Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Parasite - an organism that lives in or on another organism (the host) and
benefits by deriving nutrients at host's expense
Kevin M. Oberg
Phylogenetic tree of life
Impact on humanity
Neglected Tropical Diseases
(NTDs) affect more than 1 billion
people. 11/18 NTDs are parasites.
Impact hardest on poor, developing
countries.
decreased health
economic drag Neglected Parasitic Infections in USA
Chagas disease - 300,000 infected
Neurocysticercosis (tapeworm) - 1,000
yearly hospitalizations
Toxocariasis
- 14% population exposure
Global society (shipping and
prokaryote
eukaryote
70
people
blinded
yearly
traveling), immunosuppresion,
Toxoplasmosis
60
million
infected
still endemic
Trichomoniasis - 3.7 million infected
haploid (1 copy of chromosomes) = point mutation means immediate
phenotype expression
Transmission - direct, fecal-oral, vector, predator-prey
diploid (2 copies of chromosomes) = point mutation could be recessive or
Giardia
Malaria
dominant
lack of money
for treatment
trophozoites
cyst
oocysts
ookinetes mosquito
zygotes
www.cdc.gov
www.who.int
sporozoites
schinzonts
liver
merozoites
blood
gametocytes
Challenges in combating inf ectious parasitic disease
*parasites range from simple eukaryotes that posses bateria cellular
mechanisms to multicelled "higher" organisms that share many of the same
cellular processes as hosts
*parasite have evolved to evade host immune system and even evidence of
cooevolution (sickel cell)
*fast generation times, organism ploidy, reservoir, vectors developing
resistance, natural resistance mechanisms, ability to transfer resistance
*lack of funding as most heavily affected regions tend to poorer
human vs. animal resevoir - resistance in humans directly transmitted and
possibility of eradication
inate defenses
gene amplification - more targets for drug and organism survival enhanced
gene mutation - drug target changes and resistance emerges
- drug transport machinery changes
- drug efflux increases
many drugs were emperically discovered and most of the mechanisms of
action remain unknown so resistance pathways are also not understood
Molecular Biology of Parasitic Protozoa, Oxford University Press, 1996.
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Kevin M. Oberg
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Kevin M. Oberg
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Kevin M. Oberg
Jacobsen (Harvard): 2004
OMe
OTBS
1. H2, Ni
2. LDA, H2O
O
TBSO
O
CO2Me
CO2Me
HN
Cbz
N
CBz
1. Et2AlCl, thioanisole
2
2.
OMe
N
OH
N
cat asymm.
cat.
asymm
conj. add.
Cl
O
O
CrCl2,
Me
Me
2004 126,
2004,
J Am.
J.
A Chem.
Ch
S
Soc.
126 706.
706
Cl
B
Bpin
O
Kobayashi (Tokyo Institute of Technology): 2004
Me
Me
HO
N
CBz
Br
OMe
N
CBz
N
1. O3, NaBH4
2. I2, PPh3, im
3. BnNH2
R
N
CBz
Pd(OAc)2, Sphos
K3PO4,
MeO
N
N
H
O
CN
asymmetric
epoxidation
failed so...
R
OA
OAc
OMe
OPiv
TBDPSO
O
O
AD-mix-
N
N
N
Bz
N
Bn
OMe
HO
N
CBz
OH
i. MeC(OMe)3
R
O
R
O
OMe ii. AcBr
Me
OMe
N
N
Bz
OMe
R
R
O
+
O
R
OAc
Me
R
iii. K2CO3,
iii
MeOH
O
Br
N
Tetrahedron 1992, 48, 10515.
N
CBz
1. AD-mix2. MeC(OMe)3,
TMSCl, K2CO3
3. DIBAL
4
4.
N
OMe
N
OH
N
use of AD-mix- allows for quinidine access
Tetrahedron Lett. 2004, 45, 3783.
OEt
P OEt
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Chloroquine (Resochin)
Andersag (Bayer): 1934
Drugs brought to you by war time efforts
Cl
Me
Me2N
S+
NMe2
N
Cl-
HN
NEt2
CF3
HO
N
H
Methylene blue
N
Cl
Kevin M. Oberg
N
Cl
Cl
Cl
OH
CF3
C
CF3
Bu2N
Cl
inhibits hemozoin formation: Biochimica et Biophysica Acta 2014, 1840, 2032. Mefloquine: RushPresbyterian-St.
Luke's Army Malaria
Research Project
EtO2C
with Walter Reed
Army Institute of
CO2Et
Research
O
CO Et
NBu2
Halofantrine: SRI
International contract for
Walter Reed Army
Institute of Research
Benflumetol (lumefantrine):
synthesized by Acadamy of
Military Medical Sciences,
Beijing
2
NH2
Cl
N
Cl
OH
CO2Et
Qinghaosu (Artemisinin)
青蒿素
OH
H
Me
N
Cl
CO2Et
N
Cl
O
Me
O
O
H
Me
O
O
Me
Cl
POCl3
HN
RNH2
Cl
NEt2
N
Cl
5 step racemic synthesis = millions of saved lives
Parasitol Res. 2012, 111, 1.
N
OH
Project 523
lead investigator: Youyou Tu
China Academy of Chinese Medical Sciences
mechanism of action still not completely understood
fast acting: normally paired with benflumetol (slower acting)
W HO technical report series 1990, 805
Gutekunst GM Molecules of Traditional Chinese medicine 2009
Cell 2011, 146, 855.
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Hofheinz (Hoffmann-La Roche): 1983
Wei-Shan (Shanghai Institute of Organic Chemistry): 1983
O
Me
1. ZrBr2
2. BH3
3. BnCl
4. CrO3
O
Me
Me
O
TMS
Me
Me
Me
OB
OBn
(-)-citronellal
O
BnO
Me JACS 1973, 95, 6152.
GM Burns: Stork
1. MOMCl
2. BH3
3. BnBr
HO
8
H
Me
Me
Me
LDA,
O
H
Me
MOMO
Me
(-)-isopulegol
1. MeMgI
2. TsOH
3. Na, NH3
4. CrO3
5 CH2N2
5.
1. Ba(OH)2
2. (CO2H)2
O
H
Me
Me
TMS
JACS 1974, 96, 3682.
GM Burns: Stork
Me
OBn
TMS
Me
Me
Me
Me
H
H
MeO2C
O
1. Li, NH3
2. PCC
HO
MeO
H
Me
Me
Me
LiCH(OMe)TMS
TMS
BnO
Me
also synthesized f rom
arteannuinic acid
OBn
1. HCl,
1
HCl MeOH
2. PCC
3. LDA, I
H
TMS
Me
Kevin M. Oberg
H
Me
OBn
O
Me
O
1. O3
2. (HSCH2)2
M
3. HC(OMe)3, H+ Me
4. HgCl2, CaCO3
Me
1
O2, -78
78 °C
MeOH
MeO
MeO2C
H
Me
MeO
Me
MeO2C
Huaxue Xuebao 1983, 41, 574.
1986 42,
1986,
T t h d
Tetrahedron
42 819.
819
MeO
Me
TMS O
R
"warm" nonOMe p
polar solvent
OOH
H
R
ene
polar solvent
cool ((-78
78 °C)
C)
OMe "cool"
[ 2+2]
O
O
O
H
MeO
Me
HO2C
assumed
Me
O2, 23 °C
DCM
H
Me
O O
O
Qinghaosu
R
J. Am. Chem. Soc. 1980, 102, 3644.
GM McKerrall 2011, singlet O2
Me
1
O
OMe
O2, -78 °C
HOO
H MeOH
MeO
Me
Me
HCOOH
1
MeO
HO2C
H
O
Qinghaosu
Me
Me
1. mCPBA
2. TBAF
H
HClO4
Me
Me
Me
Me
O
O
(MeO)2HC
O
TMS
J. Am. Chem. Soc. 1983, 105, 625.
GM Maimone 2005 Classic Terpene
R
HOO
MeO
HO2C
Me
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Avery (SRI International): 1987, 1992
Me
Me
O
Me
Me
1. HOO2. NaSPh
3. mCPBA
O
1. LDA, Me
2. Al-Hg
O
O
(+)-pulegone
S
Me
O
1. TsNHNH2
2. nBuLi, DMF
O
Me
TMS
Me
O
i. TMS3Al
ii. Ac2O
Roth (George Mason University) and Acton (Walter Reed Army Insititute of
Research): 1989
Me
Me
O
Me
O2, methylene blue
O
O
H
Me
H
O
H
Me
Me
HO2C
O
Artemisinin
dihydroartemisinic acid
J. Nat. Prod. 1989, 52, 1183.
Me
HOO
Me
Me Me
Me
i. LDEA
ii LDA,
ii.
LDA MeI
M I
O
Me
O
O3
TMS
M
Me
H
HO2C
Me
Me
O
Hock cleavage
g
3
O2
O
Me Me
O
Br
Me Me
O
O
Me
O
Ph
Me Me
O
Me
Me Me
Kevin M. Oberg
Me
HOO
O
H
Me
HO2C
for mechanism: Org. Process Res. Dev. 2014, 18, 417.
GM Yuan Peroxide Chemistry (2014)
J. Am. Chem. Soc. Ravindranathan (National Chemical Lab): 1990
Me
1978, 100, 294.
Me
O
Me
1.
Me
HO2C
2. mCPBA
O
3. LiAlH4
Me Me
Me
H
O
Me
Me
Me
O
Me
O
O
O
(+)-3-carene
Me
Me
Me
Me
Me
Me
H2SO4,
O
1. NaOMe
O
1. RuCl3, NaIO4
SiO2
TMSO
2. NaIO4
H
HO
2. NaOMe, MeOH
O
3. CH2N2
O
Me
HO
O O
H
H
O
H
Me
H
O
Artemisinin
O
Me
Me
HO2C
HO2C
Me
Syn. Commun. 1980, 10, 205. O
Tetrahedron Lett. 1987, 28, 4629. "This work was funded by the U.S. Army
J. Am. Chem. Soc. 1992, 114, 974. Contract number DAMD-17-85-C-5011." Tetrahedron Lett. 1990, 31, 755.
H
Me
HO
Me
O
H
H
Me
Me
O
Me
O
H
MeO2C
Me
Wei-Shan int.
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Liu (University of Alberta): 1993
O
1. O3
M O2C
2. NaH, MeO
OMe MeO
3. PhSeCl, py
Me
Me
(-)- -pinene
Constantino (Universidade de Sao Paulo): 1996
O
Me
Me
Me
O
Me
Me
Me
1983 48,
JOC 1983,
48 4135
1. TsOH, (HOCH2)2
2. TsOH, acetone
3. NaOH, MeOH
O
S
S
Me
O
MeO2C
Me
Me
H
OMe
1. Ph3P
2. TsOH, acetone
3. NaOH, MeOH
4. LiAlH4
5. MsCl, NEt3
6. LiAlH4
Me
Me
H
BzO
Me
H
H
1. 9-BBN
2. H2CrO4
3. K2CO3, MeI
4. NaBH4, NiCl2
Me
S
Me
1. 1O2
2. TFA, O2
S
H
H
M
Me
H
HO2C
Me
1. 1O2
2. TFA, O2
H
HO2C
H
HO2C
H
Me
Artemisinin
Me
Me
engineered
S. cerevisiae
Me
Artemisinin
H
HO2C
Me
Qinghaosu
H
artemisinic acid
Nature 2006, 440, 940.
Improvements; Nature 2013, 496, 528.
H
Wei-Shan
Roth/Acton
H
Keasling (Berkeley): 2004
sugar
works on trans acid
Tetrahedron Lett. 1993, 34, 4435.
O
Me
H
Me
1. MeLi
2. TsOH
OBn
Me
Me
Me
H
O
1. HgCl2
2. NaBH4, CeCl3
3. BzOH, PPh3, DEAD
H
OB
OBn
1. H2, Pd/C
2. PDC
O
Me
S
H
Me
1. (HSCH2)2
2. LiI, collidine
Me
Me
O
H
Me
1. LDA,
2. Ba(OH)2
3. (CO2H)2
Me
O
Me
S
Me
1. BH3
2. BnCl
3. PDC
Me
()i
(-)-isopulegol
l
l
O2, TPP, hv
Ac2O, py, DMAP
H
Me
HO
Tetrahedron Lett. 1991, 32, 2005.
MeO2C
O
TMS
ZnCl2, isoprene
Kevin M. Oberg
Seeberger (Max-Planck Institute): 2012
Roth/Acton process done in flow
Angew. Chem. Int. Ed. 2012, 51, 1706.
Institute OneWorld Health
Gates Fnd.
Akibene Fnd.
Fnd
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Kevin M. Oberg
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
African trypanosomiasis (sleeping sickness) - caused by Trypanosoma brucie
2nd stage - central nervous system has been invaded
NH2
East African species - death w/in couple months
humans West African species - death w/in couple years
tsetse fly
Kevin M. Oberg
N
H2N
S
As
N
N
OH
Toxic: 2.5-5% mortality
S
N
H
inhibits glycolysis? binds trypanothione?
mechanism unknown...
melarsoprol
Sanofi Aventis and Bayer produce and donate all anti-HAT
Sanofi-Aventis
anti HAT drugs to the WHO
1st stage
O
H2N CHF2
O
H2N
HN
NH2
pentamidine
NH2
O
N
H
eflornithine
irreversible inhibitor for ornithine decarboxylase (makes polyamines and
needed for cell division)
J. Biological Chem. 1992, 267, 150.
NH
O
NH
NH2
H2N
N
H
HO3S
O
Me
suramin
SO3H
O
H
N
N
H
treatment for hirsutism (rapidly dividing cells)
kills trypanosoma (ornithine decarboxylase
needed)
NH
binds ubiquitin and/or DNA? mechanism unknown...
Chem. Biodivers. 2005, 2, 1387.
O
Me
CO2H
SO3H
coloroless
arginase
H2N
CO2H
NH
ornithine
NH2
H
N
CO2H
arginine
also nifurtimox - see Chagas disease
inhibits glycolysis? mechanism unknown...
SO3H
NH
Me
SO3H
SO3H
HO
Me
N N
N N
H2N
MeO
OH
NH2
SO3H
HO3S
O
H
N
NH
pafuramidine
killed in phase III due to kidney toxicity
trypan blue
HO3S
SO3H
Ehrlich had demonstrated polynaphthalene dyes to have trypanocidal activity
NH
MeO
T oxicol. Sci. 2012, 130, 416.
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Kevin M. Oberg
American trypanosomiasis (Chagas disease) - caused by Trypanosoma cruzi Giardiasis (beaver fever) - caused by Giardia lamblia
most common parasitic infection worldwide
kissing bug
humans
cysts
-1st stage, mild symptoms
-2nd stage, chronic - 10-30 years 1/3 get heart failure, enlarged
p g /
esophagus/colon
Lancet 2010, 375, 1388.
Ph
N
H
4 e-
Me
HO
N
NO2
N
benznidazole
nitroreductase
O2N
usually mild symptoms
R
R
N
humans
N
NH
O
3-7% in the US
some developing countries, up to 30%
NH2
N
H
treatment with nitroimidazoles
NH2
O
N
O
HO
N
OH
metronidazole
www.cdc.gov
Cryptosporidiosis - caused by Cryptosporidium
treatment primarily supportive
humans
cysts
Antimicrob. Agents Chemother. 2012, 56, 115.
OH
NO2
Me
N
O S
O
NO2
O
not oxidative stresses
N
OAc O
N
nitroreductase
nifurtimox
N
H
O
H2N O
N
OH
nitazoxanide
R
O
Biochemical Pharmacology 2010, 79, 1736.
J. Biol. Chem. 2011, 286, 13088.
HO
these drugs cure up to 80% of acute phase patients
cure rate drops to 5-20% for chronic patients
Cl
www.cdc.gov
O
HO
HO
S
O
atovaquone
(ubiquinone analogue)
H2N
HO
NH2
O
OH
H2N
NH2
O
O
OH
O OH
paromycin
typically used as a antibiotic
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Toxoplasmosis (cat poop parasite) - caused by Toxoplasma gondii
Leishmaniasis - caused by Leishmania
b t
between
10 80% infection
10-80%
i f ti in
i different
diff
t regions
i
feline
rodents/livestock
congenital toxoplasmosis - infection of the fetus from an infected mother
(worst case: miscarriage, birth defects, vision impariment)
Cl
Et
OMe
N
N
H2N
N
NH2
OMe
H2N
N
NH2
OMe
pyrimethamine
trimethoprim
O O N O
S
N
H
H2N
cutaneous (common) - open sore on skin
humans visceral - internal organs (usually spleen, liver,
bone)
sandflies
acute: influenza-like, immunocompromization
can lead to encephalitis or eye damage
latent: cysts in nervous and muscle tissue
cutaneous: skin lesions
humans
H2N
sulfamethoxazole
Pentavalent Sb introduced in the 1940's
+
H
N
O O
Me
OH
HO
Sb
HO
OH
O O
H
N
HO
Me
OH
HO
OH
OH
ONa CO2Na
O Sb O Sb O
O
O
O
O
HO
NaO2C
meglumine antimonate
OH
sodium stibogluconate
structure elucidation: Antimicrobial Agents and Chemotherapy 1998, 42,
1076. J. Inorg. Biochem. 2008, 102, 656.
O O N
S
N
N
H
Me
Kevin M. Oberg
paropmycin pentamidine,
paropmycin,
pentamidine neomycin,
neomycin sitamaquine (chloroquine derivative)
OH
sulfadiazine
Me
inhibit folate synthesis
given with folinic acid for patient
HO
O
O
Me
OH OH
OH
OH
OH OH O
CO2H
O
Me
NH
O
N
H2N
N
N
N
H
H
Folic acid
N
H
CO2H
HO2C
SMe
O
HO
HO
clindamycin
antibiotic for cyst killing
HN
OH
Cl
O
Me
O
NMe
nPr
www.cdc.org
Antibiotics: Actions, Origins, Resistance. 2003, ASM Press, Washington, D.C.
amphotericin B
actually an antifungal agent
HO
binds ergosterol in cell membrane leading to pores
less of this sterol in mammalian, but still toxic
for syntheses, see; Classics in Total Synthesis I
Nicolaou: J. Am. Chem. Soc. 1987, 109, 2821.
O
Me
OH
NH2
Baran group meeting
October 4th, 2014
F HO
Antiparasitic drugs; malaria and the forgotten ones
Amoebiasis - caused by Entamoeba histolytica
N
N
fluconazole and other triazoles
inhibits 14 -demethylase
(mamalian enzyme is less sensitive)
N
N
F
cyst
can be
b asymptoptic
t ti
symptoms develop over weeks - diarrhea
can move from intestines to systemic and cause
some real problems
humans
N
N
O O
P
O
O
Me
R
miltefosine
Kevin M. Oberg
O
O
H
Me
N
O
NMe3
O
I
Cl
O
O
lysophosphatidylcholines
OH
Cl
I
N
OH
diloxanide furoate
diiodohydroxyquinoline
Akt inhibitor
lots of antibiotics as well
antileishmaniasm activity overlooked due to potential anticancer properties
oral bioavailability, but long treatment times coupled with possible
teratogenicity may hinder global use
J. Antimicrob. Chemother. 2012, 67, 2576.
Amoebic keratitis - caused by Acanthamoeba
usually affects contact users
Chem. Rev. A.S.A.P. dx.doi.org/10.1021/cr4000552x
H
N
H
N
NH
H
N
N
H
Trichomoniasis (STD) - caused by Trichomonas vaginalis
Cl
females
males
170 million worldwide
(inapperant infections in women up to 50%
and higher in men)
NH
NH
N
H
NH
Cl
N
H
chlorhexidine
Journal of Medical Microbiology 2008, 57, 1399.
N
Me
O2N
N
OH
only approved drug in US
resistant strains have been detected...
metronidazole
Clin. Microbiol. Rev. 2004, 17, 783.
Primary amoebic meningoencephalitits - caused by Naegleria f owleri
free-living
human nervous system
"brain-eating amoeba"
95% fatality rate
treatment with amphotericin, miconazole, miltefosine, the kitchen sink
Baran group meeting
October 4th, 2014
Antiparasitic drugs; malaria and the forgotten ones
Helminths (worms) - platyhelminths (flatworms), acanthocephalins (thornyheaded worms), nematodes (roundworms)
via poor hygenine
eggs/larva
or vectors
Kevin M. Oberg
Onchocerciasis (river blindness or Robles disease) - caused by Onchocerca
volvulus
humans
black fly
humans
Drugs act in two ways: killing or stunning
MeO
HO
O
Me
killers:
O
O
H
N
O
N
OMe
OH
Me
O
O
Me
inhibits microtubule synthesis
GM Zografos
Z
f 2004 Synthesis
S th i off Imidazoles
I id
l
NO2
total syntheses of avetmicins, see;
Hanessian: Pure & Appl. Chem. 1987, 59, 299.
Danishefky: J. Am. Chem. Soc. 1989, 111, 2967.
White: J. Am. Chem. Soc. 1995, 117, 1908.
Ley: J.
J Chem.
Chem Soc.
Soc Perkin.1991,
Perkin 1991 667.
667
O
N
H
Cl
OH
niclosamide (tapeworms)
oxidative phospholytion decoupler
Nature 1969, 221, 1016.
S
O
Me
OH/OMe
in vivo screening: "by no means serendipitous;
those who were seeking found what they sought."
Cl
Me
N
O
N
Cy
O
p
praziquantel
q
membrane disruption and paralysis
thousands of microbial
fermentation products
Nematospiroides dubius
infected mice
isolation of avermectins
from Kitasato Institute (OS3153) - Streptomyces
avermitilis "capable of
separating from worms"
N
pyrantel pamoate
depolarizing neuromuscalar blocking reagent
Int. J. Pharm. Pharm. Sci. 2011, 3, 17.
Me
Me/Et
O
HO
stunners:
O
Me
O
NEt2
diethylcarbamazine
arachidonic acid metabolism inhibitor
mebendazole
MeO
O
O
Me
MeN
NH
N
Avermectins
ACS Symposium Series, 255, 5. doi: 10.1021/bk-1984-0255.ch001
Baran group meeting
October 4th, 2014
Streptomyces
avermitilis
MeO
HO
O
Me
Antiparasitic drugs; malaria and the forgotten ones
fermentation
MeO
O
O
Me
H2, (PPh3)3RhCl
avermectin
Me
Me
O
O
Me
O
Me
Me/Et
O
HO
ivermectin
interacts with ligand gated
channels causing paralysis
O
O
B1a
B1b
Me
OH
donations by Merck to WHO for erradication
Me
O
Emodepside
causes paralysis through
excessive neurotransmitter release
O
O
Me
O
N
Me
NMe
Me
O
MeN
O
O
O
O
MeN
Me
N
O
O
O
O
O
Me
Me
NMe Me
Me
Me
Int. J. Animicro. Agents 2003, 22, 318.
Solid phase synthesis; see, Eur J Org Chem 2012, 1546.
Kevin M. Oberg