3区 · 医学
Article
作者: Qin, Limei ; Griggs, David W. ; Oliva, Jonathan ; Goldberg, Daniel E. ; Tu, Zhengchao ; Sverdrup, Francis M. ; Prinsen, Michael J. ; Zeng, Wentian ; Meyers, Marvin J. ; Ding, Ke ; Liu, Xiaorong ; Xu, Wanwan ; Ruminski, Peter G. ; Xu, Jing ; Lu, Yongzhi ; Qin, Li ; Chen, Xiaoping ; Lu, Xiaoyun ; Tortorella, Micky D. ; Jacobsen, E. Jon ; Campbell, Mary A. ; Lu, Xin ; Lang, Xingfen ; Eickhoff, Christopher S. ; He, Zhengxiang ; Wood, David C.
Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure-activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.
