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Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents

Research Area: Uncategorized Year: 2012
Type of Publication: Article
Authors:
  • Sandra Gemma
  • Caterina Camodeca
  • Margherita Brindisi
  • Simone Brogi
  • Gagan Kukreja
  • Sanil Kunjir
  • Emanuele Gabellieri
  • Leonardo Lucantoni
  • Annette Habluetzel
  • Donatella Taramelli
  • Nicoletta Basilico
  • Roberta Gualdani
  • Francesco Tadini Buoninsegni
  • Gianluca Bartolommei
  • Maria Rosa Moncelli
  • Rowena E. Martin
  • Robert L. Summers
  • Stefania Lamponi
  • Luisa Savini
  • Isabella Fiorini
  • Massimo Valoti
  • Ettore Novellino
  • Giuseppe Campiani
  • Stefania Butini
Journal: JOURNAL OF MEDICINAL CHEMISTRY Volume: 55
Number: 23 Pages: 10387-10404
Month: DEC 13
ISSN: 0022-2623
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.
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