QUANTITATIVE STRUCTURE-ACTIVITY-RELATIONSHIPS AMONG MACROLIDE ANTIBACTERIAL AGENTS - IN-VITRO AND IN-VIVO POTENCY AGAINST PASTEURELLA-MULTOCIDA

Quantitative structure-activity relationships have been found among ma crolide antibacterial agents in their potencies against the bacterial pathogen Pasteurella multocida both in vitro and in mouse infections. To obtain these relationships we measured, among other things, the pK( a)'s and log P's of 15 known macrolides of diverse structures, Among t hese compounds, in vitro potency [log(1/MIC)] is a function of log P, log D, and CMR (R = 0.86). in viva potency is a function of the higher pK(a), the HPLC chromatographic capacity factor log k', log((1/MIC) a nd pNF (R = 0.93). pNF is defined as the negative logarithm of the fra ction of neutral drug molecules present in aqueous solution at pH 7,4. The same physical properties were determined for 14 macrolides not us ed in developing the original QSAR models, Using the in vivo model, we calculated the mouse protection potency ranges for these new compound s, Ten estimates agreed with those observed, three were lower by a hal f-order of magnitude, and one was calculated to be active in the range of 15-50 mg/kg, but in fact was not active at 50 mg/kg, the highest l evel tested. When these new compounds were combined with the original 15, and the QSAR's updated, the new equations for the in vitro and in vivo potencies were essentially the same as those originally found. He nce, the physical properties indicated above are major determinants of macrolide antibacterial potencies.