Synthesis, crystal structures and anti-inflammatory activity of fluorine-substituted 1,4,5,6-tetrahydrobenzo[h]quinazolin-2-amine derivatives

Abstract

Two fluorine-substituted 1,4,5,6-tetrahydrobenzo[h]quinazolin-2-amine (BQA) derivatives, namely 2-amino-4-(2-fluorophenyl)-9-methoxy-1,4,5,6-tetrahydrobenzo[h]quinazolin-3-ium chloride, (8), and 2-amino-4-(4-fluorophenyl)-9-methoxy-1,4,5,6-tetrahydrobenzo[h]quinazolin-3-ium chloride, (9), both C19H19FN3O+·Cl−, were generated by Michael addition reactions between guanidine hydrochloride and the α,β-unsaturated ketones (E)-2-(2-fluorobenzylidene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one, C18H15FO2, (6), and (E)-2-(4-fluorobenzylidene)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one, (7). Because both sides of α,β-unsaturated ketones (6) or (7) can be attacked by guanidine, we obtained a pair of isomers in (8) and (9). Single-crystal X-ray diffraction indicates that each isomer has a chiral C atom and both (8) and (9) crystallize in the achiral space group P21/c. The chloride ion, as a hydrogen-bond acceptor, plays an important role in the formation of multiple hydrogen bonds. Thus, adjacent molecules are connected through intermolecular hydrogen bonds to generate a banded structure. Furthermore, these bands are linked into an interesting 3D network via hydrogen bonds and π–π interactions. Fortunately, the solubilities of (8) and (9) were distinctly improved and can exceed 50 mg ml−1 in water or PBS buffer system (pH 7.4) at room temperature. In addition, the results of an investigation of anti-inflammatory activity show that (8) and (9), with o- and p-fluoro substituents, respectively, display more potential for inhibitory effects on LPS-induced NO secretion than starting ketones (6) and (7).