Next Article in Journal
Next Article in Special Issue
Previous Article in Journal
Previous Article in Special Issue
Molecules 2009, 14(1), 494-508; doi:10.3390/molecules14010494
Article

2-Amido-3-(1H-Indol-3-yl)-N-Substitued-Propanamides as a New Class of Falcipain-2 Inhibitors. 1. Design, Synthesis, Biological Evaluation and Binding Model Studies

1
, 1
, 2
, 1
, 1
, 1,* , 1,* , 1,*  and 1,2
Received: 7 December 2008; in revised form: 11 January 2009 / Accepted: 13 January 2009 / Published: 21 January 2009
Download PDF [420 KB, uploaded 18 June 2014]
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 IC50 values of 10.0-39.4 μM, and the inhibitory activityof compound 2k was ~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.
Keywords: 3-(1H-Indol-3-yl)-propanamide derivatives; Falcipain-2 inhibitor; Malaria; SAR 3-(1H-Indol-3-yl)-propanamide derivatives; Falcipain-2 inhibitor; Malaria; SAR
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Export to BibTeX |
EndNote


MDPI and ACS Style

Zhu, J.; Chen, T.; Chen, L.; Lu, W.; Che, P.; Huang, J.; Li, H.; Li, J.; Jiang, H. 2-Amido-3-(1H-Indol-3-yl)-N-Substitued-Propanamides as a New Class of Falcipain-2 Inhibitors. 1. Design, Synthesis, Biological Evaluation and Binding Model Studies. Molecules 2009, 14, 494-508.

AMA Style

Zhu J, Chen T, Chen L, Lu W, Che P, Huang J, Li H, Li J, Jiang H. 2-Amido-3-(1H-Indol-3-yl)-N-Substitued-Propanamides as a New Class of Falcipain-2 Inhibitors. 1. Design, Synthesis, Biological Evaluation and Binding Model Studies. Molecules. 2009; 14(1):494-508.

Chicago/Turabian Style

Zhu, Jin; Chen, Tong; Chen, Lili; Lu, Weiqiang; Che, Peng; Huang, Jin; Li, Honglin; Li, Jian; Jiang, Hualiang. 2009. "2-Amido-3-(1H-Indol-3-yl)-N-Substitued-Propanamides as a New Class of Falcipain-2 Inhibitors. 1. Design, Synthesis, Biological Evaluation and Binding Model Studies." Molecules 14, no. 1: 494-508.


Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert