疟原虫天冬氨酸蛋白酶裂殖子表面蛋白酶I和II的逆式-他汀类抑制剂的固相文库合成

Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II.

作者信息

Dahlgren Anders, Kvarnström Ingemar, Vrang Lotta, Hamelink Elizabeth, Hallberg Anders, Rosenquist Asa, Samuelsson Bertil

机构信息

Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.

出版信息

Bioorg Med Chem. 2003 Mar 20;11(6):827-41. doi: 10.1016/s0968-0896(02)00568-0.

DOI:10.1016/s0968-0896(02)00568-0

PMID:12614868

Abstract

With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 microM (K(i) for Plm II=5.4 microM).

摘要

为了开发恶性疟原虫的疟原虫蛋白酶I和II天冬氨酸蛋白酶抑制剂，我们使用溶液相和固相结合化学方法，从新型反向静菌素等排体合成了多组文库。该合成策略在整个开发路线中以良好至高的总收率提供文库化合物，并具有出色的立体化学控制。对产物进行了疟原虫蛋白酶I和II抑制特性评估，发现它们表现出适度但有前景的活性。最佳抑制剂在抑制剂浓度为0.5 microM时，对疟原虫蛋白酶II的体外活性为28%抑制（疟原虫蛋白酶II的K(i)=5.4 microM）。