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 1H 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 μm 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.
Key words: Antimalarial, falcipain‑2 (FP‑2), ligand‑based drug design