Bifunctional constructs of aspirin and ibuprofen (non-steroidal anti-inflammatory drugs; NSAIDs) that express antibacterial and alkylation activities.
Ibuprofen and aspirin are two common non-steroidal anti-inflammatory drugs (NSAIDs). Both NSAIDs have a carbonyl carbon [-C(O)-], which was utilized to attach a nitrogen mustard (N-mustard) ester group or a tripeptide group. The tripeptide consisted of a L-Gly-D-Ala-D-Ala sequence, where D-Ala-D-Ala is the reactive site for antibacterial activity and L-Gly serves as a linker to the NSAID carrier drug. The aspirin tripeptide and N-mustard show significant antibacterial activity at >or=5.0 x 10(-5) M against penicillin-susceptible or -resistant Escherichia coli. The partition coefficients (log Kow)log P of aspirin and ibuprofen tripeptide drugs were -1.05 and 2.23, respectively. The NSAIDs served as carrier drugs of the N-mustard group which expressed alkylation activity directed towards the nucleophilic primary amine of p -chloroaniline. Hydrolysis of the N-mustard agents yielded the parent structure of aspirin (or ibuprofen) and an N-mustard moiety, 2-[bis(2-chloroethyl)amino]ethanol. The (log Kow)log P for the N-mustard structures of aspirin and ibuprofen were 2.61 and 5.63, respectively. The (log Kow)log P value of 2-[bis(2-chloroethyl)amino]ethanol was 0.56. Fluorescamine was utilized to determine unreacted p -chloroaniline at known time intervals, which permitted calculation of rate constants and rate equations. The aspirin N-mustard agent expressed strong antibacterial activity against a penicillin-resistant bacteria and first-order alkylation kinetics. The ibuprofen N-mustard and 2-[bis(2-chloroethyl)amino]ethanol followed second-order alkylation kinetics. All N-mustard and tripeptide compounds showed zero violations of the Rule of 5. Values of TPSA (molecular polar surface area), C log P and molecular dipoles were calculated.
Bartzatt
Ronald
R
University of Nebraska, College of Arts & Sciences, Chemistry Department, Durham Science Center, 6001 Dodge Street, Omaha, NE 68182, USA. bartzatt@mail.unomaha.edu
Cirillo
Suat L G
SL
Cirillo
Jeffrey D
JD
Donigan
Laura
L
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001241:Aspirin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016503:Drug Delivery Systems / Q000379:methods; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects*; D007052:Ibuprofen / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D004338:Drug Combinations; D009588:Nitrogen Mustard Compounds; D001241:Aspirin; D007052:Ibuprofen