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EnglishMalaria, 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.
| Titolo: | Design, Synthesis, and Biological and Crystallographic Evaluation of Novel Inhibitors ofPlasmodium falciparumEnoyl-ACP-reductase (PfFabI) | |
| Autore/i: | BELLUTI, FEDERICA; Remo Perozzo; Leonardo Lauciello; Francesco Colizzi; Dirk Kostrewa; BISI, ALESSANDRA; GOBBI, SILVIA; RAMPA, ANGELA; BOLOGNESI, MARIA LAURA; RECANATINI, MAURIZIO; Reto Brun; Leonardo Scapozza; CAVALLI, ANDREA | |
| Autore/i Unibo: | ||
| Anno: | 2013 | |
| Rivista: | ||
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1021/jm400637m | |
| 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. | |
| Data prodotto definitivo in UGOV: | 2013-10-28 18:56:42 | |
| Appare nelle tipologie: | 1.01 Articolo in rivista |
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