Malaria Update
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Transcript of Malaria Update
Medicines for Malaria from the Natural Products
R. Thirumurugan
Anopheles mosquito
Malaria
• Caused by protozoan parasites belonging to the genus Plasmodium
• 4 species – human infections a) Plasmodium falciparum b) Plasmodium vivax c) Plasmodium malariae d) Plasmodium ovale
P. falciparum – severe disease & mortality
P. vivax & P. ovale – form resting stages in the liver (hypnozoites) that, once reactivated, can cause a clinical relapse many months after the initial event
Plasmodium - infect and destroy RBC, leading to fever, severe anaemia, cerebral malaria and, if untreated, death.
Life cycle of malarial parasite
1) Liver stage infection
2) Erythrocyte stage infection
Nature Biotech 2002 & NRDD 2009 8 879
Overview of Antimalarial drugs
NRDD 2009 8 879
N
N
OH
O
N
NH
Cl
N
N
NH
Cl
OH
N
N
NHN
O
N
NHNH2
O
N
NH
OH
CF3
CF3
N
OHCF3
Cl Cl
Cl Cl
Cl
NOH
Quinoline and related antimalarials:
Quinine Chloroquine Amodiaquine
PamaquinePrimaquineMefloquine
Halofantrine Lumifantrine
O
O
O O
O
O
O
O O
OH
O
O
O O
OR
SNH
NN
O
O
NH2
OO
N
NNH2
NH2
Cl
Cl
O
O
OH
Artemisinin DHA
R = Me (Artemether)R = Et (Arteether)R = CO(CH2)2CO2H
(Artesunate)
PyrimethamineSulphadoxine Atovaquine
Overview of Antimalarial drugs
NRDD 2009 8 879
Antimalarial History
Quinine 1820
Quinacrine/ Mepacrine 1935
Chloroquine 1945
Amodiaquine 1947
Proguanil 1948
Pyrimethamine 1951
Pyrimethamine – Sulfadoxine 1965 – 1972
Mefloquine 1984
Halofantrine 1988
Artemether 1994
Atovaquone - Proguanil 1996
Artemether - Lumefantrine 1999, 2009
Chlorproguanil - Dapsone 2003
Artesunate - Amodiaquine 2007
Artesunate - Mefloquine 2008
Global status of resistance
Nature 2002 415 686
1) Without a replacement drug having the low cost & reliability of Chloroquine, morbidity & mortality resurged, notably among children in Africa
2) Resistant P. vivax is present in several regions of southeast Asia & also occur in south America
3) Artemisinin resistance is confirmed in Thailand and Cambodia
Medicines for Malaria Venture (MMV)
• MMV – established in 1999 in Geneva (first public-private partnership)
• Aims to develop one new Antimalarial drug every five years
• MMV solicits, selects and manages discovery and development research at
different institutions. Projects are selected with the help of Expert Scientific
Advisory Committee on a competitive basis and reviewed regularly.
• The product profiles for MMV for uncomplicated malaria include the
following:
1) efficacy against drug-resistant strains
2) cure within 3 days
3) low propensity to generate rapid resistance
4) safe in small children
5) safe in pregnancy
6) appropriate formulations and packaging & low cost of goods.
NRDD 2004 3 509
The collaborations of MMV
Trends Parasitology 2006 22 301
MMV Project Portfolio
Research Translational DevelopmentLead generation
Lead Optimization
Preclinical Phase I Phase IIa Phase IIb / III Registration Phase IV
Novartis MP Novartis series
NITD 609Novartis/MMV
GSK 932121GSK/MMV
ArtemisoneUHKST/MMV
AZCQPfizer/MMV
EurartesimSigma-Tau/MMV
Coartem DispersibleNovartis/MMV
GSK MP PyridoneGSK/MMV
MK 4815MMV/GSK
TafenoquineGSK/MMV
OZ 439Monash/MMV
PyramaxUniv Iowa/MMV
ASAQ Winthrop
Broad & Genzyme MP
DHODHGenzy/MMV
CEM 101 IV ArtesunateGuilin/MMV
Pfizer screening
Genz Aminoindole
P218DHFRBiotec/MMV
Sanofi-aventis Quinoline Methanols
AstraZeneca screening
Genz DHODH
Kinases Oxaboroles
Natural Products
SSJ-183
Antimalarial St.Jude/Rutgers
Aminopyridine
11 other Projects
Pyrazoles
Quinolones
http://www.mmv.org/
Molecules launched & under development
Coartem
Artemether +Lumefantrine
ASAQ
Artesunate +Amodiaquine
Eurartesim
Dihydroartemisinin +Piperaquine
Pyramax
Pyronaridine +Artesunate
AZCQ
Azithromycin +Chloroquine
N O
O
CF3
NHNH2
O
O
H
HO
O
N
SO O
N
N
NH
N
N
OH
O
O
N
NN
N
O
OO
NH
NH2
O NH
OO
OCF3
Br
NH
NH
NH
O
ClF
Cl
Tafenoquine Artemisone Pyronaridine
SSJ 183OZ 277 (OZ 439) GSK 932121 derivative
NITD 609
NITD 609
Preclinical
Project Leader: Dr Thierry Diagana, Novartis Institute for Tropical Diseases, Singapore
MMV Project Director: Dr Julie Lotharius
1. NITD 609 is a novel, synthetic antimalarial molecule - Spiroindolone class, awarded MMV Project of the Year 2009. It is structurally related to GNF 493, a compound first identified as a potent inhibitor of P. falciparum growth in a high throughput phenotypic screen of natural products conducted at the Genomics Institute of the Novartis Research Foundation (GNF) in San Diego, California in 2006.
2. NITD 609 is one of only a handful of molecules capable of completely curing mice infected with P. berghei – a model of blood-stage malaria. Given its good physicochemical properties, promising pharmacokinetic and efficacy profile, the molecule was recently approved as a preclinical candidate and is now entering GLP toxicology studies with the aim of entering Phase I studies in humans in late 2010.
3. If its safety and tolerability are acceptable, NITD 609 would be the first antimalarial not belonging to either the artemisinin or peroxide class to go into a proof-of-concept study in malaria.
http://www.mmv.org/
Spiroazepineindole (GNF 493)
NH
NH
NH
O
Br
Spiroazepineindole
1 (racemate)
NF54 IC50 = 90 nMK1 IC50 = 80 nM
NH
O
NH
NH2
NH
NH
NH
O
BrNaBH3CN, NH4OAc
rt
5-bromoisatin
p-TsOH.H2O
110 oCSpiroazepineindole
1 (racemate)
JMC 2010 53 5155
NH
NH
NH
O
Br
NH
NH
NH
O
Br
1a (1R,3S)
NF54 IC50 = 20 nMK1 IC50 = 30 nM
1b (1S,3R)
NF54 IC50 = > 5000 nMK1 IC50 = > 5000 nM
In-vitro antimalarial activity of SAR of the Spiroindolones
JMC 2010 53 5155
Spiroindolone derivatives
NH
NH
NH
O
Cl
Spiroindolone (racemic)
NF54 IC50 = 27 nMK1 IC50 = 21 nM
NH
NH
NH
O
Cl
NH
NH
NH
O
Cl
NH
NH
NH
O
Cl
NH
NH
NH
O
Cl
(1R,3S)
NF54 IC50 = 9 nMK1 IC50 = 9 nM
(1S,3R)
NF54 IC50 = >5000 nMK1 IC50 = >5000 nM
(1S,3S) (1R,3R)
NF54 IC50 = 1808 nM NF54 IC50 = 444 nM
NH
R1
R2 NH
R1
R2
HO
NH
R1
R2
NO2
NH
R1
R2
NH2
NH
NH
NH
O
ClPOCl3
DMF
Nitroethane
NH4OAc
reflux
LiAlH4
THF
reflux
5-chloroisatin
p-TsOH.H2O
110 oCR1 = F; R2 = HR1 = H; R2 = ClR1 = F; R2 = ClR1 = R2 = F
Spiroindolone (racemic)
JMC 2010 53 5155
Comparison of the pharmacokinetic properties
JMC 2010 53 5155
In vivo efficacy data of NITD 609
Science 2010 329 1175
NH
NH
NH
O
ClF
Cl
Liriodendron tulipifera
• Commonly known as tulip tree or yellow popular
• Family: Magnoliaceae• Native to eastern United States
• Main constituents: Sesquiterpene lactones; Aporphine type alkaloids; Phenyl propanoids• Uses: cytotoxicity & substitute for quinine
Extraction procedure
Dried bark powder (Liriodendron tulipifera) (100gms)
+ 1000 ml Hexane Shake at rt, 24hrs & Filtered
Hexane extract Marc (Air dried)
+ 1000 ml 95% ethanol X 2 Shake at rt, 24hrs & Filtered
Ethanolic extract Marc
CHCl3 Extract Aqueous extract
Discarded
Basify by 5N NH4OH (30ml)pH 8-10 & extracted with CHCl3
Extraction Procedure for the plant Liriodendron tulipifera:
Crude hexane ext
Conc todryness
Acidified CHCl3 Extract
(1.733gm)
CHCl3 extract Aqueous Extract
(85mg)
(IC50 = 6.55 ug/ml)
Conc & dissolved in 3% HCl (200 ml)& extracted with CHCl3 (3X200ml)
Conc todryness
Isolated compounds from the bark of L. tulipifera L
NH
OH
OH
NH
H
OH
O
O
NH
O
OH
O
O
N
O
O
O
NH
H
O
ON
O
O
O
O
O
Asimilobine (1) Norushinsunine (2) Norglaucine (3)
Liriodenine (4) Anonaine (5)Oxoglaucine (6)
Compounds D10: IC50 (µg/mL) Dd2: IC50 (µg/mL) CHO: IC50 (µg/mL) SI RI
1 1.22 ± 0.12 5.76 ± 1.27 > 100 > 82.6 4.8
2 29.55 ± 3.90 30.86 ± 2.32 > 100 > 3.4 1.0
3 21.98 ± 2.84 32.22 ± 1.29 > 100 > 4.6 1.5
4 4.09 ± 0.98 7.86 ± 1.10 8.14 ± 0.01 2.0 1.9
5 1.22 ± 0.04 5.18 ± 0.25 >100 > 82.6 4.2
6 9.07 ± 0.09 20.78 ± 2.92 > 100 > 11.0 2.3
Chloroquine 11.00 ± 2.04 ng/mL 73.79 ± 4.75 ng/mL - - 7.9
Emetine - 0.18 ± 0.02 -
Selectivity index (SI) = IC50 CHO / IC50 D10
Resistance index (RI) = IC50 Dd2 / IC50 D10
Antimalarial activity and cytotoxicity of the compounds from L. tulipifera L
SAR
NH
O
O NH
O
O
OH
N
O
O
O
Anonaine Norushinsunine Liriodenine
Antimarial activity = 1.22 ug/mL
Cytotoxicity = > 100 ug/mL
Antimarial activity = 29.55 ug/mL
Cytotoxicity = > 100 ug/mL
Antimarial activity = 4.09 ug/mL
Cytotoxicity = 8.14 ug/mL
NH
O
O
O
O
N
O
O
O
O
O
Norglaucine Oxoglaucine
Antimarial activity = 21.98 ug/mL
Cytotoxicity = > 100 ug/mL
Antimarial activity = 9.07 ug/mL
Cytotoxicity = NT