title: 2-amido-3-(1H-indol-3-yl)-N-substituted-propanamides as a new class of falcipain-2 inhibitors. 1. Design, synthesis, biological evaluation and binding model studies.
abstract: The Plasmodium falciparum cysteine protease falcipain-2 (FP-2) is an important cysteine protease and an essential hemoglobinase of erythrocytic P. falciparum trophozoites. The discovery of new FP-2 inhibitors is now a hot topic in the search for potential malaria treatments. In this study, a series of novel small molecule FP-2 inhibitors have been designed and synthesized based on three regional optimizations of the lead (R)-2-phenoxycarboxamido-3-(1H-indol-3-yl)-N-benzylpropanamide(1), which was identified using structure-based virtual screening in conjunction with surface plasmon resonance (SPR)-based binding assays. Four compounds--1, 2b, 2k and 2l--showed moderate FP-2 inhibition activity, with IC(50) values of 10.0-39.4 microM, and the inhibitory activity of compound 2k was approximately 3-fold better than that of the prototype compound 1 and may prove useful for the development of micromolar level FP-2 inhibitors. Preliminary SAR data was obtained, while molecular modeling revealed that introduction of H-bond donor or/and acceptor atoms to the phenyl ring moiety in the C region would be likely to produce some additional H-bond interactions, which should consequently enhance molecular bioactivity.
authors.affiliation: School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, PR China. jinzh@mail.ecust.edu.cn
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Tong
authors.initials: T
authors.lastname: Chen
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lu
authors.forename: Peng
authors.initials: P
authors.lastname: Che
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D003546:Cysteine Endopeptidases; C416224:falcipain 2