The intramolecular hydrogen bond formed between a protonated amine and a neighbouring 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 P. 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 scaffold of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei-infected mice.

Mimicking the intramolecular hydrogen bond: synthesis, biological evaluation, and molecular modeling of benzoxazines and quinazolines as potential antimalarial agents / S. Gemma; C. Camodeca; M. Brindisi; S. Brogi; G. Kukreja; S. Kunjir; E. Gabellieri; L. Lucantoni; A. Habluetzel; D. Taramelli; N. Basilico; R. Gualdani; F. Tadini-Buoninsegni; G. Bartolommei; M.R. Moncelli; R.E. Martin; R.L. Summers; S. Lamponi; L- Savini; I. Fiorini; M. Valoti; E. Novellino; G. Campiani; S. Butini. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 55:(2012), pp. 10387-10404. [10.1021/jm300831b]

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

GUALDANI, ROBERTA;TADINI BUONINSEGNI, FRANCESCO;BARTOLOMMEI, GIANLUCA;MONCELLI, MARIA ROSA;
2012

Abstract

The intramolecular hydrogen bond formed between a protonated amine and a neighbouring 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 P. 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 scaffold of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei-infected mice.
2012
55
10387
10404
S. Gemma; C. Camodeca; M. Brindisi; S. Brogi; G. Kukreja; S. Kunjir; E. Gabellieri; L. Lucantoni; A. Habluetzel; D. Taramelli; N. Basilico; R. Gualdan...espandi
File in questo prodotto:
File Dimensione Formato  
JMedChem_2012.pdf

Accesso chiuso

Tipologia: Versione finale referata (Postprint, Accepted manuscript)
Licenza: Tutti i diritti riservati
Dimensione 3.52 MB
Formato Adobe PDF
3.52 MB Adobe PDF   Richiedi una copia

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/779951
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 62
  • ???jsp.display-item.citation.isi??? 57
social impact