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Open AccessArticle

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
School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, P.R. China
2
Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, P.R. China
*
Authors to whom correspondence should be addressed.
Molecules 2009, 14(1), 494-508; https://doi.org/10.3390/molecules14010494
Received: 7 December 2008 / Revised: 11 January 2009 / Accepted: 13 January 2009 / Published: 21 January 2009
(This article belongs to the Special Issue Neglected Diseases: Medicinal Chemistry and Natural Product Chemistry)
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. View Full-Text
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
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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.

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