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 activity of 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.
Highlights
Malaria, which accounts for 300-500 million clinical cases and up to 2.7 million deaths each year.remains one of the deadliest diseases on the planet
Because enzymatic assays are time-consuming, surface plasmon resonance (SPR) measurements were used for the primary screening to determine the binding affinity of these 81 candidate molecules to FP-2
Immobilization of FP-2 on the Biacore biosensor chip resulted in a resonance signal of 9,300 resonance units (RUs)
Summary
Malaria, which accounts for 300-500 million clinical cases and up to 2.7 million deaths each year. It is desirable to design non-peptidic inhibitors that would bind non-covalently to the target enzyme, in order to minimize toxicity while retaining the potential for high in vivo activity and selectivity. Using Virtual Screening or rational drug design based on homology models, some non-peptidic inhibitors of FP-2 with IC50 values in the micromolar range have been reported [14, 16, 24,25]. After the identification of compound 1 as a possible prototype to design selective inhibitor of FP-2, three regions of the molecule were selected to perform chemical modifications suitable to provide expedient and significant SAR information and improve inhibitory activity. FP-2, with the inhibitory activity of compound 2k being ~3 times greater than that of the lead compound 1 This encouraging result proves the validity of our chemical modification methods. Our molecular modeling results provided information about the binding between inhibitors and FP-2 and should be helpful for future inhibitor design
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