Malaria, 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.
Design, Synthesis, and Biological and Crystallographic Evaluation of Novel Inhibitors ofPlasmodium falciparumEnoyl-ACP-reductase (PfFabI) / Federica 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 Cavalli. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 56:(2013), pp. 7516-7526. [10.1021/jm400637m]
Design, Synthesis, and Biological and Crystallographic Evaluation of Novel Inhibitors ofPlasmodium falciparumEnoyl-ACP-reductase (PfFabI)
BELLUTI, FEDERICA;BISI, ALESSANDRA;GOBBI, SILVIA;RAMPA, ANGELA;BOLOGNESI, MARIA LAURA;RECANATINI, MAURIZIO;CAVALLI, ANDREA
2013
Abstract
Malaria, 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
