Design, synthesis, and biological and crystallographic evaluation of novel inhibitors of Plasmodium falciparum enoyl-ACP-reductase (PfFabI).
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 (PfFAS-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 PfFAS-II pathway. Among the tested compounds, 7 and 8 showed the highest inhibitory potency against Pf enoyl-ACP-reductase (PfFabI), followed by 15 and 3. Finally, we determined the crystal structures of compounds 7 and 11 in complex with PfFabI to identify their mode of binding and to confirm outcomes of docking simulations.
Department of Pharmacy and Biotechnology, University of Bologna , Via Belmeloro 6, I-40126 Bologna, Italy.
Federica
F
Belluti
Remo
R
Perozzo
Leonardo
L
Lauciello
Francesco
F
Colizzi
Dirk
D
Kostrewa
Alessandra
A
Bisi
Silvia
S
Gobbi
Angela
A
Rampa
Maria Laura
ML
Bolognesi
Maurizio
M
Recanatini
Reto
R
Brun
Leonardo
L
Scapozza
Andrea
A
Cavalli
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D018432:Drug Resistance, Multiple; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors*; D062105:Molecular Docking Simulation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000962:Antimalarials; D003374:Coumarins; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)