DFT Studies of the Structural and Electronic Properties of Fluorinated and Methoxylated 3-Amino-2-CyclopropylQuinazolin-4(3H)-one Molecules

DFT B3LYP/6-31+G(d,p) calculations were performed on the twelve fluorinated and methoxylated 3-amino-2-cyclopropylquinazolin-4(3H)-one molecules, which are abbreviated as FMACQs, in toluene, the gas phase, and aqueous solution. Among the twelve isomers, ten of them are positional isomers and two are rotational conformers. The DFT results show that the electronic properties, the HOMO, LUMO, and other five descriptors, i.e. chemical potential, electronegativity, global hardness, global softness, and electrophilicity index, are all similar among the twelve isomers and are therefore less critical in determining the bioactivity of these molecules. However, the dihedral angle between the fluorinated and methoxylated benzene ring and the quinazolinone ring is strongly correlated to the bioactivity. The three isomers with fluorine at the 2-position and no methoxy at the 6-position (FMACQ-42, FMACQ-36, and FMACQ-32) have a dihedral angle larger than 40o but smaller than 45o and are potent REV-ERBα antagonists, whereas that in FMACQ-26 is 57o or the dihedral angles of the molecules with neither functional group present at the 2- and 6-position are about 37o.