- Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure-Activity Relationship, Metabolism, and Biology Triaging
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Screening of a library of small polar molecules against Mycobacterium tuberculosis (Mtb) led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated in vivo for pharmacokinetic properties. Mtb-mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.
- Van Der Westhuyzen, Renier,Mabhula, Amanda,Njaria, Paul M.,Müller, Rudolf,Ngumbu Muhunga, Denis,Taylor, Dale,Lawrence, Nina,Njoroge, Mathew,Brunschwig, Christel,Moosa, Atica,Singh, Vinayak,Rao, Srinivasa P.S.,Manjunatha, Ujjini H.,Smith, Paul W.,Warner, Digby F.,Street, Leslie J.,Chibale, Kelly
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supporting information
p. 9444 - 9457
(2021/07/19)
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- Multinucleated late transient metal olefin polymerization catalyst
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The invention relates to a bimetallic olefin polymerization catalyst, a preparation method thereof, and an application thereof in olefin polymerization catalysis. The catalyst is group VIII transition bimetal complexes with polydentate ligand, and the structural formula of the catalyst is represented by formula I; and all groups in the formula are defined in the description. The catalyst has high activity and catalysis efficiency, is suitable for olefin polymerization reactions, and is especially suitable for preparing olefin polymers with doublet distributed molecular weights.
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Paragraph 0389; 0390; 0391; 0392
(2016/10/08)
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- Synthesis of heteroarenecarbonitriles by electrophilic cyanation; Reaction of metalated heteroarenes with p-toluenesulfonyl cyanide
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Several heteroarenecarbonitriles (5) were synthesized in moderate yields from heteroarenes (3) through metalation, followed by electrophilic cyanation using p-toluenesulfonyl cyanide. Similarly, trimethylsilylheteroarenes (8) were converted to heteroarenecarbonitriles (5) in good yields by treatment with p-toluenesulfonyl cyanide.
- Nagasaki, Izuru,Suzuki, Yumiko,Iwamoto, Ken-Ichi,Higashino, Takeo,Miyashita, Akira
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p. 443 - 450
(2007/10/03)
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- A simple synthesis of new carbinols from bis(2-benzothiazolyl) ketone
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The addition reactions of Grignard reagents to the keto group of bis(2-benzothiazolyl) ketone afford bis(2-benzothiazolyl)alkyl, allyl and alkynyl carbinols in high yields without other side reactions, such as carbonyl group reduction and addition of the
- Boga, Carla,Forlani, Luciano,Todesco, Paolo E.
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p. 197 - 200
(2007/10/03)
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- Diheteroarylmethanes. IV. Oxidations and Metal-promoted Coupling Reactions of Bis(benzoheteroaryl)methanes
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Bis(2-benzothiazolyl)methane, 1, bis(benzoxazolyl)methane, 2, and bis(N-methyl-2-benzimidazolyl)methane, 3, undergo easy oxidation by common oxidizing agents (air, KMnO4, K2Cr2O7, CrO3, H2O2) and give rise to a variety of products showing different levels of oxidation.They range from hydroxylation of the bridge methylene, e.g. in 25, to formation of the corresponding ketone, e. g. in 19, to dimerization to ethane and/or ethene derivatives as 23-24 and 20-22, respectively.The output of the oxidations is strongly dependent upon the nature of the second heteroatom in the azole ring (sulfur, oxygen or nitrogen), the oxidant, and the reaction conditions.Also the treatment of compounds 1 and 2 with the acetates of poorly azaphilic transition-metal ions promotes the dimerization couplings to the ethane or ethene products instead of leading to the formation of neutral chelates MetL2.Hydroxylation at the bridge methine in derivetives of 1 substituted at this position with a functionalized benzylic residue may result particularly easy, being simply accomplished by exposure to air.Although no mechanistic studies have been carried out on these reactions, it appears likely that a carbanionic or an enaminic intermediate is responsible for the air- and metal-promoted oxidations and oxidative couplings.
- Bradamante, Silvia,Facchetti, Antonio,Pagani, Giorgio A.
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p. 329 - 338
(2007/10/03)
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- DIHETEROARYLMETHANES. II. ACTIVE METHYLENE BEHAVIOUR OF 2-THIAZOLYL AND 2-OXAZOLYL DERIVATIVES
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The methylene group of bis(2-benzothiazolyl)methane (bbtmH), 1, bis(2-benzoxazolyl)methane (bbomH), 2, and bismethane, 3, undergoes azo-coupling with benzenediazonium chloride to the corresponding phenylhydrazono derivatives, nitrosation with nitrous acid to the corresponding oximes, and crotonic-type condensation with alkyl, aryl, and heteroaryl aldehydes.In the condensation of bbomH, 2, with salicylaldehyde, one of the benzoxazole moieties undergoes ring opening and the final product is a coumarin derivative.The methylene group of 1 and 3 is also sensitive to oxidation by air in alkaline solution leading to the corresponding carbonyl compounds 15 and 17.The analogous reaction carried out on bbomH was found to be sluggish.The behaviour of these diheteroarylmethanes thus conforms with the one typically exhibited by "active" methylene compounds, substituted by efficient electron-withdrawing groups.
- Abbotto, Alessandro,Bradamante, Silvia,Pagani, Giorgio A.
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p. 301 - 308
(2007/10/02)
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- PHOTO-OXIDATION OF SOME DI-2-BENZOTHIAZOLYLMETHANE DERIVATIVES
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We report the photo-oxidation of some di-2-benzothiazolylmethane derivatives and discuss the structure of the isolated methanols and ketones.
- Ramos, M. Teresa,Avendano, Carmen,Elguero, Jose,Jimeno, M. Luisa
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p. 497 - 502
(2007/10/02)
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- Differing Reactivities and Products in the Reaction of Some N-Methylimidazol-2-yl, Oxazol-2-yl and Thiazol-2-ylsilanes and -stannanes with Acid Chlorides
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Some new N-methylimidazoles, oxazoles and thiazoles (compounds 7-15) with a keto-function in the 2-position have been synthesized by the reaction of heterocyclic substituted silanes and stannanes with the corresponding acyl chlorides.In cases where the si
- Jutzi, Peter,Gilge, Ullrich
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p. 1011 - 1014
(2007/10/02)
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