- Hit-to-lead optimization of novel benzimidazole phenylacetamides as broad spectrum trypanosomacides
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Trypanosoma cruzi and Trypanosoma brucei are the parasitic causative agents of Chagas disease and human African trypanosomiasis (HAT), respectively. The drugs currently used to treat these diseases are not efficacious against all stages and/or parasite sub-species, often displaying side effects. Herein, we report the SAR exploration of a novel hit, 2-(4-chlorophenyl)-N-(1-propyl-1H-benzimidazol-2-yl)acetamide previously identified from high throughput screens against T. cruzi, Trypanosoma brucei brucei and Leishmania donovani. An informative set of analogues was synthesized incorporating key modifications of the scaffold resulting in improved potency whilst the majority of compounds retained low cytotoxicity against H9c2 and HEK293 cell lines. The SAR observed against T. cruzi broadly matches that observed against T.b. brucei, suggesting the possibility for a broad-spectrum candidate. This class of compounds therefore warrants further investigation towards development as a treatment for Chagas disease and HAT. This journal is
- Avery, Vicky M.,Baell, Jonathan,McNamara, Nicole,Rahmani, Raphael,Sykes, Melissa L.
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supporting information
p. 685 - 695
(2020/08/24)
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- A selective and mild glycosylation method of natural phenolic alcohols
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Several bioactive natural p-hydroxyphenylalkyl β-D-glucopyranosides, such as vanillyl β-D-glucopyranoside, salidroside and isoconiferin, and their glycosyl analogues were prepared by a simple reaction sequence. The highly efficient synthetic approach was achieved by utilizing acetylated glycosyl bromides as well as aromatic moieties and mild glycosylation promoters. The aglycones, p-O-acetylated arylalkyl alcohols, were prepared by the reduction of the corresponding acetylated aldehydes or acids. Various stereoselective 1,2-trans-O-glycosylation methods were studied, including the DDQ-iodine or ZnO-ZnCl2 catalyst combination. Among them, ZnO-iodine has been identified as a new glycosylation promoter and successfully applied to the stereoselective glycoside synthesis. The final products were obtained by conventional Zemplén deacetylation.
- Mastihubová, Mária,Poláková, Monika
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supporting information
p. 524 - 530
(2016/04/08)
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- QUINOLINE AND QUINOXALINE DERIVATIVES AS INHIBITORS OF KINASE ENZYMATIC ACTIVITY
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Compounds of formula (IA) or (IB), are inhibitors of aurora kinase activity: Formula (IA), (IB) wherein -L1Y1-[CH2]z- is a linker radical wherein Y1, L1 and z are as defined in the claims; R6 is C1-C4alkoxy, hydrogen or halo; W represents a bond, -CH2-, -O-, -S-, -S(=O)2-, or -NR5- where R5 is hydrogen or C1-C4 alkyl; Q is =N-, =CH- or =C(X1)- wherein X1 is cyano, cyclopropyl or halo; linker radicals L2 are as defined in the claims; R is a radical of formula (X) or (Y): wherein R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular carboxylesterase enzymes to a carboxylic acid group; R4 is hydrogen; or optionally substituted C1-C6 alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, heteroaryl, heteroaryl(C1-C6 alkyl)-, -(C=O)R3, -(C=O)OR3, or -(C=O)NR3 wherein R3 is hydrogen or optionally substituted (C1-C6)alkyl, C3-C7 cycloalkyl, aryl, aryl(C1-C6 alkyl)-, heteroaryl, or heteroaryl(C1-C6 alkyl)-; R41 is hydrogen or optionally substituted C1-C6 alkyl; and D is a monocyclic heterocyclic ring of 5 or 6 ring atoms.
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Page/Page column 127-128
(2008/06/13)
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- Solvolysis of benzyl alcohols and ethers in 1,2-diols and application to a deprotection of benzyl ether-type protecting groups
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Some kinds of benzyl alcohols and ethers react with 1,2-diols, such as ethylene glycol and propylene glycol, at 130-190°C to give 2-hydroxyethyl or 2-hydroxypropyl ethers. Application of this reaction to a deprotection of benzyl ether-type protecting groups, under neutral conditions, was also described. Copyright
- Miyake, Hideyoshi,Fujimura, Masahiro,Tsumura, Takatsugu,Sasaki, Mitsuru
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p. 778 - 779
(2007/10/03)
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- New cyclohexadienone derivatives: Preparation and chiral discrimination in high-pressure diels - Alder cycloadditions
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A wide range of cyclohexadienones has been synthesised in order to study their reactivity and their regio- and stereoselectivity with the enantiopure diene 1 under high-pressure conditions. Computational investigations were used to point out some paramete
- Tran-Huu-Dau, Marie-Elise,Wartchow, Rudolf,Winterfeldt, Ekkehard,Wong, Yung-Sing
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p. 2349 - 2369
(2007/10/03)
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- Highly efficient and flexible total synthesis of coelenterazine
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A new total synthesis of the bioluminescent chromophore coelenterazine 1 is described.
- Keenan, Martine,Jones, Keith,Hibbert, Frank
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p. 323 - 324
(2007/10/03)
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- Synthesis and Characterization of Copper(II) and Nickel(II) Complexes Derived from α-Substituted Malondialdehydes
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The synthesis and characterization of two series of novel bis(4'-alkyloxyphenyl)malondialdehydes of copper(II) and nickel(II), (R=CnH2n+1, n = 9, 10, 11, 12) from 2-(4'-hydroxyphenyl)-3-dimethylamino acrolein is described. - Keywords
- Reyes, V. Salas,Aguilera, C.
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p. 205 - 208
(2007/10/02)
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- Polyelectrolyte-Catalyzed Acetyl Transfer Reactions. Structure-Reactivity Relationships in the Aminolysis of Phenyl Acetates by Poly(ethyleneimine) and Glycylglycine.
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The aminolysis of a wide series of substituted phenyl acetates by poly(ethyleneimine) (PEI) is studied.Saturation kinetics are observed and the ester-polyamine association equilibrium constants, as well as the rates of decomposition of the resulting intracomplexes, are determined.Unlike the association constants, the rate constants for the reaction of the intracomplex are found to depend on the acidity of the leaving groups.Two Broensted-type relationships are found for anionic and neutral esters having different intercepts but proximate slopes -0.73 and -0.77 respectively, which decrease to lower values with very reactive phenyl acetates.Only one broken Broensted relationship is found for the bimolecular aminolysis by glycylglycine.The results are consistent with the formation of a tetrahedral intermediate by the amino groups of PEI, with a change in the rate-determining step for very reactive esters from the breakdown to the formation of the tetrahedral intermediate.The higher reactivity of PEI, which is more relevant with substrates containing anionic groups, is principally ascribed to the electrostatic polyelectrolyte-substrate binding.A minor role is played by the increase in the acidity of the conjugate acid of the leaving group, i.e. of its leaving ability, caused by the association of the ester with PEI: values of effective molarity in the range of 10 to 15 mol cm-3 are found.
- Arcelli, Antonio,Concilio, Carlo
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p. 201 - 226
(2007/10/02)
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- Synthesis of a multifunctional radioiodinatable photoaffinity probe
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Synthesis is described which results in an iodinatable photoaffinity probe and derivatives which are useful in the covalent coupling of the probe to amine, carboxylic acid, and alcoholic hydroxy function on specific ligands of biological importance. Speci
- Mende,Schulman,Baden
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p. 5307 - 5310
(2007/10/02)
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- A CHEMICAL APPROACH TO SOLVING BRIDGING PHENOMENA IN STEROID RADIOIMMUNOASSAYS
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Steroid radioimmunoassays (RIA) employ antibodies raised against a carrier protein-steroid conjugate.Individual antibodies may recognize the steroid, the protein or the chemical bridge used to join them together.Use of the same bridge in the tracer result
- Nordblom, G. D.,Webb, R.,Counsell, R. E.,England, B. G.
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p. 161 - 174
(2007/10/02)
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