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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Lu, Yen-Chu ; Adukure, Ronald D ; Roy, Satyajit ; Chien, Derek L ; McGill, Matthew J ; Polara, Sarthi , et al.
Abstract: Hydrogen atom transfer (HAT) constitutes a powerful mechanism exploited in biology and chemistry to functionalize ubiquitous C(sp3)−H bonds in organic molecules. Despite its synthetic potential, achieving stereocontrol in chemical HAT-mediated C−H functionalization transformations remains challenging. By merging the radical reactivity of thiamine (ThDP)-dependent enzymes with chemical hydrogen atom transfer, we report here a photobiocatalytic strategy for the enantioselective C(sp3)−H acylation of an organic substrate, a transformation not found in nature nor currently attainable by chemical means. This method enables the direct functionalization of benzylic C(sp3)−H sites in a broad range of substrates to furnish valuable enantioenriched ketone motifs with good to high enantioselectivity (up to 96% ee). Mechanistic and spectroscopic studies support the involvement of radical species derived from the Breslow intermediate and C−H substrate, highlight the critical role of the photocatalyst and hydrogen atom abstraction reagents for productive catalysis, and reveal a specific enzyme/photocatalyst interaction favoring single electron transfer during catalysis. Further insights into how the enantioselectivity of the C−C bond-forming reaction is controlled by the enzyme and influenced by active site mutations were gained via molecular modeling. This study illustrates the productive integration of ThDP-mediated biocatalysis with chemical HAT, expanding the range of asymmetric C(sp3)−H functionalization transformations that can be accessed through biocatalysis.
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Design and synthesis of imidazo[1,2-a]pyridine-chalcone conjugates as antikinetoplastid agents
Agarwal, Devesh S. ; Beteck, Richard M. ; Ilbeigi, Kayhan ; Caljon, Guy ; Legoabe, Lesetja J. ;
Abstract: A library of imidazo[1,2-a]pyridine-appended chalcones were synthesized and characterized using 1H NMR,13C NMR and HRMS. The synthesized analogs were screened for their antikinetoplastid activity against Trypanosoma cruzi, Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense and Leishmania infantum. The analogs were also tested for their cytotoxicity activity against human lung fibroblasts and primary mouse macrophages. Among all screened derivatives, (E)-N-(4-(3-(2-chlorophenyl)acryloyl)phenyl)imidazo[1,2-a]pyridine-2-carboxamide was found to be the most active against T. cruzi and T. b. brucei exhibiting IC50 values of 8.5 and 1.35 μM, resp. Against T. b. rhodesiense, (E)-N-(4-(3-(4-bromophenyl)acryloyl)phenyl)imidazo[1,2-a]pyridine-2-carboxamide was found to be the most active with an IC50 value of 1.13 μM. All synthesized active analogs were found to be non-cytotoxic against MRC-5 and PMM with selectivity indexes of up to more than 50.
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Keywords: antikinetoplastid ; chalcone ; drug likeliness properties ; imidazo[1,2-a]pyridine ; neglected tropical diseases (NTDs) ; Trypanosoma brucei brucei ; Trypanosoma brucei rhodesiense
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Cole, Presley C ; Martinez, Briana I ; Shell, Thomas A ;
Abstract: Phenytoin (PHT, brand name: Dilantin) is an anticonvulsant drug that is used in the treatment of epilepsy. PHT is metabolically inactivated by cytochromes P-450 (CYP) catalyzed aromatic hydroxylation at the para position. Therefore, Nelson et al. hypothesized that this metabolic pathway would be slowed or blocked for a PHT derivative with fluorines at the para positions of the aromatic rings (pF-PHT) resulting in a molecule with increased antiseizure activity and longer duration of action relative to PHT. Interestingly, pF-PHT is less active than PHT, but has a much longer duration of action. Nelson et al. hypothesized that differences in physicochemical properties must contribute to the poor activity of pF-PHT. Thus, pF-PHT was synthesized to compare its physicochemical properties with those of PHT. In addition, the kinetics of CYP catalyzed oxidation were compared using Sprague Dawley (SD) rat liver microsomes because PHT is metabolically inactivated by CYP in the liver. The previously reported synthesis of pF-PHT employs a highly toxic reagent and produces a highly poisonous gas. Therefore, a safer synthetic route for pF-PHT was developed. This synthetic approach utilizes three steps: 1) a thiamine catalyzed benzoin condensation of para-fluorobenzaldehyde, 2) a nitric acid oxidation of the benzoin product to the corresponding benzil derivative, and 3) a microwave-assisted phenytoin synthesis of this benzil derivative with urea. There are no significant differences in conjugation, acidity, and lipophilicity between PHT and pF-PHT. Therefore, our results do not support the hypothesis that the low activity of pF-PHT relative to PHT results from variations in physicochemical properties. While PHT and pF-PHT have the same apparent binding affinity for the CYP proteome of the SD rat liver microsome, pF-PHT undergoes CYP catalyzed oxidation at half the rate in comparison to PHT.
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Michael B. Dybek ;
Abstract: Memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist is FDA approved for the treatment of moderate to severe Alzheimer disease. The efficacy is believed to stem from its ability to block/mitigate excitotoxicity that stems from excessive glutamatergic activation/transmission and is thus neuroprotective. However, they display tolerability issues that hinder their ability to be utilized as neuroprotective agents. Previous studies from our lab suggest that the compounds that function as uncompetitive NMDAR antagonists and have moderate affinity to the NMDAR demonstrate the best tolerability. This observation has prompted investigations for novel neuroprotective NMDAR antagonists with improved efficacy and tolerability. Our lead compounds phencyclidine (PCP) and analogs have demonstrated the ability to protect hippocampal neurons from NMDA insult in vitro. Our studies explored synthesizing and evaluating both arylalkylamines and 1,2-diarylethylamines. A total of 76 target compounds were synthesized as part of this exploration. In vitro competitive radio-ligand binding assays were conducted for each compound to determine affinities to NMDAR in rat forebrain homogenate. Several of these compounds demonstrated binding affinities within a previously defined target range (400 nM – 2,100 nM). This range was previously determined to provide the highest tolerability for uncompetitive NMDAR antagonists. 34 compounds were further evaluated to obtain binding affinities on 44 other relevant central nervous system targets. This SAR investigation has uncovered several intriguing polypharmacological profiles have emerged, including potent affinities to NMDAR, dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT).
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Computational and Experimental Studies in Selective Organocatalysis
Corin Wagen ;
Abstract: Chemical synthesis has transformed the ability of scientists and engineers to interact with themolecular world. Yet despite almost two centuries of considerable effort, small-molecule synthesisremains a challenging task. Hundreds ofnew reactions are discovered every year, but few possessthe requisite selectivity and generality needed to be use ful for routine synthesis, and elucidation ofthe ir mechanism and underlying catalytic principles is rarely conducted. In this work, we describea variety of efforts at the interface of organic, computational, and analytical chemistry which seekto address the linked problems of discovering selective organocatalysts and understanding themechanism by which they operate. In Chapter 1, we report the development of a new analytical method that combines chiralstationary phase supercritical fluid chromatography wih mass spectrometry-based detection toenable enantiodetermination of pooled crude reaction mixtures, greatly increasing analyticalthroughput. This advance allows us to perform multi-substrate screening to discover catalystspossessing good substrate scope, which we demonstrate in the optimization of a Bronsted acidcatalyst for the enantioselective Pictet-Spengler reaction.In Chapter 2, we disclose the results of a mechanistic study aimed at understanding a hydrogenchloride/hydrogen-bond donor co-catalyzed Prins cyclization of alkenyl aldehydes whichexhibited dramatic rate acceleration compared to the background reaction. Our studies reveal that the catalyst reacts with hydrogen chloride to form a new chiral acid in siu with a higher pK, thanhydrogen chloride, which nevertheless reacts faster owing to favorable catalyst-controlledpositioning ofthe chloride anion to electrostatically stabilize the major transition state In Chapter 3, we report a computational study of our group's regio- and stereoselectiveglycosylation of` minimally protected glycosyl acceptors. The computational model describedthe first of` hydrogen-bond-donor-catalyzed glycosylation of glycosyl phosphate donors containsfeatures of the transition state previously hypothesized on the basis of experimental results, andlends support to the proposed “4H” binding mechanism. In Chapter 4, we describe the development of an enantioselective protio-semipinacol reactionof unactivated vinylic cyclopropanols. Motivated by the question of how high enantioselectivitycan be achieved in a low-barrier 1,2-rearrangement, we conduct an experimental andcomputational mechanistic investigation and come to the surprising conclusion that protonation toform a formally achiral carbocation in fact exerts stereocontrol over the subsequent rearrangementstep: the rearrangement is so rapid that the carbocation is locked in a given chiral conformationrendering the rearrangement efectively stereospecific. Finally, in chapter 5 we detail a spectroscopic and computational study of solutions ofhydrogen chloride in diethyl ether, aimed at assigning the solution structure ofhydrogen chlorideIn situ IR spectroscopy, combined with density-functional theory and molecular dynamicsprovides evidence for the existence of oxonium ions formed from complete proton transfer todiethyl ether. This observation explains the often-inhibitory effect of diethyl ether on hydrogenchloride-catalyzed reactions and has intriguing implications for catalyst design.
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Kim, Ho Young ; Lee, Ji Youn ; Hsieh, Chia-Ju ; Taylor, Michelle ; Luedtke, Robert R ; Mach, Robert H
Abstract: Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3 receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3 receptor affinities (Ki = 0.8–13.2 nM) with subtype selectivity to the D2 receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50 = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D3 receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3 receptors and TSPO. The results of this study revealed that a new class of selective D3 receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.
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Keywords: D3 receptor antagonists ; metoclopramide ; bitopic ligand ; β-arrestin recruitment assay ; computational chemistry
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Purchased from AmBeed: 5460-29-7 ; 88-13-1 ; 29886-62-2 ; 64951-08-2 ; 55-22-1 ; 1477-50-5 ; 16136-58-6 ; 62563-07-9 ; 5394-18-3 ; 5003-71-4 ; 29886-64-4 ; 105628-63-5 ; 2243-83-6 ; 459-57-4 ; 486-74-8 ; 87227-41-6 ; 105299-45-4 ; 5458-14-0 ; 72517-23-8 ; 38942-51-7
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Nitrothiazole-Thiazolidinone Hybrids: Synthesis and in Vitro Antimicrobial Evaluation
Dylan Hart ; Lesetja J. Legoabe ; Omobolanle J. Jesumoroti ; Audrey Jordaan ; Digby F. Warner ; Rebecca Steventon , et al.
Abstract: Herein we report the synthesis of novel compounds inspired by the antimicrobial activities of nitroazole and thiazolidin-4-one based compounds reported in the literature. Target compounds were investigated in vitro for antitubercular, antibacterial, antifungal, and overt cell toxicity properties. All compounds exhibited potent antitubercular activity. Most compounds exhibited low micromolar activity against S. aureus and C. albicans with no overt cell toxicity against HEK-293 cells nor haemolysis against human red blood cells. Notably, compound 3b exhibited low to sub-micromolar activities against Mtb, MRSA, and C. albicans. 3b showed superior activity (0.25 μg/ml) against MRSA compared to vancomycin (1 μg/ml).
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CAS No. : | 459-57-4 |
Formula : | C7H5FO |
M.W : | 124.11 |
SMILES Code : | O=CC1=CC=C(F)C=C1 |
MDL No. : | MFCD00003378 |
InChI Key : | UOQXIWFBQSVDPP-UHFFFAOYSA-N |
Pubchem ID : | 68023 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H225-H315-H319-H335 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P403+P235 |
Class: | 3 |
UN#: | 1989 |
Packing Group: | Ⅲ |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With piperidine In ethanol at 90℃; Inert atmosphere | General procedure: The appropriate aldehyde (1 equiv) was added to EtOH (3 mL/0.2 mmol) and the mixture was stirred until complete solution. Theoxindole (1 equiv) and piperidine (0.1 equiv) were added, and themixture was heated to 90°C for 3-7 h, and cooled. The resultingprecipitatewas filtered, washed with cold ethanol and dried to givethe pure compound. If necessary, additional recrystallization inethanol was applied to obtain the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With piperidine In ethanol for 3 h; Reflux | General procedure: The preparation of compounds 3-25 was carried out by refluxing oxindole with different aromatic aldehydes in ethanol in the presence of a catalytic amount of piperidine were refluxed for 3 h. After cooling reaction mixture was concentrated at reduced pressure to obtain solid of 3-oxindole derivatives, then washed with 1:1 mixture of hexane-ethyl acetate (25 mL) and dried to afford titles compoundsin good yields (Table 1). Only in two cases (10 and21), both E and Z isomers were obtained, these isomers wereseparated by column chromatography using 1:9 ethyl acetate: hexane as eluent. The structures of synthetic compounds 3-25 were elucidated by 1H NMR and EI MS. Elemental analysis results were also found to be satisfactory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 37 h; Inert atmosphere | 4-Hydroxypiperidine (6.24 g, 0.06 mol),4-Fluorobenzaldehyde (5 g, 0.04 mol)And K2CO3 (8.44 g, 0.06 mol)Was dissolved in dimethylformamide (150 mL)And stirred at 70 & lt; 0 & gt; C for 37 hours under a nitrogen atmosphere,K2CO3 was removed by suction filtration and the dimethylformamide was vaporized.Then, it was dried in a vacuum oven at 80 for 12 hours and then purified by a chromatographic method to obtain 4- (4-hydroxypiperidin-1-yl) benzaldehyde. [Yield = 61percent. |
52% | With sodium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 8 h; | Dimethylformamide (15 mL) was added to 4-fluorobenzaldehyde (1.5 g, 0.012 mol) and sodium carbonate (2.5 g, 0.018 mol). Piperidin-4-ol (1.47 g, 0.015 mol) was slowly added dropwise thereto, followed by stirring for 8 hours at 70 to 80°C. Dichloromethane was added to the reaction solution, and the mixture was washed with an aqueous solution of saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting residue was crystallized with n-hexane to obtain the title compound (1 .5 g, yield: 52percent). 'H-NMR(300 MHZ, DMSO-d6) δ 1 .40 (m, 2H), 1.79 (m, 2H), 3.10 (m, 2H), 3.75 (m, 3H), 4.77 (d, 1H), 7.02 (d, 2H), 7.68 (d, 2H), 9.67 (s, 1 H) |