- Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design
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Current treatment of toxoplasmosis targets the parasite’s folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC50 2-fold selectivity favoring Toxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach.
- Welsch, Matthew E.,Zhou, Jian,Gao, Yueqiang,Yan, Yunqing,Porter, Gene,Agnihotri, Gautam,Li, Yingjie,Lu, Henry,Chen, Zhongguo,Thomas, Stephen B.
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- Functionalizations of aryl C-H bonds in 2-arylpyridines via sequential borylation and copper catalysis
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Selective functionalizations of aryl C-H bonds in 2-arylpyridines have been developed via sequential borylation and aerobic oxidative copper catalysis, and the corresponding aryl halides, sulfones, azides and arylamines were obtained in good yields. The protocol uses cheap and readily available boron tribromide (BBr3) as the borylating reagent, and inorganic salts (potassium iodide, ammonium bromide, sodium alkylsulfinates, sodium azide) as the functional group sources. This method makes functionalizations of aryl C-H bonds easy. Copyright
- Niu, Liting,Yang, Haijun,Yang, Daoshan,Fu, Hua
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supporting information
p. 2211 - 2217
(2012/11/07)
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- Synthesis and antiarrhythmic activity of disubstituted phenylpyridine derivative
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A series of disubstituted phenylpyridine derivatives was synthesized and their antiarrhythmic effects against chloroform-induced ventricular arrhythmias in mice were examined. Among them, 2- and 3-[2-(3- aminobutyramido)-4-(2,2,2-trifluoroethoxy)phenyl]pyridines (23h, 24h) and 3- [2-(3-aminobutyramido)-4-ethoxyphenyl]pyridine (24i) showed potent antiarrhythmic activity. They had approximately twice the potency of mexiletine (III). Compound 24i was selected from this series as a candidate for further development; it was found to have a class I B electrophysiological character and to show a slow kinetic rate-dependent block (RDB) of the sodium channel in cardiac muscle.
- Shigyo,Sato,Shibuya,Takahashi,Yamaguchi,Sonoki,Ohta
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p. 1573 - 1582
(2007/10/02)
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- Synthesis of the New Pyridobenzo-v-triazinium System via Valence Bond Isomerization
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α-Pyridylphenyl diazonium salts 2 were found to undergo valence bond isomerization and gave the new pyridobenzo-v-triazinium salts 3.The ir and nmr studies on the products showed that isomers 2 and 3 form an equilibrium, and the ring closure is favoured by electron withdrawing substituents.
- Messmer, A.,Hajos, Gy.,Giber, J.,Holly, S.
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p. 1133 - 1135
(2007/10/02)
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