Increasing resistance of malaria parasites, P. falciparum in particular, towards existing antimalarial drugs demands a serious search for novel targets for the development of new antimalarial drugs. In this direction, the cysteine protease falcipain-2, provides an important target to design chemotherapeutic agents for the treatment of malaria due to its key role in hemoglobin degradation. Two series of conformationally constrained compounds, one with pyrrolidinone and the second with imidazolidinone ring, containing electrophilic nitrile warheads were designed and synthesized. The synthesized compounds were evaluated against falcipain-2 enzyme by performing enzyme binding studies. Most of the synthesized compounds showed weak inhibition in micromolar range for the enzyme falcipain-2, presumably due to unfavorable orientation of the molecules caused by the conformationally constrained five-membered rings. To determine the selectivity and specificity, these compounds were also evaluated against cathepsins B and L (analogous cysteine proteases for falcipain) displaying no detectable inhibition of these enzymes. The data indicates that the conformational constraint interferes with the normal binding mode of falcipain-2 to these derivatives.
Keywords: Malaria, Falcipain-2 inhibitors, Nitriles, Synthesis, Activity, Selectivity
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