- Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety
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We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC 1 μg/
- Lv, Kai,Tao, Zeyu,Liu, Qian,Yang, Lu,Wang, Bin,Wu, Shuo,Wang, Apeng,Huang, Menghao,Liu, Mingliang,Lu, Yu
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- Rational design of peptide derivatives for inhibition of MyD88-mediated toll-like receptor signaling in human peripheral blood mononuclear cells and epithelial cells exposed to Francisella tularensis
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Small molecules were developed to attenuate proinflammatory cytokines resulting from activation of MyD88-mediated toll-like receptor (TLR) signaling by Francisella tularensis. Fifty-three tripeptide derivatives were synthesized to mimic a key BB-loop region involved in toll-like/interleukin-1 receptor recognition (TIR) domain interactions. Compounds were tested for inhibition of TNF-α, IFN-γ, IL-6, and IL-1β in human peripheral blood mononuclear cells (PBMCs) and primary human bronchial epithelial cells exposed to LPS extracts from F. tularensis. From 53 compounds synthesized and tested, ten compounds were identified as effective inhibitors of F.?tularensisLPS-induced cytokines. Compound stability testing in the presence of human liver microsomes and human serum resulted in the identification of tripeptide derivative 7 that was a potent, stable, and drug-like small molecule. Target corroboration using a cell-based reporter assay and competition experiments with MyD88 TIR domain protein supported that the effect of 7 was through MyD88 TIR domain interactions. Compound 7 also attenuated proinflammatory cytokines in human peripheral blood mononuclear cells and bronchial epithelial cells challenged with a live vaccine strain of F. tularensis at a multiplicity of infection of 1:5. Small molecules that target TIR domain interactions in MyD88-dependent TLR signaling represent a promising strategy toward host-directed adjunctive therapeutics for inflammation associated with biothreat agent-induced sepsis.
- Ryan, Daniel A.,Degardin, Melissa,Alam, Shahabuddin,Kissner, Teri L.,Hale, Martha,Cameron, Michael D.,Rebek, Mitra,Ajami, Dariush,Saikh, Kamal U.,Rebek, Julius
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p. 1190 - 1205
(2017/10/06)
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- AZAARENE DERIVATIVES
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A compound represented by the general formula: wherein X1 represents a nitrogen atom or a group represented by the formula -CR10=; X2 represents a nitrogen atom or a group represented by the formula -CR11=; Y represents an oxygen atom or the like; R1 represents a C1-6 alkoxy group, an optionally substituted C6-10 aryloxy group, a group represented by the formula -NR12aR12b or the like; R2 represents a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like; R3, R4, R5, R6, R7, R8, R10 and R11 each independently represent a hydrogen atom, a halogen atom, an optionally substituted C1-6 alkyl group, or the like; R9 represents a group represented by the formula -NR16aR16b or the like; and R12a, R12b, R16a and R16b each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, or the like, a salt thereof, or a hydrate of the foregoing.
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Page/Page column 66
(2008/06/13)
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- Synthesis and antihypertensive activity of some new quinazoline derivatives
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A series of substituted 2-piperidino-4-amino-6,7-dimethoxyquinazolines was synthesized and screened as potential antihypertensive agents. The hypotensive effect of all the new compounds was studied after intravenous administrations in urethane-anesthetized normotensive rats. The furoylpiperazine moiety in the prazosin molecule could be replaced by a more stable substituted piperidine group without loss of the blood pressure lowering activity. However, the nature of the substituent profoundly influenced the hypotensive potency as well as the duration of the hypotensive action. Some of the new compounds were found to be as potent as prazosin. On the basis of potency and the duration of the hypotensive action in the anesthetized rats, five of the most promising compounds were selected for further studies. Each of these agents exerted an antihypertensive effect upon oral administrations in conscious spontaneously hypertensive rats. At small doses, the new compounds appeared to be somewhat less potent than prazosin, but at the higher doses of 10-100 μmol/kg, two of them appeared to be even more efficacious antihypertensive agents than prazosin.
- Honkanen,Pippuri,Kairisalo,Nore,Karppanen,Paakkari
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p. 1433 - 1438
(2007/10/02)
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