Analysis of structural features of bis-quaternary ammonium antimicrobial agents 4,4'-(alpha,omega-polymethylenedithio)bis (1-alkylpyridinium iodide)s using computational simulation.

The bis-quaternary ammonium compounds (QACs) consisted of two identical alkylpyridinium rings and a bridge structure linking the rings to each other. The QACs have a methylene bridge except for 4DCABP-P,12 which has a phenyl ring as a bridge. These bis-QACs are as follows; amide type: N,N'-tetramethylenebis(1-dodecyl-4-carbamoylpyridinium iodide) (4BCAP-4,12), N,N'-hexamethylenebis(1-decyl-4-carbamoylpyridinium iodide) (4BCAP-6,10), anti-amide type: 4,4'-(1,4-tetramethylenedicarbonyldiamine)bis(1-decylpyridinium iodide) (4DCABP-4,10), 4,4'-(1,4-tetramethylenedicarbonyldiamine)bis (1-dodecylpyridinium iodide) (4DCABP-4,12), 4,4'-(1,4-phenyldicarbonyldiamine)bis(1-dodecylpyridinium iodide) (4DCABP-P,12), ester type: 4,4'-(1,6-hexamethylenedioxydicarbonyl)bis(1-dodecylpyridinium iodide) (4DOCBP-6,12), thioether type: 4,4'-(1,6-hexamethylenedithio)bis(1-octylpyridinium iodide) (4DTBP-6,8). From the investigation of the relationship between the median lethal dose (LD(50)) and the minimum inhibitory concentration (MIC) of these compounds, 4DTBP-6,8 as a disinfectant, seems to be very safe for human cells. The global minimum of 4DTBP-6,8 were searched and 1125 conformers obtained. The solvation free energy (dGW) of nine samples, which were extracted from these 1125 conformers, was calculated and two minimum points of dGW were observed. In the conformer-energy analysis of four types of model bridge-molecule, the thioether type bridge indicated a gradual energy increment, while the other three (amide, anti-amide, ester) types indicated an energy jump point in their profiles. Then we considered that the delicate balance between hydrophobicity and structural feature in the bridge-region of 4DTBP-6,8 molecule seemed to be related to its safety antibacterial activity.