Synthesis and Antiplasmodial Receptor Independent 4D-QSAR Study in 4-aryl-2-trichloromethylquinazoline Series
Jean-Pierre Reboul, Pierre Verhaeghe, Didier Siri, Anouk Gaudel-Siri, Caroline Castera- Ducros, Aurélien Dumètre, Sébastien Hutter, Nadine Azas, Pascal Rathelot, Patrice Vanelle and Athanassios Iliadis
Affiliation: Laboratoire de Chimie Théorique, UMR CNRS 7273, Institut de Chimie Radicalaire, Aix-Marseille Université, Faculté des Sciences et Techniques de Saint-Jérôme, Avenue Escadrille Normandie-Niemen, 13397 Marseille cedex 20, France.
Keywords: 2-trichloromethylquinazoline scaffold, Boltzmann distribution, Drug design, In vitro antiplasmodial activity, Molecular
flexibility, Multi-linear regression model, Plasmodium falciparum, Receptor independent 4D-QSAR.
We present herein the results of a receptor independent 4D-QSAR analysis conducted on 4-aryl-2-
trichloromethylquinazoline derivatives displaying in vitro antiplasmodial properties against the W2 multi-resistant Plasmodium
falciparum strain. Conformational analysis was performed on a set of 14 molecules in order to obtain batches of
lowest energy conformers. A linear regression model with Boltzmann-weighted descriptors was therefore applied. This
QSAR approach is a two-step procedure which explores available experimental data to allow intelligent and accelerated
screening of new chemical entities. In the first step, a multi-linear regression model including 14 molecules was built up
involving molecular descriptors. In the second step, the model predicted the antiplasmodial activity (IC50) of 75 new
molecules for a set of hypothesized structures whose molecular descriptors are available. Finally, among these 75 molecules,
5 new quinazolines which activity had been predicted by the model were synthesized and biologically evaluated.
Their biological experimental activities were compared to the ones predicted by the QSAR model, so as to validate it. Out
of these 5 quinazolines, there was a quite good correlation between the predicted and experimental IC50 values of 3 molecules
while the results obtained for the 2 others pointed out two probable limitations for this QSAR model. Such 4DQSAR
approach could open the way to a rational and faster preparation of more potent antiplasmodial quinazoline leads.
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