- Tetraoxane-pyrimidine nitrile hybrids as dual stage antimalarials
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The use of artemisinin or other endoperoxides in combination with other drugs is a strategy to prevent development of resistant strains of Plasmodium parasites. Our previous work demonstrated that hybrid compounds, comprising endoperoxides and vinyl sulfones, were capable of high activity profiles comparable to artemisinin and chloroquine while acting through two distinct mechanisms of action: oxidative stress and falcipain inhibition. In this study, we adapted this approach to a novel class of falcipain inhibitors: peptidomimetic pyrimidine nitriles. Pyrimidine tetraoxane hybrids displayed potent nanomolar activity against three strains of Plasmodium falciparum and falcipain-2, combined with low cytotoxicity. In vivo, a decrease in parasitemia and an increase in survival of mice infected with Plasmodium berghei was observed when compared to control. All tested compounds combined good blood stage activity with significant effects on liver stage parasitemia, a most welcome feature for any new class of antimalarial drug.
- Oliveira, Rudi,Guedes, Rita C.,Meireles, Patrícia,Albuquerque, Inês S.,Gon?alves, Lídia M.,Pires, Elisabete,Bronze, Maria Rosário,Gut, Jiri,Rosenthal, Philip J.,Prudêncio, Miguel,Moreira, Rui,O'Neill, Paul M.,Lopes, Francisca
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Read Online
- Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators
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The present study describes the discovery and characterization of a series of 5-aryl-2H-tetrazol-3-ylacetamides as G protein-gated inwardly-rectifying potassium (GIRK) channels activators. Working from an initial hit discovered during a high-throughput screening campaign, we identified a tetrazole scaffold that shifts away from the previously reported urea-based scaffolds while remaining effective GIRK1/2 channel activators. In addition, we evaluated the compounds in Tier 1 DMPK assays and have identified a (3-methyl-1H-pyrazol-1-yl)tetrahydrothiophene-1,1-dioxide head group that imparts interesting and unexpected microsomal stability compared to previously-reported pyrazole head groups.
- Sharma, Swagat,Kozek, Krystian A.,Abney, Kristopher K.,Kumar, Sushil,Gautam, Nagsen,Alnouti, Yazen,David Weaver,Hopkins, Corey R.
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p. 791 - 796
(2019/02/06)
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- Synthesis of Hydrazines via Radical Generation and Addition of Azocarboxylic tert -Butyl Esters
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A new chemistry of azo compounds that is a radical generation and addition in situ of azocarboxylic tert-butyl esters to synthesize hydrazines has been described. The protocol provides a novel strategy for the synthesis of various hydrazines. The advantag
- Ru, Chen-Hao,Guo, Shi-Huan,Pan, Gao-Fei,Zhu, Xue-Qing,Gao, Ya-Ru,Wang, Yong-Qiang
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supporting information
p. 1910 - 1913
(2018/04/16)
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- PYRAZOLOPYRIMIDINES AS INHIBITORS OF GLUCOCORTICOID RECEPTOR TRANSLOCATION
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Provided herein are compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of Glucocorticoid Receptor (GR) translocation. Furthermore, the subject compounds and compositions are useful for the treatment of diseases involved in the hypothalamic-pituitary-adrenal (HPA) axis.
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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The invention provides novel poly-substituted 5-membered heterocyclic compounds represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, metabolites, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as selective irreversible bruton's tyrosine kinase (Btk) inhibitors and is further useful to treat inflammatory, auto immune diseases associated with aberrant B-cell proliferation such as RA (rheumatoid arthritis) and cancers. This invention also provided the preparation of a medicament using of Formula (IV), and methods of preventing or treating diseases associated with excessive Btk activity in mammals, especially humans. Formula (IV)
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- TRIAZOLONE COMPOUNDS AS mPGES-1 INHIBITORS
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The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as mPGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.
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Page/Page column 64; 119; 126
(2014/01/08)
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- Discovery of ectoparasiticidal hydrazonotrifluoromethanesulfonanilides
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A series of hydrazonotrifluorosulfonanilide derivatives were synthesized and evaluated for in vitro activity against the ectoparasites Ctenocephalides felis and Rhipicephalus sanguineus. Some compounds with excellent activity against tick were identified.
- Ali, Abdelselam,Fisara, Petr,Freemont, Jamie A.,Kyi, Stella,Meyer, Adam G.,Riches, Andrew G.,Sargent, Roger M.,Sawutz, David G.,Turner, Kathleen A.,Winzenberg, Kevin N.,Yang, Qi
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scheme or table
p. 649 - 652
(2010/06/12)
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- PURINES AS CYSTEINE PROTEASE INHIBITORS
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Substituted heteroaryl nitrile derivatives of Formula I, processes for their preparation, pharmaceutical compositions comprising such compounds and use of the compounds as cysteine protease inhibitors are provided.
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Page/Page column 41
(2008/12/07)
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- Hydrazinopyrimidines as cysteine protease inhibitors
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Substituted heteroaryl nitrile derivatives of Formula I, processes for their preparation, pharmaceutical compositions comprising such compounds and use of the compounds as cysteine protease inhibitors are provided.
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Page/Page column 25
(2008/12/04)
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- Oxaziridine-mediated amination of primary amines: Scope and application to a one-pot pyrazole synthesis
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(Chemical Equation Presented) Electrophilic amination of primary aliphatic and aromatic amines is reported using a diethylketomalonate-derived oxaziridine to afford the corresponding N-Boc hydrazines in good to excellent yields. The method allows a one-pot synthesis of pyrazoles from primary amines.
- Armstrong, Alan,Jones, Lyn H.,Knight, Jamie D.,Kelsey, Richard D.
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p. 713 - 716
(2007/10/03)
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- FUSED HETEROCYCLIC COMPOUNDS
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Certain fused pyrrole- and pyrazole-containing heterocyclic compounds are serotonin modulators useful in the treatment of serotonin-mediated diseases.
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Page/Page column 150
(2008/06/13)
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- Novel compounds and therapeutic uses thereof
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The invention discloses a novel series of compound represented by general formula (I), its derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, solvates wherein X, n, k, z, R1, R2, R3, R4, R5 and R6 are as defined in the specification that are useful in (i) normalizing elevated blood glucose levels in diabetes, (ii) treating disorders related to glucose intolerance and (iii) for scavenging free radicals of mammals. The invention also discloses pharmaceutically acceptable composition comprising these compounds, method for preparation of the compounds as defined above and method of treating mamnnals including human beings by administering an effective amount of said compounds to a subject in need thereof. The invention further discloses use of these compounds in the manufacture of a medicament useful for treatment of different disease conditions as stated above.
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- Novel compounds and therapeutic uses thereof
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The invention discloses a novel series of compound represented by general formula (I), its derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, solvates wherein X, n, k, z, R1, R2, R3, R4, R5 and R6 are as defined in the specification that are useful in (i) normalizing elevated blood glucose levels in diabetes, (ii) treating disorders related to glucose intolerance and (iii) for scavenging free radicals of mammals. The invention also discloses pharmaceutically acceptable composition comprising these compounds, method for preparation of the compounds as defined above and method of treating mammals including human beings by administering an effective amount of said compounds to a subject in need thereof. The invention further discloses use of these compounds in the manufacture of a medicament useful for treatment of different disease conditions as stated above.
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- Development and scale up of a route to cyclohexylhydrazine dimethanesulfonate
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A mild, high-yielding synthesis of cyclohexylhydrazine dimethane-sulfonate has been developed that is suitable for further scale up. The process consists of three chemical steps: condensation of cyclohexanone with tert-butyl carbazate, reduction of the hy
- Connolly, Terrence J.,Crittall, Andrew J.,Ebrahim, Alkarim S.,Ji, Guijun
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p. 526 - 529
(2013/08/07)
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- Alpha-substituted pyridazino quinoline compounds
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The invention relates to alpha-substituted pyridazino-quinoline compounds of the formula I: STR1 wherein Ring A is chosen from an ortho fused aromatic or heteroaromatic five- or six-membered ring; R1 is selected from a variety of substituents i
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