Design, Synthesis, and Biological and Crystallographic Evaluation of Novel Inhibitors ofPlasmodium falciparumEnoyl-ACP-reductase (PfFabI)

none13siMalaria, a disease of worldwide significance, is responsible for over one million deaths annually. The liver-stage of Plasmodium’s life cycle is the first, obligatory, but clinically silent step in malaria infection. The P. falciparum type II fatty acid biosynthesis pathway (Pf FAS-II) has been found to be essential for complete liver-stage development and has been regarded as a potential antimalarial target for the development of drugs for malaria prophylaxis and liver-stage eradication. In this paper, new coumarin-based triclosan analogues are reported and their biological profile is explored in terms of inhibitory potency against enzymes of the Pf FAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (Pf FabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with Pf FabI to identify their mode of binding and to confirm outcomes of docking simulations.noneFederica Belluti;Remo Perozzo;Leonardo Lauciello;Francesco Colizzi;Dirk Kostrewa;Alessandra Bisi;Silvia Gobbi;Angela Rampa;Maria Laura Bolognesi;Maurizio Recanatini;Reto Brun;Leonardo Scapozza;Andrea CavalliFederica Belluti;Remo Perozzo;Leonardo Lauciello;Francesco Colizzi;Dirk Kostrewa;Alessandra Bisi;Silvia Gobbi;Angela Rampa;Maria Laura Bolognesi;Maurizio Recanatini;Reto Brun;Leonardo Scapozza;Andrea Cavall