Influence of structural factors in the acridines upon their therapeutic effectiveness. Quantum mechanical parameters

The electron density at the ring nitrogen (q), the energy of the highest occupied molecular orbital (HOMO) and the energy of the lowest empty molecular orbital (LEMO) of a large series of acridine compounds have been calculated by the LCAO method These have been studied in relation to the pK_a and to the therapeutic indices of these compounds. For three gram-positive organisms (Clostridium welchii, Streptococcus pyogenes, and Staphylococcus aureus) the toxicities of the compounds correlate well with q and LEMO. The correlation for two gram-negative organisms (Bacterium coli and Proteus) is not as good. q, HOMO, and LEMO are discussed in terms of the pK_a and molecular structures. The correlations of the quantum values and toxicity have been viewed in relation to the possible interaction of the acridines and the cell membrane and DNA in bacteria and trypanosomes.