QSAR analysis of five generations of cephalosporins to establish the structural basis of activity against methicillin-resistant and methicillin-sensitive Staphylococcus aureus.

Solving the worldwide problem of growing bacterial drug resistance will require a short-run and medium-term strategy. Structure-activity relationship (SAR) and quantitative SAR (QSAR) analyses have recently been utilized to reveal the molecular basis of the antibacterial activity and antibacterial spectrum of penicillins, the use of which is no longer solely empirical. Likewise, a more rational drug design can be achieved with cephalosporins, the largest group of ß-lactam antibiotics. The current contribution aimed to establish the molecular and physicochemical basis of the antibacterial activity of five generations of cephalosporins on methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). With SAR and QSAR analyses, the molecular portions that provide essential and additional antibacterial activity were identified. The substitutions with greater volume and polarity on the R2 side chain of the cephem nucleus increase potency on MSSA. The best effect is produced by substitutions with polar nitrogen atoms at the alpha-carbon (Cα). Substitutions with greater volume and polarity on the R1 side chain further enhance antibacterial activity. In contrast, the effect against MRSA seems to be independent of any substitution on R2 or at the Cα, while depending on the accessory portions with greater volume and polarity on R1.

Use of the harmonic mean to the determination of dissociation constants of stereoisomeric mixtures of biologically active compounds.

Herein we introduce the derivation of a mathematical expression to evaluate the dissociation constant of a mixture of stereoisomers in equal amounts (KdMIX), when the corresponding dissociation constants (Kd) or medium response (MR50) of the pure stereoisomers are known; the final equation takes the form of the harmonic mean. In order to validate the equation, we carried out a bibliographic search of experimental data of enantiomeric molecules with biological activity, considering the Kd's or MR50's of the isolated enantiomers as well as that of the racemate. The comparisons between the experimental dissociation constants of the mixtures (KdEXP or MR50EXP) and the calculated values (KdMIX or MR50MIX) were consistent; the similarity between these values is supported through statistical analyses of group comparison and simple linear correlation. The equation we obtained, which corresponds to the harmonic mean, was used to predict the values of KdMIX (or MR50MIX) or Kd (or MR50) in systems when only two of the experimental values are known: either the dissociation constants of both enantiomers or the Kd (or MR50) of one of the enantiomers and dissociation constant of the racemate.