Insignificant in vitro falcipain-2 inhibitory activity of novel 2-(4-(substituted benzoyl) piperazine-1-yl)-N-phenylacetamide derivatives

Abstract

The cysteine protease, falcipain-2 (FP-2) is an important drug target for the management of infection by the human malaria parasite Plasmodium falciparum. The rapid emergence of resistance is the main problem with all antimalarial agents. Hence, the discovery of novel, effective drugs to counter the spread of malaria parasites that are resistant toward existing agents, especially drugs that can act on new targets, is urgently necessary. Materials and Methods: A novel series of 2-(4-(substituted benzoyl) piperazine-1-yl)-N-phenylacetamide derivatives was designed using the ligand-based approach, employing a three-point pharmacophore model. It consists of an aromatic group (monocyclic/bicyclic), which is attached to the hydrophobic moiety; commonly an aromatic residue through hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) atom(s) acting as the linker. The new chemical entities were synthesized from the key intermediate N-phenyl-2-(piperazine-1-yl) acetamide, by coupling it with various substituted acids in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) and 1 hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by [sup]1 H NMR and by mass spectral data. Results: All the synthesized compounds were evaluated for their in vitro FP-2 inhibitory activity. Two compounds 5l and 5q showed very weak enzyme inhibition activities (3-5%) and the remaining 15 compounds showed no inhibition at 10 [micro]m concentrations. However, unlike other reported FP-2 inhibitors, none of these molecules showed potent activity. Conclusion: This series of compounds did not have or had very less antimalarial activity.