- Identification of a 4-fluorobenzyl L-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)
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Novel L-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-L-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.
- Akama, Tsutomu,Zhang, Yong-Kang,Freund, Yvonne R.,Berry, Pamela,Lee, Joanne,Easom, Eric E.,Jacobs, Robert T.,Plattner, Jacob J.,Witty, Michael J.,Peter, Rosemary,Rowan, Tim G.,Gillingwater, Kirsten,Brun, Reto,Nare, Bakela,Mercer, Luke,Xu, Musheng,Wang, Jiangong,Liang, Hao
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- Amino acid benzyl ester hydrochloride salt preparation method
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The present invention discloses a preparation method for amino acid benzyl ester hydrochloride. The method comprises: by taking a metal chloride as a catalyst, in a suitable solvent, firstly generating amino acid hydrochloride by amino acid and hydrogen chloride; and then, esterifying the amino acid hydrochloride with benzyl alcohol at a reflux temperature, wherein water generated is removed by azeotrope; promoting esterification reaction; after the reaction is completed, filtering a thermal reaction liquid to remove the catalyst; removing a low-boiling-point substance (solvent) under low pressure; and performing post-treatment processes such as recrystallization and the like, thereby obtaining the object product, namely amino acid benzyl ester hydrochloride. Recrystallized mother liquor is recycled for more than 5 times. The method has advantages of relatively low raw material cost, relatively high conversion rate, relatively simple post-treatment, no use of chlorinating agents such as thionyl chloride and the like, less three waste emission, and the like, and is suitable for industrial production.
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Paragraph 0047-0049
(2018/03/13)
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- Orthogonally Protected Sch?llkopf's Bis-lactim Ethers for the Asymmetric Synthesis of α-Amino Acid Derivatives and Dipeptide Esters
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Alkylation of the aza-enolates of orthogonally protected chiral bis-lactim ethers with electrophiles proceeds with good levels of diastereocontrol to afford trans-alkylated adducts that can be efficiently deprotected via hydrolysis/hydrogenation procedures to afford non-proteinogenic α-amino acid or dipeptide ester derivatives.
- Hutchby, Marc,Sedgwick, Adam C.,Bull, Steven D.
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p. 2036 - 2049
(2016/07/06)
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- Chiral recognition of carboxylates by a static library of thiourea receptors with amino acid arms
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Chiral recognition is based on a large network of very subtle interactions whose outcome is difficult to predict. A combinatorial approach is therefore the most suitable to search for the most efficient receptor and obtain a structure-enantioselectivity correlation. We synthesized a set of 12 receptors constructed with 1,9-diaminoantracene and α-amino acid esters, linked via thiourea groups. The association constants and enantioselectivities for the complexes with mandelate and N-acetylphenylalanine were determined by competitive NMR titrations. Association constants quite regularly depend on the substituents in the receptor structure, but the distribution of enantioselectivities across the library could not easily be rationalized.
- Ulatowski, Filip,Jurczak, Janusz
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p. 4235 - 4243
(2015/05/13)
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- Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents
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Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas disease and African sleeping sickness, respectively. There is an urgent need for the development of new drugs against both diseases due to the lack of adequate cures and emerging drug resistance. One promising strategy for the discovery of small-molecule therapeutics against parasitic diseases has been to target the major cysteine proteases such as cruzain for T. cruzi, and rhodesain/TbCatB for T. brucei. Azadipeptide nitriles belong to a novel class of extremely potent cysteine protease inhibitors against papain-like proteases. We herein report the design, synthesis, and evaluation of a series of azanitrile-containing compounds, most of which were shown to potently inhibit both recombinant cruzain and rhodesain at low nanomolar/picomolar ranges. A strong correlation between the potency of rhodesain inhibition (i.e., target-based screening) and trypanocidal activity (i.e., whole-organism-based screening) of the compounds was observed. To facilitate detailed studies of this important class of inhibitors, selected hit compounds from our screenings were chemically converted into activity-based probes (ABPs), which were subsequently used for in situ proteome profiling and cellular localization studies to further elucidate potential cellular targets (on and off) in both the disease-relevant bloodstream form (BSF) and the insect-residing procyclic form (PCF) of Trypanosoma brucei. Overall, the inhibitors presented herein show great promise as a new class of anti-trypanosome agents, which possess better activities than existing drugs. The activity-based probes generated from this study could also serve as valuable tools for parasite-based proteome profiling studies, as well as bioimaging agents for studies of cellular uptake and distribution of these drug candidates. Our studies therefore provide a good starting point for further development of these azanitrile-containing compounds as potential anti-parasitic agents. Copyright
- Yang, Peng-Yu,Wang, Min,Li, Lin,Wu, Hao,He, Cynthia Y.,Yao, Shao Q.
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p. 6528 - 6541
(2012/07/13)
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- Effect of substituents on enantioselectivity in chiral oxazaborolidine mediated asymmetric ketone reduction reaction
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Various new chiral ligands have been synthesized by the condensation of different esters of L-Valine with different substituted salicylaldehydes in order to find the most effective catalyst for the enantioselctive ketone reduction. Chiral amine synthesized from L-Valine methyl ester and 5-chloro salicylaldehyde is found to catalyse the enantioselective reduction of prochiral ketone with high yield (99%) and enantiomeric excess (91%) with 20 mol% of the catalyst using borane dimethylsulphide as a stoichiometric reducutant. Different subsituted prochiral ketones have also been reduced in high yield upto 90% and the corresponding secondary alcohols are formed with good enantiomeric excess upto 99%. The mechanism of this reduction can be very well explained by considering a plausible mechanism for the CBS catalyst.
- Balakrishnan,Ananthi,Velmathi
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experimental part
p. 1157 - 1164
(2011/10/13)
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- Esterification of unprotected a-Amino acids in ionic liquids as the reaction media
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Ionic liquid 1,3-dimethylimidazolium methanesulfonate was used to prepare a-amino acids benzylic esters from unprotected amino acids and benzyl chloride. Esterification of several amino acids was achieved with satisfactory yields: by-products can be removed by a simple work-up procedure to afford the pure product. The described method is simple, mild, rapid and save.
- Biondini, Daniele,Brinchi, Lucia,Germani, Raimondo,Goracci, Laura,Savelli, Gianfranco
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experimental part
p. 39 - 44
(2010/08/22)
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- A class of novel carboline intercalators: Their synthesis, in vitro anti-proliferation, in vivo anti-tumor action, and 3D QSAR analysis
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Based on DOCK scores 18 N-(3-benzyloxycarbonylcarboline-1-yl)ethylamino acid benzylesters (6a-r) were synthesized as anti-tumor agents. Their IC 50 values against five human carcinoma cell lines ranged from 11.1 μM to more than 100 μM. The in vivo assay identified five derivatives of them had no anti-tumor action, the anti-tumor activity of nine derivatives of them equaled that of cytarabine, and the anti-tumor activity of three derivatives of them was higher than that of cytarabine. The UV and fluorescence spectra, as well as the relative viscosity and melting temperature measurements of calf thymus DNA (CT DNA) with and without the representative compound suggested that DNA intercalation could be their action mechanism. The 3D QSAR analysis of N-(3-benzyloxycarbonylcarboline-1-yl)ethylamino acid benzylesters (6a-r) revealed that their in vivo anti-tumor activity significantly depends on the molecular electrostatic and steric fields of the side chain of the amino acid residue.
- Wu, Jianhui,Li, Chunyu,Zhao, Ming,Wang, Wenjing,Wang, Yuji,Peng, Shiqi
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experimental part
p. 6220 - 6229
(2010/10/04)
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- Study on synthesis, characteristics and catalysis properties of novel chiral metal complexes catalysts for 1,3-dipolar cycloaddition reactions of nitrone with electron-rich alkene
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As a new class of potential catalysts for 1,3-dipolar cycloaddition reactions, fourteen L-amino acid Schiff base Cu(II) and Ti(IV) complexes were synthesized, characterized, and evaluated for their catalytic activities in the reaction between C, N-diphenylnitrone and electron-rich ethyl vinyl ether under both homogeneous and in situ conditions. The methods for preparation and utilization of the catalysts were elucidated in detail, and the results of the catalytic reactions were described and discussed as well. Excellent reaction results were found in the presence of some catalysts (20 mol%) with > 90% endo-isoazolidines produced, compared with predominantly exo-isoazolidine produced without a catalyst. In addition, the reaction rate is found to be enhanced remarkably by a Cu(II) complex Schiff base catalyst at room temperature.
- You, Jun,Liu, Bo,Wang, Yi
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experimental part
p. 1010 - 1017
(2010/08/13)
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- PEPTIDIC COMPOUNDS
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The present invention provides a compound of formula (I), (II), (III) and (IV) as defined herein and pharmaceutically acceptable derivatives thereof. The present invention further provides use of the compounds of the present invention in the treatment of bacterial infection and in the treatment of HIV infection. Also provided are pharmaceutical compositions comprising the compounds of the present invention.
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Page/Page column 34-35
(2008/06/13)
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- Synthesis of the amide analog of alternariolide (AM-toxin I), a host specific phytotoxin for apple leaves
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The amide analog of alternariolide (AM-toxin I) was synthesized with high efficiency. The analog showed comparable biological activity to that of alternariolide.
- Sakai, Mitsuru,Okuno, Toshikatsu,Hashimoto, Kimiko,Shirahama, Haruhisa
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p. 623 - 633
(2007/10/03)
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