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US 20120196835A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0196835 A1 Olafield et al. (43) Pub. Date: Aug. 2, 2012 (54) ENZYME INHIBITING COMPOUNDS AND A6II 3/663 (2006.01) METHODS A6II 3/94 (2006.01) CI2N 9/99 (2006.01) (76) Inventors: Eric Olafield, Champaign, IL (US); A6II 3L/225 (2006.01) Ke Wang, Urbana, IL (US); A6II 3/662 (2006.01) Weixue Wang, Urbana, IL (US); A6II 3/665 (2006.01) Yonghui Zhang, Urbana, IL (US) A6IP3L/04 (2006.01) A6IP33/00 (2006.01) (21) Appl. No.: 13/500,845 C07F 9/113 (2006.01) A 6LX 3L/95 (2006.01) (22) PCT Filed: Oct. 8, 2010 (52) U.S. Cl. ........... 514/89; 558/152; 514/106; 558/155; 514/108: 514/574: 514/563; 514/547: 514/119; (86). PCT No.: PCT/US 10/52049 514/99: 435/184 S371 (c)(1), (2), (4) Date: Apr. 6, 2012 (57) ABSTRACT The invention provides compounds, compositions, and meth Related U.S. Application Data ods for studying the Rohmer pathway and for treating bacte (60) Provisional application No. 61/249,929, filed on Oct. rial infections or parasitic infections. The parasitic infection 8, 2009. can be a protozoan infection, such as malaria. The compounds and compositions can also be used as antibiotics, for example, O O to kill bacteria or parasites, or to inhibit bacterial or parasite Publication Classification growth. The invention further provides inhibitors of iso (51) Int. Cl. prenoid biosynthesis enzymes, and methods of inhibiting the A6 IK3I/675 (2006.01) activity ofisoprenoid biosynthesis enzymes. The compounds A6 IK3I/665 (2006.01) can be, for example, alkynes or allenes that bind to a unique C07F 9/40 (2006.01) Fe of an Fe4S4 cluster of an isoprenoid biosynthesis enzyme. Patent Application Publication Aug. 2, 2012 Sheet 1 of 5 US 2012/0196835 A1 Acetylene Series: o O O O O O e1O YO1 13OH sulf- CPP.O1 OH BPH-1061 BPH-1077 BPH-1093 to ROH HO O OFOH n a 1 E. BPH-1085 O O O O HO, OH NN HO OH 21P-PS: nsuch a. of aoh BPH-1081 BPH-1082 Figure 1 Patent Application Publication Aug. 2, 2012 Sheet 2 of 5 US 2012/0196835 A1 Cationic Series: ROH ROH ROH n OH n OH n OH OH N OpHan O1. OpHan 1. NOHOpH2n BPH-2 BPH-21 BPH-9 g ROH g n OH n NOH n OH 1. 2P 1. 2P CH3 O1. OpHanI N OpHa' N OpHY BPH-2OO BPH-290 BPH-299 O MOH ROH OH OH NS-s PCO. O.N si-n- OH rich1 2P O1 OH an 2n OH OpH OpH BPH-297 BPH-650 BPH-639 NYo'no.'HO, SohOH N1 YO)'Ho YO1"YOHOH N 1 2N BPH-293 BPH-1026 BPH-1027 to. OH HoY as aOH 21 ro no- YOH 1. C N F Cro O OH (OluseSa O1' O1"E-OH OH BPH-1029 BPH-1060 BPH-1030 OH ROH i O O n OH n HoO1 NO- i.YOH HO al i Y OH r -N-N-P. r),2n H N OP BPH-1032 BPH-1028 BPH-272 Figure 2 Patent Application Publication Aug. 2, 2012 Sheet 3 of 5 US 2012/0196835 A1 Anionic, Thiol and Neutral Series: HOJiu-25 of SoFSoiOH HO, 1.N. toO'O' -OHOH HOJus N1O-O-SOHHo -OH O BPH-988 BPH-991 BPH-296 ROH ROH 's OH Hsn-n-2SoH OH sr- O?OH MeO Jusu:O1 O1"E-OH OH OH OH BPH-993 BPH-994 BPH-990 O O O O O O Mole-3-3HO OH OL>-CPP HO OH HO1\1\oHO Yo-SoHOH O BPH-989 BPH-432 BPH-1031 Figure 3 1.O O.8 O c. 0.6 S. 0.4 0.2 O.O O. 1 1O 1 OOO Inhibitor Concentration (uM) Figure 4 Patent Application Publication Aug. 2, 2012 Sheet 5 of 5 US 2012/0196835 A1 Figure 6 US 2012/0196835 A1 Aug. 2, 2012 ENZYME INHIBITING COMPOUNDS AND METHODS -continued RELATED APPLICATIONS - E - --> 0001. This application claims priority under 35 U.S.C. N OPP 2H+2e- OPP " S119(e) to U.S. Provisional Patent Application No. 61/249, OH IPP (3) 929, filed Oct. 8, 2009, which is incorporated herein by ref HMBPP (2) erence in its entirety. GOVERNMENT SUPPORT --. 0002 This invention was made with government support DMAPP (4) under Grant Nos. GM073216, GM65307, and AI074233, awarded by the United States Public Health Service, National 0006. The structure of IspG has not yet been reported, Institutes of Health. The United States Government has cer while two structures have been published for IspH, one from tain rights in the invention. Aquifex aeolicus (Rekittke et al., J. Am. Chem. Soc. 2008, 130, 17206), and the other from E. coli (Grawertet al., Angew: BACKGROUND OF THE INVENTION Chem. Int. Ed. Engl. 2009, 48(31), 5756). According to these 0003 Enzymes that catalyze the formation of isoprenoids reports, both structures contain FeS clusters. However, are of interest as drug targets. The Rohmer pathway, also these observations are in contrast to the conclusions drawn known as the methyl erythritol phosphate or non-mevalonate from both Mössbauer spectroscopy (Xiao et al., J. Am. Chem. pathway, is responsible for isoprenoid biosynthesis in most Soc. 2009, 131 (29), 9931) and EPR spectroscopy (Wolff et pathogenic bacteria and in malaria parasites, such as Plasmo al., FEBS Lett. 2003, 541(1-3), 115). Both spectroscopic dium faciparum (Rohmer et al., Lipids 2008, 43(12), 1095; methods lead to the conclusion that FeS clusters are respon Wiesner and Jomaa, Current Drug Targets 2007, 8(1), 3). sible for catalysis. The same conclusion was arrived at from Enzymes found in the pathway are potentially important as the results of microchemical analyses. It therefore seems anti-infective drug targets because isoprenoids are essential possible that the FeS cluster, while catalytically active, may for Survival of these microorganisms and because the non be relatively labile, as found, for example, inaconitase and in mevalonate pathway is absent in humans (Williams and pyruvate-formation lyase activating factor. To date, there has McCammon, Chem. Biol. Drug Des. 2009, 73(1), 26; de been only one report of an IspH inhibitor (Van Hoof, J. Org. Ruyck and Wouters, Curr. Protein Pept. Sci. 2008, 9(2), 117). Chem. 2008, 73, 1365), which provided an ICso value of -1-2 0004 The structures and mechanisms of action of six of mM. the eight enzymes present in the pathway are now known. 0007 Accordingly, newly identified inhibitors of iso Fosmidomycin, which inhibits the second enzyme in the prenoid biosynthesis enzymes are needed to further study the pathway, has shown promising results for treating malaria Rohmer pathway. New compounds are also needed to (Jomaa et al., Science 1999, 285, (5433), 1573; Borrmannet develop effective therapeutic methods, including methods to al., Antimicrobial Agents and Chemotherapy 2006, 50(8), inhibit the activity of isoprenoid biosynthesis enzymes, and 2713). An inhibitor of one of the six known enzymes, deox methods for treating diseases such as malaria and other infec yxylulose-5-phosphate reductoisomerase, has been used tions, due to increased resistance to currently known antibi clinically to treat both malaria and Pseudomonas aeruginosa Ot1CS. infections (Wiesner et al., Curr: Pharm. Des. 2008, 14, 855: Cheng et al., Biochem. Pharmacol. 1973, 22, 3099). SUMMARY 0005 Less is known, however, about the structures and mechanism of action of the last two enzymes in the pathway: 0008. The invention provides compounds, compositions, IspG and IspH. IspG is E-4-hydroxy-3-methyl-but-2-enyl and methods for treating bacterial infections or parasitic diphosphate (HMBPP) synthase, EC 1.17.1.1, also known as infections. The parasitic infection can be a protozoan infec GcpF. IspH is E-4-hydroxy-3-methyl-but-2-enyl diphos tion, such as malaria. The compounds and compositions can phate (HMBPP) reductase, EC 1.17.1.2, also known as LytB. also be used as antibiotics, for example, to kill bacteria or The penultimate enzyme is IspG, which catalyzes the 2H/ parasites, or to inhibit their growth or proliferation. The 2e reduction of methylerythritol-cyclo-diphosphate invention further provides inhibitors ofisoprenoid biosynthe (MEcPP 1) to HMBPP (2), while the terminal enzyme, IspH, sis enzymes, and methods of inhibiting the activity of iso catalyzes the 2H"/2e reduction of HMBPP (2) to isopentenyl prenoid biosynthesis enzymes. The compounds can be, for diphosphate (IPP 3) and dimethylallyl diphosphate example, alkynyl diphosphate inhibitors of the iron-sulfur (DMAPP 4) in a -5:1 ratio. proteins IspG or IspH (LytB). 0009. Thus, described herein are potent inhibitors of iso prenoid biosynthesis enzymes, such as IspG and IspH. In Some embodiments, the inhibitory compounds include com plexation moieties that include heteroatoms or pie systems that can complex with an FeS cluster of a protein. For example, the inhibitors can contain alkynyl groups that, based on EPR, H, H, C and "Feelectron-nuclear double reso nance (ENDOR) spectroscopy and computational docking, MEcPP (1) form TC/o “metallacycle' complexes with the FeS clusters of IspH. Such clusters have previously been detected by Möss US 2012/0196835 A1 Aug. 2, 2012 bauer and EPR spectroscopy. This complexation and the 0018 each R is independently H, (C-C)alkyl, (C-C) resulting inhibition are of broad general interest because it alkanoyl, or —(C-C)alkyl(aryl); represents the first potent inhibitor of the IspH enzyme, 0019 each R" is independently H, (C-C)alkyl, or (C- together with a novel inhibition mechanism, involving bioor Cs)cycloalkyl: ganometallic complex formation.
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    DISSERTATION Titel der Dissertation „Isolation of positive, allosteric GABAA receptor modulators from Chinese herbal drugs traditionally used in the treatment of anxiety and insomnia“ Verfasserin Mag. pharm. Judith Singhuber angestrebter akademischer Grad Doktorin der Naturwissenschaften (Dr.rer.nat.) Wien, 2011 Studienkennzahl lt. A 091 449 Studienblatt: Dissertationsgebiet lt. Dr.-Studium der Naturwissenschaften Pharmazie Studienblatt: Betreuerin / Betreuer: Univ. Prof. Mag. Dr. Brigitte Kopp For Maximillian & Lennox ACKNOWLEDGMENTS In this place I would like to thank the people which contributed to the success of my thesis: Prof. Brigitte Kopp, my supervisor, for providing an interesting topic and for her guidance. Prof. Steffen Hering (Department of Pharmacology and Toxicology, University of Vienna) for the possibility to work in his Department. Dr. Igor Baburin (Department of Pharmacology and Toxicology, University of Vienna) for the pharmacological investigations on the 56 extracts and the HPLC fractions of A. macrocephala and C. monnieri. Dr. Sophia Khom (former Department of Pharmacology and Toxicology, University of Vienna) for her assistance as well as interesting discussions on GABAergic neurotransmission and other topics. Prof. Gerhard F. Ecker (Department of Medicinal Chemistry) for the binary QSAR and help with the pharmacophore model. Prof. Ernst Urban (Department of Medicinal Chemistry, University of Vienna) und Prof. Hanspeter Kählig (Institute of Organic Chemistry, University of Vienna) for the NMR- measurements. Dr.
  • Natural Agents Affecting Excitatory and Inhibitory Neurotransmission: Adenosine Receptor Antagonism: Caffeine (Coffea Spp/C

    Natural Agents Affecting Excitatory and Inhibitory Neurotransmission: Adenosine Receptor Antagonism: Caffeine (Coffea Spp/C

    Natural Agents Affecting Excitatory and Inhibitory Neurotransmission: Adenosine receptor antagonism: ● Caffeine (Coffea spp/Coffee) Primary GABA inhibition: ● Anisatin (Japanese star anise/Illicium anisatum) ○ non-competitive GABA (channel) inhibition 1’2 ● Bicuculline (Dicentra cucullaria/Dutchman's breeches) ○ competitive inhibition GABA site ○ (and probably non-competitive via allosteric change) 3 ● Cicuta maculata (Water Hemlock) & Cicuta Virosa (Cowbane or Northern Water Hemlock) ○ Cicutoxin- GABA +/- inhibition potassium channels 4’5 ○ Virol A: non-competitive with GABA binding site, but does produce competitive GABA channel (chloride) inhibition ■ structurally similar to cicutoxin 6 ● Colchicine (Colchicum autumnale/autumn crocus) ○ competitive antagonist 7 ● Oenanthe fistulosa (Water Dropwort) [Toxin] ○ probably competitive inhibition of GABA Chloride channel (dose dependent blockade) ○ structure similar to cicutoxin ○ from island of Sardinia; ? glycine antagonism- risus sardonicus 8 ● Picrotoxin (Anamirta cocculus/Fishberries) ○ non-competitive inhibition 9 1 Rietjens IM, Martena MJ, Boersma MG, et al. Molecular mechanisms of toxicity of important food-borne phytotoxins. Molecular mechanisms of toxicity of important food-borne phytotoxins. Mol Nutr Food Res. 2005 Feb;49(2):131-58. PMID: 15635687 2 Perret C, Tabin R, Marcoz JP et al. [Apparent life-threatening event in infants: think about star anise intoxication!]. [Article in French] Arch Pediatr. 2011 Jul;18(7):750-3. doi: 10.1016/j.arcped.2011.03.024. 3 Ueno S, Bracamontes J, Zorumski C, et al. Bicuculline and gabazine are allosteric inhibitors of channel opening of the GABAA receptor. J Neurosci. 1997 Jan 15;17(2):625-34.PMID: 8987785 4 Schep LJ, Slaughter RJ, Becket G, Beasley DM. Poisoning due to water hemlock. Clin Toxicol (Phila). 2009 Apr;47(4):270-8.