Derivatives of cephalothin that inhibit ampicillin resistant Escherichia coli.
Two derivatives of cephalothin, compound I and II, were synthesized and demonstrated strong growth inhibition of ampicillin resistant Escherichia coli (E. coli). Compound I is the propyl ester of the parent cephalothin antibiotic, while compound II is the butyl ester derivative. The ester substituent replaces the former carboxyl group of cephalothin. Compounds I and II are stable at room temperature and have increased lipophilicity compared to cephalothin due to the presence of the ester substituent. The MIC50 of I and II were determined to be 55 microg/mL and 30 microg/mL, respectively. Cephalothin showed less than 20% growth inhibition of E. coli at all concentrations based on assay of colony forming units. Compounds I and II showed greater than 50% growth inhibition of E. coli at all concentrations greater than 50 microg/mL (more than 65% at 400 microg/mL). Pharmacological properties such as octanol/water partition Log P and polar surface area were determined. Values for polar surface area suggested 35% of I or II present in the intestinal system would be absorbed. The Log P values for I and II are 2.061 and 2.62, respectively, which indicate I and II will penetrate the blood-brain barrier more effectively than cephalothin. The lipophilic substituent constant (pi) for I and II are 1.592 and 1.95, respectively, which indicates the ester substituents contribute a strong lipophilic trait. Properties of molar refractivity, parachor, and molar volume, which describe van-der-Waals interactions, are also determined.
Bartzatt
Ronald
R
University of Nebraska, College of Arts and Sciences, Dept. of Chemistry, 6001 Dodge Street, Omaha, Nebraska 68182, USA. rbartzatt@mail.unomaha.edu
Cirillo
Suat L G
SL
Cirillo
Jeffrey D
JD
D000668:Ampicillin Resistance / Q000187:drug effects*; D002512:Cephalothin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015169:Colony Count, Microbial; D015195:Drug Design; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects*; D007202:Indicators and Reagents; D012984:Software; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D002512:Cephalothin