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Home , Antiparasitic, Diiodohydroxyquinoline, Halofantrine

Baran group meeting October 4th, 2014 ; and the forgotten ones Kevin M. Oberg

Parasite - an organism that lives in or on another organism (the host) and Phylogenetic tree of life benefits by deriving nutrients at host's expense 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 in USA lack of money - 300,000 infected for treatment Neurocysticercosis (tapeworm) - 1,000 yearly hospitalizations Global society (shipping and Toxocariasis - 14% population exposure prokaryote eukaryote traveling), immunosuppresion, 70 people blinded yearly still endemic - 60 million infected Trichomoniasis - 3.7 million infected haploid (1 copy of chromosomes) = point mutation means immediate Transmission - direct, fecal-oral, vector, predator-prey phenotype expression diploid (2 copies of chromosomes) = point mutation could be recessive or Giardia Malaria dominant

schinzonts trophozoites sporozoites human vs. animal resevoir - resistance in humans directly transmitted and oocysts liver possibility of eradication

cyst ookinetes mosquito merozoites inate defenses gene amplification - more targets for and organism survival enhanced zygotes gene mutation - drug target changes and resistance emerges - drug transport machinery changes www.cdc.gov - drug efflux increases www.who.int gametocytes Challenges in combating inf ectious many drugs were emperically discovered and most of the mechanisms of *parasites range from simple eukaryotes that posses bateria cellular action remain unknown so resistance pathways are also not understood mechanisms to multicelled "higher" organisms that share many of the same cellular processes as hosts *parasite have evolved to evade host 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 Molecular Biology of Parasitic , 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 1. Et2AlCl, thioanisole OMe OTBS 2. N N 1. H2,Ni TBSO O O CBz 2. LDA, H2O CO Me CO Me 2 OH HN 2 N N Cbz CN O N H cat. asymm. Cl Cl J. Am. Chem. Soc. 2004, 126, 706. conj. add. B Bpin O O O Kobayashi (Tokyo Institute of Technology): 2004 CrCl , 2 Me Me Me Me R 1. O3,NaBH4 R 2. I2, PPh3, im N N HO OAc CBz CBz 3. BnNH2

Pd(OAc) , Sphos 2 Br asymmetric K3PO4, OMe OMe MeO epoxidation OEt failed so... OPiv O N TBDPSO O P OEt N CBz AD-mix-

N N N N Bn Bz OMe HO N R O i. MeC(OMe)3 OMe ii. AcBr CBz Me 1. AD-mix- OH R O OMe 2. MeC(OMe)3, OMe N N TMSCl, K CO 2 3 N Bz OMe 3. DIBAL iii. K CO , 4. R R 2 3 N OH O OAc MeOH N + Me O CBz N O Br R R use of AD-mix- allows for access N Tetrahedron 1992, 48, 10515. Tetrahedron Lett. 2004, 45, 3783. Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

Chloroquine (Resochin) Drugs brought to you by war time efforts Andersag (Bayer): 1934 Cl

Me + CF3 Me2N S NMe2 HO N HN - Cl Cl N Cl H NEt2 Cl Methylene blue OH Cl N N CF3 Bu N 2 OH CF3 Cl Benflumetol (): inhibits hemozoin formation: Biochimica et Biophysica Acta 2014, 1840, 2032. : Rush- NBu2 synthesized by Acadamy of Presbyterian-St. Military Medical Sciences, Luke's Army Malaria : SRI Beijing Research Project International contract for EtO2C with Walter Reed Walter Reed Army Army Institute of Institute of Research CO2Et Research O CO2Et Qinghaosu () Cl NH Cl N CO Et 2 2 青蒿素

Me OH OH H O Me O O Cl N CO2Et Cl N H O Me O Me Cl POCl HN Project 523 3 RNH2 lead investigator: Youyou Tu NEt2 China Academy of Chinese Medical Sciences Cl N Cl N mechanism of action still not completely understood fast acting: normally paired with benflumetol (slower acting) 5 step racemic synthesis = millions of saved lives WHO technical report series 1990, 805 Gutekunst GM Molecules of Traditional Chinese medicine 2009 Parasitol Res. 2012, 111,1. Cell 2011, 146,855. Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

Wei-Shan (Shanghai Institute of Organic Chemistry): 1983 Hofheinz (Hoffmann-La Roche): 1983 O Me Me Me Me 1. HCl, MeOH O Me 1. ZrBr2 Me Me 1. MOMCl 2. PCC 2. BH3 TMS 2. BH Me 3 3. LDA, I TMS 3. BnCl HO 3. BnBr LDA, 8 MOMO O 4. CrO3 O H H O H Me JACS 1974, 96, 3682. JACS 1973, 95, 6152. Me Me Me Me BnO GM Burns: Stork GM Burns: Stork (-)-isopulegol OBn Me OBn (-)-citronellal TMS TMS Me Me 1. MeMgI Me Me Me Me 1. Ba(OH) 2. TsOH 2 1. Li, NH 2. (CO H) 3. Na, NH3 3 2 2 4. CrO LiCH(OMe)TMS HO 2. PCC 3 Me H O H 5. CH N H MeO 2 2 O H H Me MeO2C Me TMS Me BnO Me OBn also synthesized f rom arteannuinic acid OBn O O Me 1. O3 Me O 2. (HSCH ) TMS Me Me 2 2 1 3. HC(OMe) ,H+ Me O2,-78 °C Me Me Me 3 Me Me 4. HgCl ,CaCO MeOH MeO O 2 3 1. mCPBA 1 H O O2,-78°C (MeO) HC H MeO HOO MeO 2 2. TBAF H MeOH Me MeO MeO2C Me MeO MeO2C TMS O H H HO2C Me MeO Huaxue Xuebao 1983, 41,574. HO2C Me 1986 HClO4 Tetrahedron , 42, 819. O Me assumed

Qinghaosu O 1 Me O2,23°C Me O HCOOH O DCM R H "warm" non- H polar solvent O Me HOO R OMe polar solvent R OMe "cool" (-78 °C) O O [2+2] O MeO ene Qinghaosu Me OOH OMe HO2C R J. Am. Chem. Soc. 1980, 102, 3644. J. Am. Chem. Soc. 1983, 105,625. GM McKerrall 2011, singlet O2 GM Maimone 2005 Classic Terpene Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

Avery (SRI International): 1987, 1992 Roth (George Mason University) and Acton (Walter Reed Army Insititute of Me Me Me Research): 1989 Me Me Me 1. HOO- O O O O O , methylene blue Me 2. NaSPh 1. LDA, Me Br 2 O 3. mCPBA O 2. Al-Hg O Me Me Me H S H H O O Ph Me (+)-pulegone HO C Me 2 O Artemisinin Me Me Me Me dihydroartemisinic acid i. TMS3Al J. Nat. Prod. 1989, 52, 1183. Me 1. TsNHNH2 Me ii. Ac2O O O 2. nBuLi, DMF O O Me Me Me O Me O Hock cleavage O 3 Me O2 HOO HOO Me Me Me Me Me H O H HO C Me HO C Me Me Me 2 2 O O O O i. LDEA for mechanism: Org. Process Res. Dev. 2014, 18,417. Me Me ii. LDA, MeI O3 GM Yuan Peroxide Chemistry (2014) TMS TMS H J. Am. Chem. Soc. Ravindranathan (National Chemical Lab): 1990 Me Me O Me 1978, 100,294. Me HO2C Me 1. O 2. mCPBA 3. LiAlH HO Me Me 4 Me H Me H H O Me O O Me Me Me O O Me O (+)-3-carene O Me Me Me Me Me Me Me H SO , O 2 4 O 1. NaOMe TMSO SiO 1. RuCl3,NaIO4 Me 2 HO H 2. NaIO4 O 2. NaOMe, MeOH O O Me HO 3. CH2N2 O H H H O O O Me H H Artemisinin O MeO2C Me HO2C Me HO2C Me Me Syn. Commun. 1980, 10,205. O Wei-Shan int. 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. Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

Liu (University of Alberta): 1993 Constantino (Universidade de Sao Paulo): 1996 O O 1. O O TMS 3 Me 2. NaH, MeO OMe MeO2C Me Me ZnCl2, isoprene 1. BH3 1. LDA, 3. PhSeCl, py 2. BnCl Me Me 2. Ba(OH)2 3. PDC Me Me 3. (CO2H)2 (-)- -pinene HO H O H Tetrahedron Lett. 1991, 32, 2005. Me Me (-)-isopulegol OBn Me Me O O MeO2C O2, TPP, hv 1. (HSCH ) MeO2C 2 2 1. MeLi Ac2O, py, DMAP O 2. LiI, collidine 1. H2,Pd/C 2. PDC 2. TsOH Me Me Me O O Me Me H H H H JOC 1983, 48, 4135 H Me Me HO2C Me O 1. TsOH, (HOCH2)2 O OBn S 2. TsOH, acetone S 3. NaOH, MeOH Me 1 S S 1. O2 Me Wei-Shan Me Me 2. TFA, O2 H Me H H Artemisinin Roth/Acton Me Me H 1. Ph3P OMe H 2. TsOH, acetone Me S HO2C Me 3. NaOH, MeOH 1. HgCl2 2. NaBH ,CeCl 4. LiAlH4 S 4 3 Keasling (Berkeley): 2004 Me 5. MsCl, NEt 3. BzOH, PPh3, DEAD 3 Me 6. LiAlH4 H H engineered S. cerevisiae Artemisinin Me sugar Me H H Me Me 1. 9-BBN HO2C BzO 2. H CrO 1 2 4 1. O2 artemisinic acid 3. K2CO3,MeI Institute OneWorld Health 2. TFA, O2 4. NaBH4,NiCl2 Gates Fnd. Me H Me H Nature 2006, 440,940. Akibene Fnd. H H Improvements; Nature 2013, 496,528. Me HO2C Me Qinghaosu works on trans acid Seeberger (Max-Planck Institute): 2012 Roth/Acton process done in flow Tetrahedron Lett. 1993, 34, 4435. Angew. Chem. Int. Ed. 2012, 51, 1706. 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

African trypanosomiasis (sleeping sickness) - caused by Trypanosoma brucie 2nd stage - central has been invaded

NH2 S OH East African species - death w/in couple months As Toxic: 2.5-5% mortality tsetse fly humans West African species - death w/in couple years N N S

H2N N N H inhibits glycolysis? binds trypanothione? mechanism unknown... Sanofi-Aventis and Bayer produce and donate all anti-HAT drugs to the WHO

1st stage H2N CHF2 treatment for hirsutism (rapidly dividing cells) O O H2N CO2H kills trypanosoma ( decarboxylase HN NH2 needed) NH2 NH binds ubiquitin and/or DNA? mechanism unknown... irreversible inhibitor for ornithine decarboxylase (makes polyamines and needed for cell division) Chem. Biodivers. 2005, 2, 1387. J. Biological Chem. 1992, 267,150.

SO3H O O NH NH H 2 arginase H 2 O N H N H N N Me N N N 2 CO H 2 CO H H H H 2 2 NH O NH Me HO3S SO3H ornithine arginine coloroless also - see Chagas disease

O NH SO3H inhibits glycolysis? mechanism unknown...

NH Me Me O SO3H H NH N SO3H HO N N N N OH MeO MeO H2N NH2 NH pafuramidine SO3H HO3S killed in phase III due to kidney toxicity

trypan blue HO3S SO3H Toxicol. Sci. 2012, 130,416. Ehrlich had demonstrated polynaphthalene dyes to have trypanocidal activity Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

American trypanosomiasis (Chagas disease) - caused by Trypanosoma cruzi (beaver fever) - caused by Giardia lamblia

most common parasitic worldwide

kissing bug humans 3-7% in the US cysts humans some developing countries, up to 30% -1st stage, mild symptoms N -2nd stage, chronic - 10-30 years 1/3 get heart failure, enlarged Me esophagus/colon N Lancet 2010, 375, 1388. usually mild symptoms O2N OH

NH treatment with O 4e- R R N NH2 Ph N N H www.cdc.gov H HO NH2 N NO 2 O - caused by Cryptosporidium nitroreductase N O N HO treatment primarily supportive cysts humans Antimicrob. Agents Chemother. 2012, 56,115.

OH NO NO 2 2 HO O Me O not oxidative stresses HO OAc O S H2N N H2N O N NH N nitroreductase N N HO O 2 O H O OH O S OH NH2 nifurtimox O R O O OH H2N O OH Biochemical 2010, 79, 1736. paromycin J. Biol. Chem. 2011, 286, 13088. HO typically used as a these drugs cure up to 80% of acute phase patients cure rate drops to 5-20% for chronic patients O Cl (ubiquinone analogue)

www.cdc.gov Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

Toxoplasmosis (cat poop parasite) - caused by Toxoplasma gondii - caused by Leishmania

between 10-80% infection in different regions cutaneous (common) - open sore on skin feline rodents/livestock sandflies humans visceral - internal organs (usually spleen, liver, acute: influenza-like, immunocompromization ) can lead to encephalitis or eye damage humans latent: cysts in nervous and muscle tissue Pentavalent Sb introduced in the 1940's cutaneous: skin lesions + OH H congenital toxoplasmosis - infection of the fetus from an infected mother N OH ONa CO Na Me O O OH 2 (worst case: miscarriage, birth defects, vision impariment) Sb HO O Sb O Sb O Cl HO OH O O Et O O OMe H O O N HO N N OH HO Me HO NaO2C OH H2N N NH2 OMe H N N NH OMe 2 2 meglumine antimonate trimethoprim structure elucidation: Agents and 1998,42, 1076. J. Inorg. Biochem. 2008, 102,656. O O N O O O N Me S S paropmycin, pentamidine, , sitamaquine ( derivative) N N N H H H2N H2N sulfamethoxazole OH OH Me O OH inhibit folate synthesis given with folinic acid for patient HO O OH OH OH OH O Me CO2H O Me O NH SMe Cl O O Me N N N CO2H O Me H HO actually an agent HO OH HN O H N N N HO C HO binds ergosterol in cell membrane leading to pores 2 2 OH NH2 H H less of this sterol in mammalian, but still toxic Folic acid NMe for syntheses, see; Classics in Total Synthesis I antibiotic for cyst killing Nicolaou: J. Am. Chem. Soc. 1987, 109, 2821. www.cdc.org nPr : Actions, Origins, Resistance. 2003, ASM Press, Washington, D.C. Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

N - caused by histolytica F HO N fluconazole and other triazoles N can beasymptoptic inhibits 14 -demethylase cyst humans symptoms develop over weeks - diarrhea N (mamalian enzyme is less sensitive) F N can move from intestines to systemic and cause some real problems N Me Cl I O O N P NMe O Cl Me O O 3 O O R O H I N lysophosphatidylcholines O O OH furoate OH 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 Amoebic keratitis - caused by Acanthamoeba J. Antimicrob. Chemother. 2012, 67, 2576. usually affects contact users Chem. Rev. A.S.A.P. dx.doi.org/10.1021/cr4000552x Cl NH NH H H H N N N Trichomoniasis (STD) - caused by vaginalis N N N H H H NH NH Cl 170 million worldwide females males (inapperant infections in women up to 50% and higher in men) Journal of 2008, 57, 1399.

N Me only approved drug in US N Primary amoebic meningoencephalitits - caused by O2N OH resistant strains have been detected...

free-living human nervous system "brain-eating " metronidazole 95% fatality rate

Clin. Microbiol. Rev. 2004, 17,783. treatment with amphotericin, , miltefosine, the kitchen sink Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

Helminths (worms) - platyhelminths (flatworms), acanthocephalins (thorny- (river blindness or Robles disease) - caused by Onchocerca headed worms), (roundworms) volvulus via poor hygenine eggs/larva humans or vectors black fly humans

Drugs act in two ways: killing or stunning MeO HO Me O killers: MeO O OH O Me O Me Me O O O O H N NEt2 OMe Me N MeN O NH Me Me/Et N O O arachidonic acid inhibitor total syntheses of avetmicins, see; Hanessian: Pure & Appl. Chem. 1987, 59,299. HO inhibits microtubule synthesis Danishefky: J. Am. Chem. Soc. 1989, 111, 2967. White: J. Am. Chem. Soc. 1995, 117, 1908. O Me GM Zografos 2004 Synthesisof Imidazoles Ley: J. Chem. Soc. Perkin.1991, 667. OH/OMe stunners:

NO2 O in vivo screening: "by no means serendipitous; Cl those who were seeking found what they sought." N H Cl O OH (tapeworms) N isolation of avermectins oxidative phospholytion decoupler Cy thousands of microbial from Kitasato Institute (OS- Nature 1969, 221, 1016. fermentation products 3153) - Streptomyces O Nematospiroides dubius avermitilis "capable of Me separating from worms" N infected mice S membrane disruption and paralysis N pamoate depolarizing neuromuscalar blocking reagent

Int. J. Pharm. Pharm. Sci. 2011, 3,17. ACS Symposium Series, 255, 5. doi: 10.1021/bk-1984-0255.ch001 Baran group meeting October 4th, 2014 Antiparasitic drugs; malaria and the forgotten ones Kevin M. Oberg

Streptomyces fermentation H , (PPh ) RhCl avermitilis 2 3 3

MeO HO Me O MeO O Me O Me Me O O Me O Me Me/Et O O B1b B1a HO interacts with ligand gated channels causing paralysis O Me OH

donations by Merck to WHO for erradication

Emodepside Me Me O causes paralysis through excessive neurotransmitter release O O O MeN O N Me Me NMe O O N Me Me O O O O O NMe Me O MeN O Me Me

Me Int. J. Animicro. Agents 2003, 22, 318. Solid phase synthesis; see, Eur J Org Chem 2012, 1546.