A QSAR for the mutagenic potencies of twelve 2-amino-trimethylimidazopyridine isomers: structural, quantum chemical, and hydropathic factors.
An isomeric series of heterocyclic amines related to one found in heated muscle meats was investigated for properties that predict their measured mutagenic potency. Eleven of the 12 possible 2-amino-trimethylimidazopyridine (TMIP) isomers were tested for mutagenic potency in the Ames/Salmonella test with bacterial strain TA98, and resulted in a 600-fold range in potency. Structural, quantum chemical, and hydropathic data were calculated on the parent molecules and the corresponding nitrenium ions of all of the tested isomers to establish models for predicting the potency of the unknown isomer. The principal determinants of higher mutagenic potency in these amines are: (1) a small dipole moment, (2) the combination of b-face ring fusion and N3-methyl group, (3) a lower calculated energy of the pi electron system, (4) a smaller energy gap between the amine HOMO and LUMO orbitals (Pearson "softness"), and (5) a more stable nitrenium ion. Based on predicted potency from the average of six regression models, the isomer not yet synthesized and tested is expected to have a mutagenic potency of 0.77 revertants/microg in tester strain TA98, which is near the low end of the potency range of the isomers.
Knize
M G
MG
Biosciences Directorate, Lawrence Livermore National Laboratory, University of California, Livermore, California 94550, USA. knize1@llnl.gov
Hatch
F T
FT
Tanga
M J
MJ
Lau
E Y
EY
Colvin
M E
ME
D003198:Computer Simulation; D007536:Isomerism; D015233:Models, Statistical; D015394:Molecular Structure; D009152:Mutagenicity Tests; D011725:Pyridines / Q000737:chemistry* / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D012475:Salmonella / Q000187:drug effects*
D011725:Pyridines