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Molecules 2009, 14(1), 494-508; doi:10.3390/molecules14010494

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

School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, P.R. China
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.
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)
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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 (CC BY 3.0).

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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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