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Bifunctional constructs of aspirin and ibuprofen (non‐steroidal anti‐inflammatory drugs; NSAIDs) that express antibacterial and alkylation activities
Author(s) -
Bartzatt Ronald,
Cirillo Suat L. G.,
Cirillo Jeffrey D.,
Donigan Laura
Publication year - 2003
Publication title -
biotechnology and applied biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 70
eISSN - 1470-8744
pISSN - 0885-4513
DOI - 10.1042/ba20020108
Subject(s) - chemistry , tripeptide , ibuprofen , aspirin , antibacterial activity , stereochemistry , medicinal chemistry , biochemistry , pharmacology , amino acid , bacteria , medicine , biology , genetics
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 5.0×10 −5 M against penicillin‐susceptible or ‐resistant Escherichia coli . The partition coefficients (logKow)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(2‐chloroethyl)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]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 logP and molecular dipoles were calculated.