1,721,235 research outputs found
An efficient approach to D-threo-3-hydroxyaspartic acid for the synthesis of novel L-threo-oxazolines as selective blockers of glutamate reversed uptake
No full textAn efficient, stereoselective synthetic strategy to D-threo-3- hydroxyaspartic acid was developed. Starting from L-(2S,3S)-N-benzoyl-3- hydroxyaspartic acid dimethyl ester by a Deoxo-fluor-catalyzed cyclization reaction, an inversion of configuration at the β-center (erythro isomer), was observed. A base-induced epimerization reaction led to the D-trans-isomer, which was hydrolyzed to give D-threo-3-hydroxyaspartic acid with excellent stereoselectivity and overall yield. Starting from D-threo-3-hydroxyaspartic acid, L-threo-oxazolines can be stereoselectively synthesized. © 2004 Elsevier Ltd. All rights reserved
An approach to open chain and modified heterocyclic analogues of the acetylcholinesterase inhibitor, huperzine A, through a bicyclo[3.3.1]nonane intermediate
No full textThe use of the bicyclo[3.3.1]nonane derived keto urethane (3) in a general synthesis of open chain and modified heterocyclic analogues of huperzine A was investigated and resulted in the preparation of the dimethylcarbamoyloxy analogue (27). Thiazole annulation by the Gewald procedure gave only the undesired regioisomer (36). © 1994
Polycondensed heterocycles. VI. A new efficient synthesis of 4H-pyrrolo[2,1-c][1,4]benzothiazines
No full textA novel and efficient method to obtain 4H-pyrrolo [2,1-c][1,4] benzothiazine and its 4-alkyl and 4-aryl derivatives via an intramolecular nucleophilic aromatic fluoride displacement has been developed. © 1990, Taylor & Francis Group, LLC. All rights reserved
Polycondensed heterocycles. IV. Synthesis of 1,4-Dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzothiazine
No full textA method for the synthesis of the title compound 3 consisted of an intramolecular cyclization in a stannic chloride catalyzed Friedel‐Crafts reaction of N‐(2‐methylthiophenyl)‐5‐oxoproline chloride 10, prepared by chlorination of the corresponding acid 9 obtained by hydrolysis of its ethyl ester 8. Condensation of 2‐methylthioaniline 4 with diethyl bromomalonate 5 afforded diethyl 2‐methylthioanilinomalonate 6 which gave 8 either directly by reaction with ethyl acrylate or by alkylation with ethyl β‐bromopropionate or ethyl acrylate and cyclization of resulting triethyl 2‐(2‐methylthio)anilino‐2‐carboxyglutarate 7. This method was not convenient because of the poor yield of 3 (14%). On the other hand, cyclization of N‐(2‐mercaptophenyl)‐5‐oxoproline 14 with DCC and DMAP provided 3 in 45% yield. Oxidation with m‐CPBA of the esters 11 and 8, demethylation via the Pummerer rearrangement of the respective sulphoxides 12 and 17 with TFAA and oxidation with iodine of resulting N‐(2‐mercap‐tophenyl)‐5‐oxoproline esters 13 and 18 gave the corresponding disulphides 16 and 19. Hydrolysis of these latter compounds and reduction of the resulting bis[2‐[2‐(hydroxycarbonyl)‐5‐oxo‐1‐pyrrolidinyl]phenyl] disulphide 15 with sodium dithionite afforded the required 14. Deprotection of t‐butyl ester 13 with TFA at 55° to obtain 14 led to 3 in 42% yield. Finally the Pummerer rearrangement of N‐(2‐methylsulphinylphenyl)‐5‐oxo‐proline 20 yielded the mixture of 14 and 15. Copyright © 1990 Journal of Heterocyclic Chemistry
Natural Compounds and Synthetic Drugs to Target FAAH Enzyme
No full textThe fatty acid amide hydrolase (FAAH) executes a unique role in terminating endocannabinoid signaling, and is the major regulator of anadamide catabolism in vivo. Inhibition of FAAH elicits indirect agonism on cannabinoid receptors, and therapeutic efficacy, devoid of psychotropic effects. This supports its relevance as an attractive therapeutic target. Great efforts in the medicinal chemistry, biochemistry, and crystallography fields have synergistically provided pivotal information key to the production of a number of inhibitors, characterized by different structures and mechanisms of action, for attaining FAAH inhibition. As the knowledge about the enzyme structure and functioning grew, in the past two decades, the developed compounds became more specific and structurally different from the natural substrates, thus allowing better selectivity and inhibition potency to be attained. This was pivotal for the identification of leads and druggable compounds to be clinically exploited for the treatment of a number of diseases. The lesson learned by the tragic outcome of the clinical studies with BIA 10-2474 have drawn a clear trajectory for pre-clinical assessment of off-target liabilities, while offering a chance to clearly outline the safety of FAAH as a drug target. A number of natural compounds from mammalian and vegetal sources have been identified so far and have been characterized as FAAH inhibitors and modulators. These compounds may inspire the design of further effective FAAH inhibitors that encompass the enzyme physiological functioning and enzyme trafficking. This issue may offer a new view that considers the crucial events that regulate substrates and compounds accessibility to the FAAH catalytic site and that may affect in vivo efficacy. © The Royal Society of Chemistry 2021
Computer-driven development of an in silico tool for finding selective histone deacetylase 1 inhibitors
Full text linkHistone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R2 = 0.958) and a satisfactory predictive power (Q2 = 0.822; Q2F3 = 0.894). The model was validated (r2ext_ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner–Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity
Discovery of novel hit compounds as potential HDAC1 inhibitors: The case of ligand- and structure-based virtual screening
Full text linkHistone deacetylases (HDACs) as an important family of epigenetic regulatory enzymes are implicated in the onset and progression of carcinomas. As a result, HDAC inhibition has been proven as a compelling strategy for reversing the aberrant epigenetic changes associated with cancer. However, non-selective profile of most developed HDAC inhibitors (HDACIs) leads to the occurrence of various side effects, limiting their clinical utility. This evidence provides a solid ground for ongoing research aimed at identifying isoform-selective inhibitors. Among the isoforms, HDAC1 have particularly gained increased attention as a preferred target for the design of selective HDACIs. Accordingly, in this paper, we have developed a reliable virtual screening process, combining different ligand- and structure–based methods, to identify novel benzamide-based analogs with potential HDAC1 inhibitory activity. For this purpose, a focused library of 736,160 compounds from PubChem database was first compiled based on 80% structural similarity with four known benzamide-based HDAC1 inhibitors, Mocetinostat, Entinostat, Tacedinaline, and Chidamide. Our inclusive in-house 3D-QSAR model, derived from pharmacophore-based alignment, was then employed as a 3D-query to discriminate hits with the highest predicted HDAC1 inhibitory activity. The selected hits were subjected to subsequent structure-based approaches (induced-fit docking (IFD), MM-GBSA calculations and molecular dynamics (MD) simulation) to retrieve potential compounds with the highest binding affinity for HDAC1 active site. Additionally, in silico ADMET properties and PAINS filtration were also considered for selecting an enriched set of the best drug-like molecules. Finally, six top-ranked hit molecules, CID_38265326, CID_56064109, CID_8136932, CID_55802151, CID_133901641 and CID_18150975 were identified to expose the best stability profiles and binding mode in the HDAC1 active site. The IFD and MD results cooperatively confirmed the interactions of the promising selected hits with critical residues within HDAC1 active site. In summary, the presented computational approach can provide a set of guidelines for the further development of improved benzamide-based derivatives targeting HDAC1 isoform
An improved synthetic route to huperzine A; New analogues and their inhibition of acetylcholinesterase
No full textA bicycloannulation approach to huperzine A is detailed together with syntheses of the methylene analogue 8, the diamino compound 12 and their inhibition of acetylcholinesterase
Benzothiazine and Benzothiazepine derivatives: synthesis and preliminary biological evaluation
No full textSeveral tricyclic benzothiazines and benzothiazepines have been synthesized by different intramolecular cyclization reactions. Their functionalization led to biologically active compounds. Some stereochemical aspects as well as biological responses have been outlined
Polycondensed heterocycles. VII. A convenient synthesis of pyrrolo[1,2-a]quinoxaline derivatives by intramolecular aromatic nucleophilic displacement
No full text4-(4-Methyl-1-piperazinyl)-7-trifluoromethylpyrrolo[1,2-a]quinoxaline (CGS 12066B) and related analogs were prepared in good overall yield through a reaction sequence involving as a key step the intramolecular substitution of aromatic fluoride or nitro groups by a carboxamide moiety. © 1991, Taylor & Francis Group, LLC. All rights reserved
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