- Synthesis and antileishmanial evaluation of thiazole orange analogs
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Cyanine compounds have previously shown excellent in vitro and promising in vivo antileishmanial efficacy, but the potential toxicity of these agents is a concern. A series of 22 analogs of thiazole orange ((Z)-1-methyl-4-((3-methylbenzo[d]thiazol-2(3H)-ylidene)methyl)quinolin-1-ium salt), a commercial cyanine dye with antileishmanial activity, were synthesized in an effort to increase the selectivity of such compounds while maintaining efficacy. Cyanines possessing substitutions on the quinolinium ring system displayed potency against Leishmania donovani axenic amastigotes that differed little from the parent compound (IC50 12–42 nM), while ring disjunction analogs were both less potent and less toxic. Changes in DNA melting temperature were modest when synthetic oligonucleotides were incubated with selected analogs (ΔTm ≤ 5 °C), with ring disjunction analogs showing the least effect on this parameter. Despite the high antileishmanial potency of the target compounds, their toxicity and relatively flat SAR suggests that further information regarding the target(s) of these molecules is needed to aid their development as antileishmanials.
- Abdelhameed, Ahmed,Liao, Xiaoping,McElroy, Craig A.,Joice, April C.,Rakotondraibe, Liva,Li, Junan,Slebodnick, Carla,Guo, Pu,Wilson, W. David,Werbovetz, Karl A.
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supporting information
(2019/11/28)
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- Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors
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Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-amino
- Cinelli, Maris A.,Li, Huiying,Chreifi, Georges,Poulos, Thomas L.,Silverman, Richard B.
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p. 3958 - 3978
(2017/05/19)
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- Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors
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Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low
- Pensa, Anthony V.,Cinelli, Maris A.,Li, Huiying,Chreifi, Georges,Mukherjee, Paramita,Roman, Linda J.,Martásek, Pavel,Poulos, Thomas L.,Silverman, Richard B.
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p. 7146 - 7165
(2017/09/07)
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- NOVEL CYCLIC COMPOUND HAVING QUINOLYLALKYLTHIO GROUP
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The present invention relates to a synthesis study of novel cyclic compounds having a quinolylalkylthio group represented by the formula (1), and pharmacological actions of the compounds. In the formula, the ring X represents: which may have halogen and/or alkyl; R1 and R2 independently represent hydrogen, alkyl, cycloalkyl, aryl or a (non) aromatic heterocycle; R3 represents qinolyl; A represents sulfur, sulfinyl or sulfonyl; and B represents alkylene.
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Page/Page column 13-14
(2010/11/28)
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- MIXED LINEAGE KINASE MODULATORS
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The present invention provides a compound of the formula: (Formula I); or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising an effective amount of a compound of Formula I in combination with a suitable carrier, diluent, or excipient, and methods for treating physiological disorders, particularly congestive heart disease, comprising administering to a patient in thereof an effective amount of a compound of Formula I.
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