- 2-AMINO-N-(AMINO-OXO-ARYL-LAMBDA6-SULFANYLIDENE)ACETAMIDE COMPOUNDS AND THEIR THERAPEUTIC USE
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The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain 2-amino-N-(amino-oxo-aryl-λ6- sulfanylidene)acetamide compounds (referred to herein as ANASIA compounds) that, inter alia, inhibit (e.g., selectively inhibit) bacterial aminoacyl-tRNA synthetase (aaRS) (e.g., bacterial leucyl-tRNA synthetase, LeuRS). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit (e.g., selectively inhibit) bacterial aminoacyl-tRNA synthetase; to treat disorders that are ameliorated by the inhibition (e.g., selective inhibition) of bacterial aminoacyl-tRNA synthetase; to treat bacterial infections; etc.
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Page/Page column 97; 98
(2021/06/26)
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- Synthesis of pyrimidine nucleoside and amino acid conjugates
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The synthesis of novel pyrimidine nucleoside bioconjugates with amino acids is presented. The N4-amino acid-acylated 2′-deoxycytidine analogues, modified with various amino acids, were synthesized using a three-step synthesis and obtained in moderate overall yields. Novel amino acid-alkylated 2′-deoxycytidine derivatives were obtained during the rearrangement of amino acid-acylated derivatives that occurred during Boc deprotection.
- Koplūnait?, Martyna,Butkut?, Kamil?,Me?kys, Rolandas,Taurait?, Daiva
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supporting information
(2020/11/13)
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- Design, synthesis and anxiolytic activity evaluation of N-Acyltryptophanyl- containing dipeptides, potential TSPO ligands
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Background: The 18 kDa translocator protein (TSPO), previously known as the peripheral- type benzodiazepine receptor, plays a key role for the synthesis of neurosteroids by promoting transport of cholesterol from the outer to the inner mitochondrial membrane, which is the ratelimiting step in neurosteroid biosynthesis. Neurosteroids interact with nonbenzodiazepine site of GABAa receptor causing an anxiolytic effect without the side effects. Methods: Using the original peptide drug-based design strategy, the first putative dipeptide ligand of the TSPO N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23) was obtained. Molecular docking of GD-23 in the active pocket of the TSPO receptor using Glide software was carried out. The lead compounds GD-23 and its analogues were synthesized using activated succinimide esters coupling method. The anxiolytic activity of GD-23 and its analogues was investigated in vivo, using two validated behavioral tests, illuminated open field and elevated plus-maze. Results: The in vivo studies revealed that the following parameters are necessary for the manifestation of anxiolytic activity of new compounds: the L-configuration of tryptophan, the presence of an amide group at the C-terminus, the specific size of the N-acyl substituent at the Nterminus. Compound GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide) demonstrated a high anxiolytic-like effect in the doses of 0.05-1.0 mg/kg i.p. comparable with that of diazepam. Compound GD-23 was also active in the open field test when was administered orally in the doses of 0.1-5.0 mg/kg. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by the antagonism of compound GD-23 with TSPO selective inhibitor PK11195 as well as with inhibitors of enzymes which are involved in the biosynthesis of neurosteroids, trilostane and finasteride. Conclusion: A series of N-acyl-tryptophanyl-containing dipeptides were designed and synthesized as 18 kDa translocator protein (TSPO) ligands. Using a drug-based peptide design method a series of the first dipeptide TSPO ligands have been designed and synthesized and their anxiolytic activity has been evaluated. In general, some of the compounds displayed a high level of anxiolytic efficacy comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic activity of new compounds was proved using two methods. On this basis, the N-acyl-Ltryptophanyl- isoleucine amides could potentially be a novel class of TSPO ligands with anxiolytic activity.
- Deeva, Olga A.,Dyabina, Alina S.,Gudasheva, Tatiana A.,Mokrov, Grigory V.,Seredenin, Sergey B.,Yarkova, Milada A.
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p. 383 - 399
(2019/07/12)
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- Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome
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Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.
- Tereshchenkov, Andrey G.,Dobosz-Bartoszek, Malgorzata,Osterman, Ilya A.,Marks, James,Sergeeva, Vasilina A.,Kasatsky, Pavel,Komarova, Ekaterina S.,Stavrianidi, Andrey N.,Rodin, Igor A.,Konevega, Andrey L.,Sergiev, Petr V.,Sumbatyan, Natalia V.,Mankin, Alexander S.,Bogdanov, Alexey A.,Polikanov, Yury S.
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p. 842 - 852
(2018/02/26)
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- CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF
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The present technology relates to compounds, kits, compositions, and methods useful for the treatment of fibrotic disease. In some aspects, the present technology provides for treatment of various diseases or disorders associated or mediated, at least in part, by calpains, such as CAPN1, CAPN2, and/or CAPN9. The present technology is generally applicable to compounds which inhibit myofibroblast differentiation.
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Paragraph 00457
(2017/09/27)
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- N,O-Bis(trimethylsilyl)acetamide/N-hydroxysuccinimide ester (BSA/NHS) as coupling agents for dipeptide synthesis
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A method using N,O-bis(trimethylsilyl)acetamide/N-hydroxysuccinimide ester (BSA/NHS) as coupling agents for dipeptide synthesis is descried. The coupling reaction between N-hydroxysuccinimide (NHS) esters and amines could be performed under mild conditions with N,O-bis(trimethylsilyl)acetamide (BSA) as coupling reagent and no additional acid/base is required. All byproducts and excessive reactants are water soluble or hydrolysable and easy to eliminate through water-washing at the purification stage. Moreover, all the reactants are inexpensive and widely used in conventional drug production.
- Huang, Ye,Feng, Wen-Hua
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p. 357 - 360
(2016/03/16)
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- CYCLIC HEMIACETAL DERIVATIVE AND USE THEREOF
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A compound represented by the following formula (I) wherein R1 is a lower alkyl group, R2 is a hydrogen, a halogen, a cyano group, a lower alkyl group or a lower alkoxy group, and n is 0 or 1, which has a calpain inhibitory activity, is provided.
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- New cyanopeptide-derived low molecular weight inhibitors of trypsin-like serine proteases
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This paper deals with the design, syntheses, and inhibition tests of new low molecular weight thrombin inhibitors utilizing cyanopeptides, the secondary metabolites of cyanobacteria with interesting biological activities, as new lead structures. Starting with aeruginosin 98-B (1) as a lead structure, we have developed and synthesised new, selective acting inhibitors of serine proteases (RA-1005 and RA-1009), which are suitable targets for further structure-activity studies.
- Radau, Gregor,Schermuly, Sonja,Fritsche, Alexandra
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p. 300 - 309
(2007/10/03)
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- LARGE-SCALE SYNTHESIS OF ANTICOAGULANT DECAPEPTIDE MDL 28050
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A solution phase synthesis of the anticoagulant decapeptide Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Cha-D-Glu-OH ( 1, MDL 28050) on a large scale is decribed.Our strategy employed in the 24-step total synthesis relies on a convergent approach.The basic feature is the preparation and the coupling of two protected pentapeptides, 2 and 3.Several key intermediates were purified by crystallizations including the protected decapeptide 21.Only a single purification required preparative HPLC.Using this synthetic route, we prepared 98percent pure final product on a 40-g scale.The overall yield of this process is about 20percent.
- Hoekstra, William J.,Sunder, Shyam S.,Cregge, Robert J.,Ashton, Louis A.,Stewart, Kenneth T.,King, Chi-Hsin R.
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p. 307 - 318
(2007/10/02)
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- Tripodal peptides with chiral conformations stabilized by interstrand hydrogen bonds
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C3 symmetric trispeptides are described that form chiral conformations and are therefore eminently suited to provide a new family of chiral receptor molecules when extended by appropriate binding sites. These trispeptides are composed of C3 symmetric trisamines as anchors and three symmetrically extending chiral amino acid residues. Their conformations in apolar solvents fall into two main classes. One is comprised of propeller-like conformations of preferred chiral sense that are stabilized by a belt of intramolecular H-bonds (hydrogen bonds) between adjacent strands. The other class has two of its strands connected by two H-bonds to form a 10-membered ring, while the third strand may hydrogen-bond to one of the other two. The effect of the anchors and amino acids on the relative stability of the H-bonded, chiral conformations has been established by a combination of spectroscopic and theoretical means. Trispeptides derived from more lipophilic α-amino acids show a higher population of the chiral conformations. Moreover, trispeptides that are based on tris(2-aminoethyl)amine (TREN) as anchor form stronger H-bonds than those relying on 1,3,5-tris(aminomethyl)benzene (TRAM).
- Tor, Yitzhak,Libman, Jacqueline,Shanzer, Abraham,Felder, Clifford E.,Lifson, Shneior
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p. 6653 - 6661
(2007/10/02)
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- Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679
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A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.
- DeSolms,Giuliani,Guare,Vacca,Sanders,Graham,Wiggins,Darke,Sigal,Zugay,Emini,Schleif,Quintero,Anderson,Huff
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p. 2852 - 2857
(2007/10/02)
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- LE CHLOROFORMIATE D'ISOPROPENYLE (IPCF) EN CHIMIE DES AMINO-ACIDES ET DES PEPTIDES - III SYNTHESE D'ESTERS ACTIFS D'AMINO ACIDES N-PROTEGES
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Isopropenyl chloroformate (IPCF) was used for preparation of mixed carbonates (Aryl and isopropenyl) which are very suitable reagents for active ester synthesis of amino acid derivatives (Boc derivatives in particular).
- Jaouadi, M.,Selve, C.,Dormoy, J. R.,Castro, B.,Martinez, J.
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p. 1721 - 1722
(2007/10/02)
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