Document Report Card

ID: ALA2176916

Journal: J Med Chem

Title: Mimicking the intramolecular hydrogen bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents.

Authors: Gemma S, Camodeca C, Brindisi M, Brogi S, Kukreja G, Kunjir S, Gabellieri E, Lucantoni L, Habluetzel A, Taramelli D, Basilico N, Gualdani R, Tadini-Buoninsegni F, Bartolommei G, Moncelli MR, Martin RE, Summers RL, Lamponi S, Savini L, Fiorini I, Valoti M, Novellino E, Campiani G, Butini S.

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.

CiteXplore: 23145816

DOI: 10.1021/jm300831b