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Parasite - an organism that lives in or on another organism (the host) andbenefits by deriving nutrients at host's expense
Impact on humanity
Phylogenetic tree of life
Antiparasitic drugs; malaria and the forgotten onesBaran group meetingOctober 4th, 2014 Kevin M. Oberg
Impact on humanityNeglected Tropical Diseases(NTDs) affect more than 1 billionpeople. 11/18 NTDs are parasites.Impact hardest on poor, developingcountries.
decreased healthdecreased health
economic draglack of moneyfor treatment
Neglected Parasitic Infections in USAChagas disease - 300,000 infectedNeurocysticercosis (tapeworm) - 1,000
yearly hospitalizationsToxocariasis - 14% population exposureGlobal society (shipping and Toxocariasis 14% population exposure
70 people blinded yearlyToxoplasmosis - 60 million infectedTrichomoniasis - 3.7 million infected
Global society (shipping andtraveling), immunosuppresion,still endemic
Transmission - direct, fecal-oral, vector, predator-preyGiardia Malaria
prokaryote eukaryote
haploid (1 copy of chromosomes) = point mutation means immediatephenotype expressiondiploid (2 copies of chromosomes) = point mutation could be recessive ordominant
cyst
trophozoites
zygotes
ookinetes
oocystssporozoites schinzonts
merozoitesmosquito
liver
blood
human vs. animal resevoir - resistance in humans directly transmitted andpossibility of eradication
inate defensesgene amplification - more targets for drug and organism survival enhancedgene mutation - drug target changes and resistance emerges
www.cdc.govwww.who.int
zygotes
gametocytes
Challenges in combating infectious parasitic disease*parasites range from simple eukaryotes that posses bateria cellularmechanisms to multicelled "higher" organisms that share many of the same
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 ofaction remain unknown so resistance pathways are also not understood
Molecular Biology of Parasitic Protozoa, Oxford University Press, 1996.
cellular processes as hosts*parasite have evolved to evade host immune system and even evidence ofcooevolution (sickel cell)*fast generation times, organism ploidy, reservoir, vectors developingresistance, natural resistance mechanisms, ability to transfer resistance*lack of funding as most heavily affected regions tend to poorer
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten onesJacobsen (Harvard): 2004
OMe 1. Et2AlCl, thioanisole2
OMeOTBS
1. H2, Ni2. LDA, H2O
J A Ch S 2004 126 706cat asymm
NH
O
CO2MeTBSO
CO2Me
N
N
CBzO
2.N
OHN
OTBS
HN
O
Cbz CN
CrCl2,O
BO
Cl Cl
MeMeMe
Me
J. Am. Chem. Soc. 2004, 126, 706.
Kobayashi (Tokyo Institute of Technology): 2004
HO OAR 1. O3, NaBH4
2. I2, PPh3, im
cat. asymm.conj. add.
O
R
Bpin
Pd(OAc)2, SphosK3PO4,
MeOBr
N
OMe
HO OAc 2, 3,3. BnNH2
TBDPSOOPiv O
OMe
PO
OEtOEt
NCBz
R
asymmetricepoxidationfailed so...
NCBz
N
N
N
CBz AD-mix-
OMe
NBn
TBDPSO
NBz
O
N
P OEt
N
N
CBzHO
OHNBz
OMe
i. MeC(OMe)3
O
O
R
R
MeOMe ii. AcBr
iii K COOMe
N
OMe1. AD-mix-2. MeC(OMe)3,
TMSCl, K2CO33. DIBAL4
Tetrahedron Lett. 2004, 45, 3783.
N
Tetrahedron 1992, 48, 10515.
O
O
R
RMe+
OAc
R
R
Br
iii. K2CO3,MeOH N
N
CBzOOH
N
4.
use of AD-mix- allows for quinidine access
Chloroquine (Resochin)Andersag (Bayer): 1934
Drugs brought to you by war time effortsCl
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones
N
S+ NMe2Me2N
NCl
HN
Me
NEt2
Methylene blueN
HONH
CF3
Cl- Cl
Bu N
ClCl
CF3
OH
Benflumetol (lumefantrine):synthesized by Acadamy ofMilitary Medical Sciences,Beijing
NCl
inhibits hemozoin formation: Biochimica et Biophysica Acta 2014, 1840, 2032. Mefloquine: Rush-Presbyterian-St.Luke's Army MalariaResearch Projectwith Walter Reed
CF3
C 3OH
Bu2N
EtO2C
Cl
NBu2
Halofantrine: SRIInternational contract forWalter Reed Army
Me
with Walter ReedArmy Institute ofResearch
Qinghaosu (Artemisinin)Cl NH2
CO2EtO
EtO2C
Cl N CO2Et
CO2Et
Walter Reed ArmyInstitute of Research
青蒿素
OO
OO
Me
HMe
HMe
O
Cl N CO2Et
OH
Cl N
OH
O
Project 523lead investigator: Youyou Tu
China Academy of Chinese Medical Sciences
POCl3
Cl N
Cl
NCl
HN
Me
NEt2RNH2
Parasitol Res. 2012, 111, 1.
WHO technical report ser ies 1990, 805Gutekunst GM Molecules of Traditional Chinese medicine 2009Cell 2011, 146, 855.
mechanism of action still not completely understoodfast acting: normally paired with benflumetol (slower acting)
NCl
5 step racemic synthesis = millions of saved lives
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones
Wei-Shan (Shanghai Institute of Organic Chemistry): 1983
Me MeO
Hofheinz (Hoffmann-La Roche): 1983
Me Me 1 HCl MeOHMe
O
MeMe
1. ZrBr22. BH33. BnCl4. CrO3
Me
O
MeOB
HLDA,
TMSO
MeMe
O
Me
H
Me
JACS 1973, 95, 6152.GM Burns: Stork
8
Me
HO
1. MOMCl2. BH33. BnBr
Me
MOMO
Me
H
OBn
1. HCl, MeOH2. PCC3. LDA, I TMS
Me
JACS 1974, 96, 3682.GM Burns: StorkBnO (-)-isopulegol
OBn MeGM Burns: Stork
1. Ba(OH)22. (CO2H)2
Me
HO
1. MeMgI2. TsOH3. Na, NH34. CrO35 CH2N2
Me
HMeH
OBn
O
Me MeMe
LiCH(OMe)TMS HOMeO
Me
TMS TMS
1. Li, NH32. PCC
(-)-citronellal
MeOBn
H 5. CH2N2MeO2C Me
also synthesized f romarteannuinic acid
1. O32. (HSCH2)2
+
Me
M
O MeMe
Me
O H
OBnMeBnO
HTMS
TMS MeMe
OO
1O 78 °C3. HC(OMe)3, H+
4. HgCl2, CaCO3
MeO2C Me
HMeO
Me
MeO2C Me
H(MeO)2HCO
O
MeMeO
Huaxue Xuebao 1983, 41, 574.T t h d 1986 42 819
Me
H
Me
OTMS
MeO1. mCPBA2. TBAF H
MeOMeHO2C
1O2, -78 °CMeOH
Me
H
Me
MeOMeHO2C
MeOHOO
1O2, -78 °CMeOH
HClOTetrahedron 1986, 42, 819. O assumed
HCOOH
OO
OO
Me
Me
HMe
Qinghaosu
OMeH
R"warm" non-polar solvent
polar solvent"cool" (-78 °C)OMeR OO
HClO4
MeR
HOO
1O2, 23 °CDCM
O
J. Am. Chem. Soc. 1983, 105, 625.GM Maimone 2005 Classic Terpene
Qinghaosu
OMeR
J. Am. Chem. Soc. 1980, 102, 3644.GM McKerrall 2011, singlet O2
p cool ( 78 C)
OOH ene [2+2]OO
OMeR
MeHO2CMeO
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten onesAvery (SRI International): 1987, 1992
MeMe
MeMeRoth (George Mason University) and Acton (Walter Reed Army Insititute ofResearch): 1989
Me
Me Me
O1. HOO-
2. NaSPh3. mCPBA
SO
Me
PhO
1. LDA,2. Al-Hg
MeOO
Br
Me
HO2C Me
HMeH
O2, methylene blue
OO
OO
Me
Me
HMe
O(+)-pulegone
O
Me
MeOO
MeMe
1. TsNHNH22. nBuLi, DMF
Me
MeOO
MeMe
O
i. TMS3Alii. Ac2O
2
dihydroartemisinic acidOArtemisinin
J. Nat. Prod. 1989, 52, 1183.
MeHock cleavage
Me
M
O
O
Me
MeOO
MeMe
i. LDEAii LDA M I
Me
MeOO
MeMe
O
HO2C Me
HHOO
Me
g3O2
HO2C Me
H
for mechanism: Org. Process Res. Dev. 2014, 18, 417.GM Yuan Peroxide Chemistry (2014)
HOOMe
O
MeTMS
O
O
Me
ii. LDA, MeI Me
H
HO2C Me
TMSO3
MeMe
Me
Ravindranathan (National Chemical Lab): 1990
H
Me
Me H
Me
H
1.2. mCPBA3. LiAlH4 HO
Me
GM Yuan Peroxide Chemistry (2014)
J. Am. Chem. Soc.1978, 100, 294.
Me
TMSOH2SO4,SiO2
MeOO
MeMe
O
OHO
OO
OO
Me
Me
HMe
MeMe
H
MeO
H
MeO
HMe
1. RuCl3, NaIO42. NaOMe, MeOH
Me
HO
1. NaOMe2. NaIO43. CH2N2
Me
Me
O
O
(+)-3-carene
H
HO2C Me
O O H
HO2C Me
OO
MeO
Tetrahedron Lett. 1987, 28, 4629.J. Am. Chem. Soc. 1992, 114, 974.
"This work was funded by the U.S. ArmyContract number DAMD-17-85-C-5011."
H
MeO
HHO
Me
O Wei-Shan int.
Artemisinin
3. CH2N2
Syn. Commun. 1980, 10, 205.
Me
H
MeO2C
Tetrahedron Lett. 1990, 31, 755.
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten onesLiu (University of Alberta): 1993
1. O3O O
M O C
Constantino (Universidade de Sao Paulo): 1996
Me MeTMS
O
Me
MeMe
2. NaH,3. PhSeCl, py
MeO OMe
Tetrahedron Lett. 1991, 32, 2005.
MeMe
MeO2C
(-)- -pinene
ZnCl2, isopreneMe
HO H
Me( ) i l l
1. BH32. BnCl3. PDC
Me
O H
MeOB
1. LDA,2. Ba(OH)23. (CO2H)2
Me
O
MeMe
Me
MeO2C
H
O2, TPP, hvAc2O, py, DMAP
O
MeMe
Me
MeO2C
H
O1. (HSCH2)22. LiI, collidine
(-)-isopulegol OBnMe
HO
1. H2, Pd/C2. PDC
Me
HOH
1. MeLi2. TsOH
JOC 1983 48 4135 H
O
MeMe
MeH
S
S
1. TsOH, (HOCH2)22. TsOH, acetone3. NaOH, MeOH
O
MeH
S
S
H
MeOBn
HO2C Me
Me
M
1. 1O22. TFA, O2
ArtemisininWei-ShanRoth/Acton
JOC 1983, 48, 4135
Me1.2. TsOH, acetone3. NaOH, MeOH4. LiAlH45. MsCl, NEt36. LiAlH4
Ph3P OMeMe
MeH
S
S
H
1. HgCl22. NaBH4, CeCl33. BzOH, PPh3, DEAD
HO2C Me
HMeH
Keasling (Berkeley): 2004
engineered
Me
Me
HMeH
Me
Me
MeH H
BzO1. 9-BBN2. H2CrO43. K2CO3, MeI4. NaBH4, NiCl2
1. 1O22. TFA, O2
sugar S. cerevisiae
HO2C
HMeH
Nature 2006, 440, 940.
Artemisinin
Institute OneWorld HealthGates Fnd.Akibene Fnd
artemisinic acid
Tetrahedron Lett. 1993, 34, 4435.
HO2C Me
HHH H
MeQinghaosu
works on trans acid
Improvements; Nature 2013, 496, 528.
Seeberger (Max-Planck Institute): 2012
Angew. Chem. Int. Ed. 2012, 51, 1706.
Akibene Fnd.
Roth/Acton process done in flow
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten onesAfrican trypanosomiasis (sleeping sickness) - caused by Trypanosoma brucie 2nd stage - central nervous system has been invaded
NH2 S OH
tsetse fly humans
Sanofi Aventis and Bayer produce and donate all anti HAT drugs to the WHO
N
N
N
NH
H2N
NH2As S
S OH
melarsoprol
East African species - death w/in couple monthsWest African species - death w/in couple years
Toxic: 2.5-5% mortality
inhibits glycolysis? binds trypanothione?mechanism unknown...
Sanofi-Aventis and Bayer produce and donate all anti-HAT drugs to the WHO
1st stageO O
HN NH2
pentamidine
H2NCO2H
CHF2H2N
eflornithine
treatment for hirsutism (rapidly dividing cells)kills trypanosoma (ornithine decarboxylaseneeded)
NH2 NHpentamidine
binds ubiquitin and/or DNA? mechanism unknown...Chem. Biodivers. 2005, 2, 1387.
O HNO
OSO3H
irreversible inhibitor for ornithine decarboxylase (makes polyamines andneeded for cell division)J. Biological Chem. 1992, 267, 150.
H NH2arginaseNH2
suramin coloroless
inhibits glycolysis? mechanism unknown...
NH
NH
N
O
O
NH
NHO
Me
SO3H
NH
Me HO3S SO3H
NCO2H
H2N
NHarginine
arginaseH2NCO2H
ornithine
also nifurtimox - see Chagas diseaseinhibits glycolysis? mechanism unknown...
NN
MeMe
NHOH2N
N OHNH2
NHO SO3H
SO3HSO3H O
NH
NHHN
NHMeO MeO
pafuramidineSO3H
2
HO3S
2HO3S
SO3Htrypan blue
Ehrlich had demonstrated polynaphthalene dyes to have trypanocidal activity
pafuramidinekilled in phase III due to kidney toxicity
Toxicol. Sci. 2012, 130, 416.
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten onesAmerican trypanosomiasis (Chagas disease) - caused by Trypanosoma cruzi Giardiasis (beaver fever) - caused by Giardia lamblia
most common parasitic infection worldwide
kissing bug humans
-1st stage, mild symptoms-2nd stage, chronic - 10-30 years 1/3 get heart failure, enlargedesophagus/colon
most common parasitic infection worldwide
cysts humans3-7% in the USsome developing countries, up to 30%
N
NMe
NH
O
N NO2
p g /Lancet 2010, 375, 1388.
NHO
R
NH2O
NH
NH2
NHR4 e-
Ph
usually mild symptoms NO2N OH
metronidazoletreatment with nitroimidazoles
www.cdc.gov
N
NO2
benznidazole
NHO
Antimicrob. Agents Chemother. 2012, 56, 115.
OO
nitroreductase Cryptosporidiosis - caused by Cryptosporidium
cysts humans
treatment primarily supportive
SN
NMe
O
ONO2
nitroreductase ON
not oxidative stresses H2N
NH2O
O
O
H2NHO
HO
OH
OHOHONH2OH
OAc O
NH
N
SNO2
O nifurtimox
these drugs cure up to 80% of acute phase patientsJ. Biol. Chem. 2011, 286, 13088.Biochemical Pharmacology 2010, 79, 1736.
R OHO
2
OHH2NO
paromycintypically used as a antibiotic
nitazoxanide
OHO
cure rate drops to 5-20% for chronic patientsO
Cl atovaquone(ubiquinone analogue)
www.cdc.gov
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones
Toxoplasmosis (cat poop parasite) - caused by Toxoplasma gondii
b t 10 80% i f ti i diff t i
Leishmaniasis - caused by Leishmania
feline rodents/livestock
humans
between 10-80% infection in different regions
acute: influenza-like, immunocompromizationcan lead to encephalitis or eye damagelatent: cysts in nervous and muscle tissuecutaneous: skin lesions
sandflies humans
Pentavalent Sb introduced in the 1940's+ OH
cutaneous (common) - open sore on skinvisceral - internal organs (usually spleen, liver,bone)
congenital toxoplasmosis - infection of the fetus from an infected mother(worst case: miscarriage, birth defects, vision impariment)
NOMe
O
O
O
O
OH
OH
HOHN
Me
HNMe
OH
HO
HO
Sb
+
O SbOO
ONa
O
SbOO
OH
O
NaO2C
HO
OHCO2Na
OHHON
EtCl
NOMe
OMeNH2H2N
trimethoprim
SOO ON
Me paropmycin pentamidine neomycin sitamaquine (chloroquine derivative)
meglumine antimonate
structure elucidation: Antimicrobial Agents and Chemotherapy 1998, 42,1076. J. Inorg. Biochem. 2008, 102, 656.
NaO2C OH
sodium stibogluconate
SOO N
N NH2H2N
pyrimethamine
H2N
SNH
sulfamethoxazole
inhibit folate synthesisgiven with folinic acid for patient
paropmycin, pentamidine, neomycin, sitamaquine (chloroquine derivative)
O
HOMe
Me
O OH OH
OH
OH OH O
OHOH
CO2H
H2N
SNH
N
sulfadiazine
O
SMe
HOHO
OHHN O
Me
ClMe
Me
O
CO2H
O Me
OHNH
HOamphotericin Bactually an antifungal agentbinds ergosterol in cell membrane leading to pores
N
N N
NO
H2N
NH
NH
O
CO2H
HO2C OH
NMe
nPr
clindamycinantibiotic for cyst killing
www.cdc.orgAntibiotics: Actions, Origins, Resistance. 2003, ASM Press, Washington, D.C.
NH2binds ergosterol in cell membrane leading to poresless of this sterol in mammalian, but still toxicfor syntheses, see; Classics in Total Synthesis INicolaou: J. Am. Chem. Soc. 1987, 109, 2821.
NH
NH
H2N HO2C
Folic acid
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones
Amoebiasis - caused by Entamoeba histolyticaHO NF
N
Nfluconazole and other triazoles
b t ti
OO INMe Cl
NF
N
NN
inhibits 14 -demethylase(mamalian enzyme is less sensitive)
cyst humanscan be asymptopticsymptoms develop over weeks - diarrheacan move from intestines to systemic and causesome real problems
OP
ONMe3
miltefosine NOH
I
diiodohydroxyquinoline
O
O
O
N
OCl
diloxanide furoate
Me
OH
HR O
Olysophosphatidylcholines
Akt inhibitor
antileishmaniasm activity overlooked due to potential anticancer propertiesoral bioavailability, but long treatment times coupled with possibleteratogenicity may hinder global useJ. Antimicrob. Chemother. 2012, 67, 2576.
lots of antibiotics as well
Amoebic keratitis - caused by Acanthamoeba
usually affects contact users
Trichomoniasis (STD) - caused by Trichomonas vaginalis
170 million worldwide
Chem. Rev. A.S.A.P. dx.doi.org/10.1021/cr4000552x
HN
HN
HN
NH
NH
ClNH NH
NH NH
NH
Cl
chlorhexidine
females males (inapperant infections in women up to 50%and higher in men)
N
N
O NMe
OHonly approved drug in US Primary amoebic meningoencephalitits - caused by Naegleria fowler i
Journal of Medical Microbiology 2008, 57, 1399.
Clin. Microbiol. Rev. 2004, 17, 783.
O2N OH
metronidazole
resistant strains have been detected... Primary amoebic meningoencephalitits - caused by Naegleria fowler i
free-living human nervous system "brain-eating amoeba"95% fatality rate
treatment with amphotericin, miconazole, miltefosine, the kitchen sink
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten onesHelminths (worms) - platyhelminths (flatworms), acanthocephalins (thorny-headed worms), nematodes (roundworms)
Onchocerciasis (river blindness or Robles disease) - caused by Onchocercavolvulus
eggs/larva humansvia poor hygenineor vectors
Drugs act in two ways: killing or stunning
black fly humans
MeO Avermectins
HN
OOMe
O
MeNN NEt2
O
OO
MeMeO
Me
OMeO
OMe
OMeHO
MeO
OH
Avermectins
killers:
NNH
mebendazole
inhibits microtubule synthesis
MeN
diethylcarbamazinearachidonic acid metabolism inhibitor
MeO
Me/EtO
MeO
HO
GM Z f 2004 S th i f I id l
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 Chem Soc Perkin 1991 667
NH
OCl
Cl
NO2
O
OH/OMeMeGM Zografos 2004 Synthesis of Imidazoles Ley: J. Chem. Soc. Perkin.1991, 667.
stunners:
in vivo screening: "by no means serendipitous;those who were seeking found what they sought."
OHCl
niclosamide (tapeworms)oxidative phospholytion decouplerNature 1969, 221, 1016.
MeNS
N
O
Cy
O
praziquantel
thousands of microbialfermentation products
Nematospiroides dubiusinfected mice
isolation of avermectinsfrom Kitasato Institute (OS-3153) - Streptomycesavermitilis "capable ofseparating from worms"
N
NS
pyrantel pamoatedepolarizing neuromuscalar blocking reagent
p qmembrane disruption and paralysis
ACS Symposium Series, 255, 5. doi: 10.1021/bk-1984-0255.ch001Int. J. Pharm. Pharm. Sci. 2011, 3, 17.
Kevin M. ObergBaran group meetingOctober 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones
Streptomycesavermitilis fermentation avermectin H2, (PPh3)3RhCl
MeMeOMeO
OMe
OMeHO
MeO
OO
O
MeO
Me/EtO
Me
HOivermectininteracts with ligand gated
B1aB1b
OHMeO
channels causing paralysis
donations by Merck to WHO for erradication
MeN
Me Me
O NO
NMeMe
OO
Me
OEmodepsidecauses paralysis throughexcessive neurotransmitter release
O
ONMe
Me
MeO
MeO
OMeN
OO O
NMe
Me
Me
NO
Solid phase synthesis; see, Eur J Org Chem 2012, 1546.
Me
Me
Int. J. Animicro. Agents 2003, 22, 318.
