title: Looking for new antiplasmodial quinazolines: DMAP-catalyzed synthesis of 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines and their in vitro evaluation toward Plasmodium falciparum.
abstract: A DMAP catalyzed synthesis of new 4-benzyloxy- and 4-aryloxy-2-trichloromethylquinazolines was studied, in a view to react 4-chloroquinazolines with poorly nucleophilic alcohols such as benzylic alcohols, via a simple and cheap SNAr reaction approach. A fast (1 h) general operating procedure, affording good reaction yields, was achieved under microwave irradiation. Thus, a series of 35 molecules was obtained and evaluated in vitro on the K1 multi-resistant Plasmodium falciparum strain, in parallel with a cytotoxicity assessment on the human HepG2 cell line. 5 hit-molecules were identified, presenting both promising antiplasmodial activity (1.5 μM < IC50 < 2 μM) and low cytotoxicities (25 μM < CC50 < 45 μM). Apart for 2 molecules, the global series displayed a satisfying solubility in the aqueous biological media. Structure-activity relationships showed that the molecules presenting a benzyloxy moiety were less cytotoxic than the ones bearing a phenoxy moiety at position 4 of the quinazoline ring. It also appeared that the introduction of a heteroaryl moiety afforded inactive compounds. Finally, the most active and selective molecules (Selectivity Index = 22-27) were the ones presenting either an unsubstituted benzyloxy group or a phenoxy group, this last bearing a p-bromo or an o-acetyl substituent.
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille cedex 05, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Gellis
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille cedex 05, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Primas
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille cedex 05, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Hutter
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille cedex 05, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Lanzada
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille cedex 05, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Remusat
authors.affiliation: Université Paul Sabatier, Faculté des Sciences Pharmaceutiques - CNRS UPR 8241, Laboratoire de Chimie de Coordination, 205 Route de Narbonne, 31077 Toulouse cedex 04, France. Electronic address: pierre.verhaeghe@univ-tlse3.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Verhaeghe
authors.affiliation: Aix-Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille cedex 05, France. Electronic address: patrice.vanelle@univ-amu.fr.
authors.forename: Patrice
authors.initials: P
authors.lastname: Vanelle
authors.affiliation: Aix-Marseille Université, UMR MD 3, Infections Parasitaires, Transmission et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin - CS30064, 13385 Marseille cedex 05, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Azas
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D011725:Pyridines / Q000737:chemistry*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: C417980:4-(dimethylamine)pyridine; D000962:Antimalarials; D011725:Pyridines; D011799:Quinazolines
keywords: 2-trichloromethylquinazoline; 4-benzyloxyquinazoline; 4-phenoxyquinazoline; Antiplasmodial activity; DMAP-catalysis; HepG2 cytotoxicity; Microwave-assisted chemistry; Plasmodium falciparum; S(N)Ar reaction; SARs