title: Mimicking the intramolecular hydrogen bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents.
abstract: The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against  Plasmodium falciparum ) and in vivo (against  Plasmodium berghei ). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's "chloroquine resistance transporter" (PfCRT) in a  Xenopus laevis  oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to  P. berghei -infected mice.
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Dipartimento di Neuroscienze, University of Siena, Via Aldo Moro, 53100 Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Caterina
authors.initials: C
authors.lastname: Camodeca
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.forename: Gagan
authors.initials: G
authors.lastname: Kukreja
authors.forename: Sanil
authors.initials: S
authors.lastname: Kunjir
authors.forename: Emanuele
authors.initials: E
authors.lastname: Gabellieri
authors.forename: Leonardo
authors.initials: L
authors.lastname: Lucantoni
authors.forename: Annette
authors.initials: A
authors.lastname: Habluetzel
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.forename: Roberta
authors.initials: R
authors.lastname: Gualdani
authors.forename: Francesco
authors.initials: F
authors.lastname: Tadini-Buoninsegni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolommei
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Moncelli
authors.forename: Rowena E
authors.initials: RE
authors.lastname: Martin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Summers
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamponi
authors.forename: Luisa
authors.initials: L
authors.lastname: Savini
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Massimo
authors.initials: M
authors.lastname: Valoti
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D048588:Benzoxazines / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000962:Antimalarials; D048588:Benzoxazines; D011799:Quinazolines