- Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs
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Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower Ki values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest Ki values obtained for the two parasite enzymes were 0.1?μM (Pf) and 0.2?μM (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture with IC50 values of 0.8 and 1.5?μM. These two compounds exhibited low cytotoxicity in human A549 cells having CC50 values of >300?μM resulting in an excellent selectivity index.
- ?pa?ek, Petr,Keough, Dianne T.,Chavchich, Marina,Dra?ínsky, Martin,Janeba, Zlatko,Naesens, Lieve,Edstein, Michael D.,Guddat, Luke W.,Hocková, Dana
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- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 001322
(2018/09/12)
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- MODULATORS OF SESTRIN-GATOR2 INTERACTION AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00412; 00413
(2018/11/22)
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- MODULATORS OF SESTRIN-GATOR2 INTERACTION AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 0514
(2017/05/15)
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- NUCLEOTIDE AND NUCLEOSIDE THERAPEUTICS COMPOSITIONS AND USES RELATED THERETO
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This disclosure relates to nucleotide and nucleoside therapeutic compositions and uses in treating infectious diseases, viral infections, and cancer, where the base of the nucleotide or nucleoside contains at least one thiol, thione or thioether.
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Page/Page column 352; 351
(2016/09/26)
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- Development of a practical and scalable synthesis of (R)- and (S)-3-amino-2-[(benzyloxy)methyl]propan-1-ol monohydrochloride: A useful C-4 Chiral Building Block
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The development of a practical and scalable synthesis of a C-4 chiral amine building block (R)-1·HCl and (S)-1·HCl is described. This important chiral intermediate (R)-1·HCl is efficiently synthesized from the commercially available, inexpensive, and simple 2-(hydroxymethyl)-1,3- propanediol (31) using lipase-catalyzed enantioselective hydrolysis as a key reaction. Development resulted in a telescoped process that was operated successfully and reproducibly in a pilot-plant-scale synthesis, and 22 kg of chiral amine (R)-1·HCl was prepared in the first scale-up synthesis. This synthetic method is also useful for preparation of the important chiral building block (S)-1·HCl, which is the enantiomer of (R)-1·HCl.
- Yoshida, Shinya,Obitsu, Kazuyoshi,Hayashi, Yasumasa,Shibazaki, Mitsuyoshi,Kimura, Takenori,Takahashi, Takumi,Asano, Toru,Kubota, Hirokazu,Mukuta, Takashi
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p. 1527 - 1537
(2013/02/23)
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- 2-[2-Substituted-3-(3,4-dichlorobenzylamino)propylamino]-1H-quinolin-4-ones as Staphylococcus aureus methionyl-tRNA synthetase inhibitors
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New analogues of 2-[2-substituted-3-(3,4-dichlorobenzylamino)propylamino]quinolin-4-ones, 26a, 26b, 31a-e, 34, 35, 38 and 40, have been synthesized and evaluated against Staphylococcus aureus methionyl-tRNA synthetase. All of the synthesized compounds were less active than the reference compound 2. The compounds were also screened against various strains of S. aureus and Enterococci for their antibacterial activities. Among the compounds, 26b, 31c and 31e displayed significant inhibitory properties against various strains of Enterococci compared to compound 2.
- Farhanullah,Kang, Taehee,Yoon, Eun-Jung,Choi, Eun-Chil,Kim, Sunghoon,Lee, Jeewoo
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experimental part
p. 239 - 250
(2009/04/07)
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- Pyrazole glucokinase activators
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Disclosed herein are pyrazole glucokinase activators of the formula (I) useful for the treatment of metabolic diseases and disorders, preferably diabetes mellitus.
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Page/Page column 81
(2008/06/13)
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- Bifunctional acyclic nucleoside phosphonates: 2. Symmetrical 2-{[bis(phosphono)methoxy]methyl}ethyl derivatives of purines and pyrimidines
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Novel bisphosphonate alkylating agent, tetraisopropyl (2-[(mesyloxy)methyl] propane-1,3-diyl]bis(oxymethylene)bisphosphonate 19, was synthesized from diethyl 2,2-bis-(hydroxymethyl)malonate. Decarbethoxylation of the diethyl 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate was followed by chloromethylation of 2-[(benzyloxy)methyl]propane-1,3-diol and Arbuzov reaction with triisopropyl phosphite. Bisphosphonate building block 19 was used in the alkylation of various nucleobases (2-amino-6-chloropurine, adenine, 2-amino-6-(cyclopropyl) aminopurine, cytosine, uracil and 4-methoxy-5-methylpyrimidin-2(1H)-one). N 9-Substituted purines and N1-substituted pyrimidines were converted to appropriate free bisphosphonic acids. No antiviral or cytostatic activity was detected.
- Vrbkova, Silvie,Dracinsky, Martin,Holy, Antonin
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p. 965 - 983
(2008/09/20)
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- 3-Acyloxy-2-phenalkylpropyl amides and esters of homovanillic acid as novel vanilloid receptor agonists
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A series of 3-acyloxy-2-phenalkylpropyl amides and esters of homovanillic acid were designed and synthesized as vanilloid receptor agonists containing the three principal pharmacophores of resiniferatoxin. Amide analogues 23, 5 and 11 were found to be potent agonists in vanilloid receptor assay both for ligand binding and for activation.
- Lee, Jeewoo,Park, Shin-Ung,Kim, Ji-Young,Kim, Jin-Kwan,Lee, Jiyoun,Oh, Uhtaek,Marquez, Victor E.,Beheshti, Maryam,Wang, Qiming J.,Modarres, Shayan,Blumberg, Peter M.
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p. 2909 - 2914
(2007/10/03)
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- Antiviral phosphonomethoxyalkylene purine and pyrimidine derivatives
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A series of compounds of Formula I which have anti-tumor activity, and are useful in treating viral infections, their compositions and use. STR1 In Formula I B is a purine or pyrimidine base; alk1 alk2 and alk3 are chemical bonds or alkylene groups; Q is hydrogen or hydroxyl; and R1 -R4 are hydrogen or alkyl.
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