflunomide and brequinar analogs
			10.4.2.3 - Triazolopyrimidines
			10.4.2.4 - Benzimidazolyl thiophene-2-carboxamides
			10.4.2.5 - Biaryl carboxoamides
			10.4.2.6 - Dihydrothiophenones and dihydrofuranones
	10.5 - Type II NADH dehydrogenase (NDH2)
		10.5.1 - Introduction
		10.5.2 - Inhibitors of PfNDH2H
	10.6 - Other mitochondrial targets
		10.6.1 - Complex II (Succinate dehydrogenase)
		10.6.2 - ATP synthase
		10.6.3 - Potential targets in the TCA cycle
		10.6.4 - Potential targets in heme biosynthesis
	10.7 - Resistance to mitochondrial drugs
	10.8 - Chapter summary
	References
Chapter 11 - The Plasmodium falciparum proteasome as a drug target
	11.1 - Structure and function of the proteasome
	11.2 - Irreversible inhibitors
		11.2.1 - β-Lactones
			11.2.1.1 - Lactacystin
			11.2.1.2 - Salinosporamide A
		11.2.2 - Epoxyketones
			11.2.2.1 - Epoxomicin
			11.2.2.2 - Carfilzomib
			11.2.2.3 - Carmaphycin
		11.2.3 - Vinyl sulfones
		11.2.4 - Sulfonyl fluorides
		11.2.4 - Gliotoxin
	11.3 - Reversible inhibitors
		11.3.1 - Asparagine ethylenediamines
		11.3.2 - Aldehydes
		11.3.3 - Peptide boronates
		11.3.4 - Cyclic peptides
			11.3.4.1 - TMC95A and analogs
			11.3.4.2 - Thiostrepton
	11.4 - Alternative targets
		11.4.1 - Calpain inhibitors
		11.4.2 - Cyclic GMP-dependent protein kinase G and regulatory ATPases
		11.4.3 - Alternative proteasome targets
	References
Chapter 12 - Transferases and their inhibition
	12.1 - Farnesyltransferases
		12.1.1 - Introduction
		12.1.2 - Mechanism of action
		12.1.3 - Farnesyltransferase inhibitors—peptidomimetic agents designed to mimic Caax
		12.1.4 - Farnesyltransferase inhibitors with an ethylenediamine scaffold
		12.1.5 - Farnesyltransferase inhibitors with a tetrahydroquinoline scaffold
		12.1.6 - Natural products as FTase inhibitors
		12.1.7 - Miscellaneous FT inhibitors
	12.2 - N-Myristoyltransferase (NMT)
		12.2.1 - Introduction
		12.2.2 - NMT inhibitors
		12.2.3 - Piggy backing on antifungal agents acting as NMT inhibitors
		12.2.4 - Miscellaneous NMT inhibitors
	12.3 - Phosphoethanolamine methyltransferase
		12.3.1 - Introduction
		12.3.2 - Inhibitors
	12.4 - Plasmodium falciparum CTP:phosphocholine cytidylyltransferase
	12.5 - Other transferases
	References
Chapter 13 - Kinases and kinase inhibitors
	13.1 - Introduction
	13.2 - Calcium-dependent protein kinases
		13.2.1 - Introduction
		13.2.2 - P. falciparum calcium-dependent kinase-1 (PfCDKP1)
		13.2.3 - P. falciparum calcium-dependent kinase-4 (PfCDKP4)
	13.3 - P. falciparum cGMP-dependent protein kinase (PfPKG)
	13.4 - P. falciparum cAMP-dependent protein kinase (PfPKA)
	13.5 - Plasmodium falciparum MO15-related kinase (PfMRK)
	13.6 - P. falciparum cyclin-dependent kinase 5 (PfPK5)
	13.7 - P. falciparum glycogen synthase kinase 3 (PfGSK-3)
		13.7.1 - Thienopyridines
		13.7.2 - Manzamine A and analogs
	13.8 - P. falciparum never-in-mitosis gene A-related kinases (PfNIMA/NEK)
	13.9 - Phe(F)-Ile(I)-Lys(K)-Lys(K) (FIKK)
	13.10 - Plasmodium falciparum protein kinase 7 (PfPK7)
	13.11 - Phosphoinositide 3-kinase
	13.12 - Phosphatidylinositide 4-kinase (PfPI4K IIIβ) inhibitors
	13.13 - Choline kinase (CK)
	13.14 - Guanylate kinase
	13.15 - Thymidylate kinase
	13.16 - Other kinases
	References
Chapter 14 - Miscellaneous agents of clinical interest
	14.1 - Introduction
	14.2 - Plasmodium falciparum ATP4ase inhibitors
		14.2.1 - Introduction
		14.2.2 - The spiroindolone KAE609
		14.2.3 - The dihydroisoquinolone (+)-SJ733
		14.2.4 - Other agents
	14.3 - Inhibitors of protein transport and localization
	14.4 - P. falciparum translation elongation factor 2 (PfeEF2)
	14.5 - MK-4815
	14.6 - NCGC00100599
	14.7 - Choline transport inhibitors
		14.7.1 - Biosynthesis of phosphatidyl choline and phosphatidylethanolamine
		14.7.2 - Inhibitors of the choline transporter
	References
Chapter 15 - Inhibitors of purine and pyrimidine pathways
	15.1 - The purine salvage pathway
	15.2 - Adenosine deaminase
	15.3 - Purine nucleoside phosphorylases
		15.3.1 - Introduction
		15.3.2 - Immucillins as inhibitors
	15.4 - 6-Oxopurine phosphoribosyltransferases
		15.4.1 - Introduction
		15.4.2 - Phosphonate inhibitors of HG[X]PRT
		15.4.3 - Aza bisphosphonate inhibitors of HG[X]PRT
		15.4.4 - Partially rigidified phosphonate inhibitors of HG[X]PRT
		15.4.5 - Immucillins as inhibitors of HG[X]PRT
	15.5 - Adenylosuccinate synthetase and adenylosuccinate lyase
	15.6 - De novo pyrimidine synthesis pathway in P. falciparum
	15.7 - Orotidine 5’-monophosphate decarboxylase
	15.8 - Deoxyuridine triphosphate nucleotidohydrolase (dUTPase)
	References
Chapter 16 - Miscellaneous targets
	16.1 - Introduction
	16.2 - Farnesyl pyrophosphate/geranylgeranyl pyrophosphate synthase
	16.3 - Glutamate dehydrogenase
	16.4 - Glyceraldehyde-3-phosphate dehydrogenase
	16.5 - Glucose-6-phosphate dehydrogenase
	16.6 - Lactate dehydrogenase
		16.6.1 - Introduction
		16.6.2 - Inhibitors based on the natural product gossypol
			16.6.2.1 - Gossypol and analogs
			16.6.2.2 - Simplified analogs of gossypol
		16.6.3 - Azole-based inhibitors
		16.6.4 - Dual-target inhibitors
			16.6.4.1 - Hydroxamates as inhibitors
			16.6.4.2 - Oxamates as inhibitors
		16.6.5 - Interactions with 3-acetylpyridine adenine dinucleotide
	16.7 - S-Adenosylhomocysteine hydrolase
	16.8 - Phosphodiesterases
	16.9 - HSP-90
	16.10 - Histone deacetylase
		16.10.1 - Histone deacetylases: role and mechanism of action
		16.10.2 - Cyclic tetrapeptide inhibitors
		16.10.3 - Hydroxamates
		16.10.4 - Amides
		16.10.5 - Inhibitors of PfSir2 activity
	16.11 - Stearoyl-CoA desaturase
	16.12 - Aminoacyl-tRNA synthetases
		16.12.1 - Introduction
		16.12.2 - Isoleucyl-tRNA synthetase
		16.12.3 - Lysyl-tRNA synthetase
		16.12.4 - Prolyl-tRNA synthetase
		16.12.5 - Phenylalanyl-tRNA synthetase
		16.12.6 - Alanyl-tRNA synthetase
		16.12.7 - Threonyl-tRNA synthetase
		16.12.8 - Tryptophanyl-tRNA synthetase
	References