- 1-(1-Arylethylpiperidin-4-yl)thymine analogs as antimycobacterial TMPK inhibitors
-
A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM).
- Boshoff, Helena I. M.,Caljon, Guy,Forbes, He Eun,Hulpia, Fabian,Jian, Yanlin,Munier-Lehmann, Hélène,Risseeuw, Martijn D. P.,van Calenbergh, Serge
-
-
- COMPOSITIONS AND METHODS FOR SUBSTRATE-SELECTIVE INHIBITION OF ENDOCANNABINOID OXYGENATION
-
Methods for selectively inhibiting endocannabinoid oxygenation but not arachidonic acid oxygenation. In some embodiments, the methods include contacting a COX-2 polypeptide with an effective amount of a substrate-selective COX-2 inhibitor. Also provided are methods for elevating a local endogenous cannabinoid concentrations; methods of reducing depletion of an endogenous cannabinoid; methods for inducing analgesia; methods of providing anxiolytic therapy; methods for providing anti-depressant therapy; and compositions for performing the disclosed methods.
- -
-
Page/Page column 57; 59
(2014/02/15)
-
- Substrate-selective inhibition of cyclooxygenase-2: Development and evaluation of achiral profen probes
-
Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 μM for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.
- Windsor, Matthew A.,Hermanson, Daniel J.,Kingsley, Philip J.,Xu, Shu,Crews, Brenda C.,Ho, Winnie,Keenan, Catherine M.,Banerjee, Surajit,Sharkey, Keith A.,Marnett, Lawrence J.
-
p. 759 - 763
(2012/10/29)
-
- Design, synthesis and evaluation of novel molecules with a diphenyl ether nucleus as potential antitubercular agents
-
A series of compounds with a diphenyl ether nucleus were synthesized by incorporating various amines into the diphenyl ether scaffold with an amide bond. Their antitubercular activities were evaluated against Mycobacterium tuberculosis H37Rv by a microdilution method, with MIC values ranging from 4 to 64 μg/mL. Through structure-activity relationship studies, the two chlorine atoms at 3 and 4 positions in the phenyl ring of R2 group were found to play a significant role in the antitubercular activity. The most potent compound 6c showed an MIC value of 4 μg/mL and a good safety profile in HepG2 cell line by the MTT assay. Compound 6c was further found to be effective in a murine model of BCG infection, providing a good lead for subsequent optimization.
- Yang, Yinghong,Wang, Zhenling,Yang, Jianzhong,Yang, Tao,Pi, Weiyi,Ang, Wei,Lin, Yanni,Liu, Yuanyuan,Li, Zicheng,Luo, Youfu,Wei, Yuquan
-
supporting information; experimental part
p. 954 - 957
(2012/03/11)
-
- Esters and amides of substituted phenyl acetic acids
-
Esters and amides of substituted phenyl acetic acids having the formula wherein Q is a deprotonated residue of a polymer or macromolecular structure having a molecular weight of at least 1000 containing at least two primary and/or secondary amino groups and/or hydroxy groups;, n is an integer of at least 2;, R1 and R2 are independently selected from, hydrogen, halogen, alkyl, alkenyl, alkinyl or halo alkyl;, R3 is one or more substituents selected from halogen, alkyl, alkenyl or alkinyl, cycloalkyl, oxo-substituted alkylcycloalkyl, haloalkyl, alkoxy, alkenyloxy, alkinyloxy, alkylamino, alkenylamino, alkinylamino, alkysulfonyl, alkenylsulfonyl, alkinylsulfonyl, alkylsulfinyl, alkenylsulfinyl, alkinylsulfinyl, alkylsulfenyl, alkenylsulfenyl, alkinylsulfenyl, pyrrolyl, piperidinyl, benzoyl, imidazolpyridinyl, isoindolyl, oxo-substituted isoindolyl, thionylcarbonyl, phenyl, phenoxy and halo-substituted phenoxy, are useful in the treatment of colonic polyps.
- -
-
-
- Convenient Preparation of Arylacetic Acids by Tetracarbonylcobaltate Anion Catalysed Carbonylation
-
Tetracarbonylcobaltate catalyst -, has been prepared in 6 hr by pressure carbonylation of cobalt salt in aq alkaline solution containing cyanide catalyst.Carbonylation of arylchloromethyl derivatives in aq methanolic solutions using this catalyst affords arylacetic acids in good yields.
- Rao, B. Nageswara,Adapa, Srinivas R.,Pardhasaradhi, M.
-
-
- Benzoylphenylacetic acid derivatives with antiinflammatory and analgesic activities
-
Several derivatives of m benzoylphenylacetic acid showed interesting antiinflammatory and analgesic properties associated with good gastric tolerance.
- Allais,Rousseau,Meier,et al.
-
p. 381 - 389
(2007/10/06)
-