Design of ciprofloxacin derivatives that inhibit growth of methicillin resistant Staphylococcus aureus (MRSA) and methicillin susceptible Staphylococcus aureus (MSSA).
Three derivatives of ciprofloxacin (compound B, C, and D) were constructed utilizing microwave synthesis methodology (compound D) or diazoalkane reaction in nonaqueous solvent (compounds B and C). The final structures of the derivatives featured an ester group in place of the original carboxyl group of the ciprofloxacin. These ester groups contained aliphatic single carbon (compound B), two carbon length (compound C), or three carbon length propyl ester group (compound D). The ester groups strongly affected the molecular properties of the parent ciprofloxacin. As the size of the ester group increased the formula weight, molar volume, and number of rotatable bonds increased. The Log P for these compounds were -0.701, -0.441, -0.065, 0.437 for ciprofloxacin, B, C, and compound D, respectively. Numerical values of dermal permeability coefficient (Kp) increased rapidly as length of the ester carbon chain increased. The immediate consequence of Kp increase is an increased skin penetration rate based on dose and time span of administration. Polar surface area for ciprofloxacin is 74.569 Angstroms(2), but decreases to 63.575 Angstroms(2) for all three derivatives. All three derivatives of ciprofloxacin showed zero violations of the Rule of 5, indicating these drugs would have favorable bioavailability. Compounds A, B, C, and D were placed into tissue culture with methicillin resistant and susceptible Staphylococcus aureus (MRSA and MSSA, respectively) to determine levels of bacterial growth inhibition. All compounds induced greater than 60 % inhibition of MSSA at concentrations as low as 15.63 micrograms/milliliter. All four compounds induced greater than 80 % inhibition of MRSA at concentratins as low as 15.63 micrograms/milliliter. Development of novel drug designs will benefit the clinical treatment of dangerous infections of MSSA and MRSA.
Bartzatt
Ronald
R
University of Nebraska, College of Arts & Sciences, Durham Science Center, Chemistry Department, 6001 Dodge Street, Omaha, Nebraska 68182, USA. rbartzatt@mail.unomaha.edu
Cirillo
Suat L G
SL
Cirillo
Jeffrey D
JD
D002939:Ciprofloxacin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D008712:Methicillin / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002939:Ciprofloxacin; D008712:Methicillin