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 greater than or equal to 5.0 x 10(-5) M against penicillin-susceptible or -resistant Escherichia coli. The partition coefficients (log Kow)-logP 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(2chloroethyl)amino]ethanol. The (logKow)logP for the N-mustard structures of aspirin and ibuprofen were 2.61 and 5.63, respectively. The (logKow)logP value of 2-[bis(2-chloroethyl)amino]ethano was 0.56. Fluoresc-amine 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 S. Values of TPSA (molecular polar surface area), C log P and molecular dipoles were calculated.