Structure of 1,4-dihydro-1-ethyl-4-iminecinnoline-3-carboxylic acids, classical isosters of quinolone antibacterials: Crystal structures of hydrochlorides of 7-chloro and 7-methyl derivatives

Crystal structures of hydrochlorides of 7-chloro- and 7-methyl-4-iminecinnoline analogs of antibacterial quinolones have been determined by X-ray diffraction methods. The cell parameters for the 7-chloro (1) analog in the space group P2₁/c are a = 9.061(1), b = 19.062(1), c = 7.310(1)Å, = 104.92(1)°, Z = 4, and D _calc = 1.569 g/cm³ and for the 7-methyl (2) analog in the space group P are a = 7.277(5), b = 9.080(5), c = 10.058(5) Å, = 106.10(1), = 102.38(1), = 90.18(1)°, Z = 2, and D _calc = 1.429 g/cm³. Despite geometrical equivalency of methyl and chlorine and some resemblance of their packings, the crystal structures are not isostructural. Each compound forms a strong intramolecular hydrogen bond between protonated 4-imine (a donor) and 3-carboxylic (an acceptor) groups. Compounds with a similar bond, but with reversed functionality and orientation of the 3-carboxylic group, form common quinolones, being mostly 4-oxoquinoline-3-carboxylic acids. The difference should exclude chemical affinity of 4-imine analogs to the guanine base of a bacterial DNA in DNA-gyrase complex, as proposed by Shen et al. ² for 4-oxoquinoline-3-carboxylic acids showing antibacterial activity. Also the free acidic function of a carboxyl group may significantly lower permeability of 4-imine-3-carboxylic analogs of quinolones. Surprisingly, they have demonstrated antibacterial activity comparable with that of nalidixic acid.