- Nocarimidazoles C and D, antimicrobial alkanoylimidazoles from a coral-derived actinomycete Kocuria sp.: Application of 1JC,H coupling constants for the unequivocal determination of substituted imidazoles and stereochemical diversity of anteisoalkyl chains in microbial metabolites
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Chemical investigation of secondary metabolites from a marine-derived actinomycete strain of the genus Kocuria, isolated from a stony coral Mycedium sp., led to the identification of two new alkanoylimidazoles, nocarimidazoles C (1) and D (2) as well as three known congeners, nocarimidazoles A (3) and B (4) and bulbimidazole A (5). Structure analysis of 1 and 2 by NMR and MS revealed that both are 4-alkanoyl-5-aminoimidazoles with a 6-methyloctanoyl or decanoyl chain, respectively. Two possible positions of the amino group on the imidazole rings (C-2 and C-5) posed a challenge in the structure study, which was settled by the measurement of 1JC,H coupling constants for comparison with those of synthetically prepared model imidazoles. The absolute configurations of the anteisoalkanoyl group present in 1, 4, and 5 were determined by low-temperature HPLC analysis of the degradation products labeled with a chiral anthracene reagent, which revealed that 1 is a mixture of the R- and S-enantiomers with a ratio of 73:27, 4 is the pure (S)-enantiomer, and 5 is the (S)-enantiomer with 98% ee. The present study illustrates the diversity in the stereochemistry of anteiso branching in bacterial metabolites. Compounds 1-4 were moderately antimicrobial against Gram-positive bacteria and fungi, with MIC ranges of 6.25-25 μg/mL.
- Akasaka, Kazuaki,Harunari, Enjuro,Igarashi, Yasuhiro,Karim, Rokon Ul,Oku, Naoya,Sharma, Amit Raj,Sibero, Mada Triandala,Urabe, Daisuke
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- Discovery and Characterization of Selective and Ligand-Efficient DYRK Inhibitors
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Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-b]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound 11 exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of 11 in an in vivo setting. These pyrazolo[1,5-b]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.
- Ashall-Kelly, Alexander,Bennett, James,Elkins, Jonathan M.,Fedorov, Oleg,Godoi, Paulo H.,Hanley, Marcus T.,Henderson, Scott H.,Hopkins Navratilova, Iva,Robinson, Sean,Ruela De Sousa, Roberta,Sorrell, Fiona,Walter, Daryl S.,Ward, Simon E.
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supporting information
p. 11709 - 11728
(2021/08/24)
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- Therapeutic compounds
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The invention provides a compound of formula I: or a salt thereof, wherein R2-R4 and p have any of the values described in the specification, as well as compositions comprising a compound of formula I. The compounds are useful as ant
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Page/Page column 25; 26
(2021/01/17)
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- 2,4-Disubstituted thiazolyl derivatives
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This invention concerns the use of a compound of formula (I′) a N-oxide, pharmaceutically acceptable addition salt, quaternary amine and stereochemically isomeric form thereof, wherein Q is optionally substituted C3-6cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzthiazolyl, benzoxazolyl, benzimidazolyl, indazolyl, or imidazopyridyl; or Q is a radical of formula wherein X and Y each independently are O, NR3, CH2 or S, with R3 being hydrogen or C1-4alkyl; q is 1 to 4; Z is O or NR4 with R4 being hydrogen or C1-4alkyl; r is 1 to 3; L is optionally substituted phenyl or L is Het with Het being an optionally substituted five- or six-membered heterocyclic ring or an optionally substituted bicyclic heterocyclic ring; for the manufacture of a medicament for the prevention or the treatment of diseases mediated through cytokines.
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