1531-18-6Relevant articles and documents
Rational Design of Novel Highly Potent and Selective Phosphatidylinositol 4-Kinase IIIβ (PI4KB) Inhibitors as Broad-Spectrum Antiviral Agents and Tools for Chemical Biology
Mejdrová, Ivana,Chalupská, Dominika,Pla?ková, Pavla,Müller, Christin,?ála, Michal,Klíma, Martin,Baumlová, Adriana,H?ebabecky, Hubert,Procházková, Eli?ka,Dejmek, Milan,Strunin, Dmytro,Weber, Jan,Lee, Gary,Matou?ová, Marika,Mertlíková-Kaiserová, Helena,Ziebuhr, John,Birkus, Gabriel,Boura, Evzen,Nencka, Radim
, p. 100 - 118 (2017)
Phosphatidylinositol 4-kinase IIIβ (PI4KB) is indispensable for the replication of various positive-sense single stranded RNA viruses, which hijack this cellular enzyme to remodel intracellular membranes of infected cells to set up the functional replication machinery. Therefore, the inhibition of this PI4K isoform leads to the arrest of viral replication. Here, we report on the synthesis of novel PI4KB inhibitors, which were rationally designed based on two distinct structural types of inhibitors that bind in the ATP binding side of PI4KB. These “hybrids” not only excel in outstanding inhibitory activity but also show high selectivity to PI4KB compared to other kinases. Thus, these compounds exert selective nanomolar or even subnanomolar activity against PI4KB as well as profound antiviral effect against hepatitis C virus, human rhinovirus, and coxsackievirus B3. Our crystallographic analysis unveiled the exact position of the side chains and explains their extensive contribution to the inhibitory activity.
Ethionamide biomimetic activation and an unprecedented mechanism for its conversion into active and non-active metabolites
Laborde, Julie,Deraeve, Céline,Duhayon, Carine,Pratviel, Geneviève,Bernardes-Génisson, Vania
, p. 8848 - 8858 (2016)
Ethionamide (ETH), a second-line anti-tubercular drug that is regaining a lot of interest due to the increasing cases of drug-resistant tuberculosis, is a pro-drug that requires an enzymatic activation step to become active and to exert its therapeutic effect. The enzyme responsible for ETH bioactivation in Mycobacterium tuberculosis is a monooxygenase (EthA) that uses flavin adenine dinucleotide (FAD) as a cofactor and is NADPH- and O2-dependant to exert its catalytic activity. In this work, we investigated the activation of ETH by various oxygen-donor oxidants and the first biomimetic ETH activation methods were developed (KHSO5, H2O2, and m-CPBA). These simple oxidative systems, in the presence of ETH and NAD+, allowed the production of short-lived radical species and the first non-enzymatic formation of active and non-active ETH metabolites. The intermediates and the final compounds of the activation pathway were well characterized. Based on these results, we postulated a consistent mechanism for ETH activation, not involving sulfinic acid as a precursor of the iminoyl radical, as proposed so far, but putting forward a novel reactivity for the S-oxide ethionamide intermediate. We proposed that ETH is first oxidized into S-oxide ethionamide, which then behaves as a ketene-like compound via a formal [2 + 2] cycloaddition reaction with peroxide to give a dioxetane intermediate. This unstable 4-membered intermediate in equilibrium with its open tautomeric form decomposes through different pathways, which would explain the formation of the iminoyl radical and also that of different metabolites observed for ETH oxidation, including the ETH-NAD active adduct. The elucidation of this unprecedented ETH activation mechanism was supported by the application of isotopic labelling experiments.
SUBSTITUTION OF ALKYL AND HYDROXYALKYL GROUP FOR RING HYDROGEN AND OF HYDROXYALKYL GROUP FOR CYANO GROUP IN GAMMA-IRRADIATION OF PYRIDINECARBONITRILES IN ALCOHOL
Sugimori, Akira,Mori, Shoji,Maeda, Kazuo,Nishijima, Masayuki
, p. 769 - 772 (1984)
Gamma-irradiation of pyridinecarbonitriles in alcohol in the presence of sulfuric acid brings about the substitution of the alkyl group derived from alcohol for,the ring hydrogen, while that in the absence of sulfuric acid causes the substitution of hydroxyalkyl group for CN at the 2- and 4-positions.Hydroxyalkyl radicals and solvated electrons play important role in the substitution.
Use of PyBOP as a convenient activator for the synthesis of nitriles from primary amides
Bose,Narsaiah
, p. 373 - 375 (2001)
Various types of primary carboxamides were reacted with benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) and N-ethyldiisopropylamine to obtain the corresponding nitriles in high yields.
Preparation method of 2-ethyl-4-cyanopyridine
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Paragraph 0017; 0024; 0026; 0028; 0031-0032, (2021/01/20)
The invention provides a preparation method of 2-ethyl-4-cyanopyridine. According to the preparation method, 1-(4-bromopyridin-2-yl)ethanone is used as an initial raw material, 2-ethyl-4-bromopyridineis prepared through reduction of a catalyst and a reducing agent, and 2-ethyl-4-cyanopyridine is obtained through cyanation. The total yield is 85% or more, and the product purity is 99% or more. Theroute is simple and convenient, auxiliary materials are common compounds, and the solvent can be recycled. The product is a single compound. Compared with a traditional synthesis method, the synthesis method has the advantages that isomer 3-ethyl-4-cyanopyridine is not generated, and the requirement for post-treatment of synthesis of ethylthio isonicotinamide is low. The synthetic route is safe,simple and convenient to operate, environment-friendly, capable of relaxing the bowels and suitable for industrial production.
Metal-free dehydrosulfurization of thioamides to nitriles under visible light
Xu, Tianxiao,Cao, Tianpeng,Feng, Qingyuan,Huang, Shenlin,Liao, Saihu
supporting information, p. 5151 - 5153 (2020/05/26)
A visible light-mediated, metal-free dehydrosulfurization reaction of thioamides to nitriles is described. This reaction features high yields, mild reaction conditions, and the use of a cheap organic dye as the photoredox catalyst and air as the oxidant.
Diarylthiazole: An antimycobacterial scaffold potentially targeting PrrB-PrrA two-component system
Bellale, Eknath,Naik, Maruti,Vb, Varun,Ambady, Anisha,Narayan, Ashwini,Ravishankar, Sudha,Ramachandran, Vasanthi,Kaur, Parvinder,McLaughlin, Robert,Whiteaker, James,Morayya, Sapna,Guptha, Supreeth,Sharma, Sreevalli,Raichurkar, Anandkumar,Awasthy, Disha,Achar, Vijayshree,Vachaspati, Prakash,Bandodkar, Balachandra,Panda, Manoranjan,Chatterji, Monalisa
supporting information, p. 6572 - 6582 (2014/10/15)
Diarylthiazole (DAT), a hit from diversity screening, was found to have potent antimycobacterial activity against Mycobacterium tuberculosis (Mtb). In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to optimize the potency and physicochemical properties. The effort led to more than 10 compounds with submicromolar MICs and desirable physicochemical properties. The potent antimycobacterial activity, in conjunction with low molecular weight, made the series an attractive lead (antibacterial ligand efficiency (ALE) >0.4). The series exhibited excellent bactericidal activity and was active against drug-sensitive and resistant Mtb. Mutational analysis showed that mutations in prrB impart resistance to DAT compounds but not to reference drugs tested. The sensor kinase PrrB belongs to the PrrBA two component system and is potentially the target for DAT. PrrBA is a conserved, essential regulatory mechanism in Mtb and has been shown to have a role in virulence and metabolic adaptation to stress. Hence, DATs provide an opportunity to understand a completely new target system for antimycobacterial drug discovery.
Facile synthesis of nitriles via manganese oxide promoted oxidative dehydrosulfurization of primary thioamides
Yamaguchi, Kazuya,Yajima, Kazuhisa,Mizuno, Noritaka
supporting information, p. 11247 - 11249 (2013/01/15)
In the presence of manganese oxides, dehydrosulfurization of various kinds of primary thioamides including aromatic, heterocyclic, and aliphatic ones efficiently proceeded to give the corresponding nitriles in high yields. The observed catalysis was truly heterogeneous, and manganese oxides could be reused.
One-pot synthesis of nitriles from aldehydes and hydroxylamine hydrochloride over silica gel, montmorillonites K-10, and KSF catalysts in dry media under microwave irradiation
Dewan, Sharwan K.,Singh, Ravinder,Kumar, Anil
, p. 2025 - 2029 (2007/10/03)
A rapid and facile one-pot synthesis of nitriles has been carried out from the corresponding aldehydes and hydroxylamine hydrochloride in the presence of environmentally benign silica gel (84-95%), Mont K-10 (85-96%), and Mont KSF clay (88-98%) catalysts in dry media under microwave irradiation.
An efficient and improved method for the preparation of nitriles from primary amides and aldoximes
Venkat Narsaiah,Nagaiah
, p. 1271 - 1274 (2007/10/03)
The pivaloyl chloride-pyridine system has been utilized as a novel and efficient reagent for the preparation of nitriles from primary amides and aldoximes. The reaction proceeds smoothly under mild reaction conditions and the products are obtained in excellent yields. This method is applicable to a wide range of substrates including aromatic, heterocyclic and aliphatic species. The dehydration takes place at room temperature in the case of primary amides and dichloromethane at reflux temperature is required for rapid conversion in the case of aldoximes.
