- Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin
-
Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.
- Hidaka, Koushi,Kimura, Tooru,Ruben, Adam J.,Uemura, Tsuyoshi,Kamiya, Mami,Kiso, Aiko,Okamoto, Tetsuya,Tsuchiya, Yumi,Hayashi, Yoshio,Freire, Ernesto,Kiso, Yoshiaki
-
scheme or table
p. 10049 - 10060
(2009/04/07)
-
- 1,4-Benzodioxin-2(3H)-one and Some of its Derivatives
-
The methods of synthesis of 1,4-benzodioxin-2(3H)-one have been reexamined.Frequently quoted in the literature the method of Ghosh has been found to give impure (2-hydroxyphenoxy)acetic acid rather than the lactone.Using various methods some simple derivatives of the title lactone substituted in the benzene ring have been prepared and characterized.The bromination of the lactone with NBS gives predominantly 7-bromo-1,4-benzodioxin-2(3H)-one under electrophilic conditions, while 6-bromo-1,4-benzodioxin-2(3H)-one is obtained as a major isomer under photolytic conditions.
- Sampson, Peter,Crook, Michelle,Piorko, Adam
-
p. 1011 - 1016
(2007/10/02)
-
