Analysis of homologous derivatives of cephalothin by multivariate methods for clinical efficacy.
This work presents the analysis of pharmacological properties of a homologous set of cephalothin derivatives formed after inserting an aliphatic ester substituent having from one to ten carbon atoms (ie. -CH3 or -CH2CH3) in place of the former carboxyl group (-C(O)OH). These compounds were shown to have significant correlations and associations in their properties after analysis by pattern recognition methods including cluster analysis, detrended correspondence analysis, and K-means cluster analysis. Formula weight of all derivatives is directly correlated and increases with molar volume, parachor, and molar refractivity. Index of refraction decreases as formula weight of derivatives increases. Polar surface area of all derivatives remains constant at 102.02 A2 as formula weight increases. Partitioning between 1-octanol/water values of Log P increases as the length of the aliphatic ester group increases. The number of nitrogens, oxygens, -NH and -OH groups, remains constant for all derivatives remains the same at 2, 6, and 1, respectively. Homologs 1 to 7 (based on number carbon atoms of ester group) show zero violations of the Rule of 5, which indicates effective drug bioavailabilty. Values of polar surface area indicate that more than 25% of any derivative present in the intestinal system would be absorbed. The ethyl and propyl derivative of cephalothin have Log P values indicating efficient permeation of the central nervous system. Detrended correspondence analysis and K-means cluster analysis showed associations and interrelationships among these derivatives that will be clinically useful for the treatment of bacterial infections.
Bartzatt
Ronald
R
University of Nebraska, College of Arts and Sciences, Department of Chemistry, Omaha, Nebraska 68182, USA. rbartzatt@mail.unomaha.edu
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D002512:Cephalothin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016000:Cluster Analysis; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D008581:Meningitis / Q000188:drug therapy; D015999:Multivariate Analysis; D010363:Pattern Recognition, Automated; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D002512:Cephalothin