Novel fluorinated piperazine based-amino acid derivatives as antiplasmodial agents: Synthesis, bioactivity and computational studies

A library of twenty novel analogues of fluorinated, N-(3-hydroxy-1-phenyl-4-(4-phenylpiperazin-1-yl)alkyl)amides containing different amino acids were synthesized and tested for the activity against Plasmodium falciparum (Pf3D7) culture. All the tested compounds showed TC50 values >100 mu M on HepG2 cells. Hit analogues 12c and 12e, displayed IC50 values in the sub-micromolar range, i.e., 0.696 +/- 0.0462 mu M and 0.9377 +/- 0.0461 mu M, respectively. Compounds 12c and 12e were also evaluated in combination with artemisinin, which slightly improved the activity of both the compounds with IC50 values of 0.19 mu M and 0.26 mu M, respectively. For compounds 12c and 12e, in-silico studies were carried out. Overall, results obtained from both in vitro and in-silico studies, indicated that 12c and 12e were hit compounds with maximum potency.