title: Determination of acid dissociation constants (pKa) of cephalosporin antibiotics: Computational and experimental approaches.
abstract: Cefapirin (CEPA) and ceftiofur (CEF) are two examples of widely used veterinarian cephalosporins presenting multiple ionization centers. However, the acid dissociation constants (pKa) of CEF are missing and experimental data about CEPA are rare. The same is true for many cephalosporins, where available data are either incomplete or even wrong. Environmentally relevant biotic and abiotic processes depend primordially on the antibiotic pH-dependent speciation. Consequently, this physicochemical parameter should be reliable, including the correct ionization center identification. In this direction, two experimental techniques, potentiometry and spectrophotometry, along with two well-known pKapredictors, Marvin and ACD/Percepta, were used to study the macro dissociation constants of CEPA and CEF. Additionally, the experimental dissociation constants of 14 cephalosporins available in the literature were revised, compiled and compared with data obtained in silico. Only one value was determined experimentally for CEF (2.68 ± 0.05), which was associated to the carboxylic acid group deprotonation. For CEPA two values were obtained experimentally: 2.74 ± 0.01 for the carboxylic acid deprotonation and 5.13 ± 0.01 for the pyridinium ring deprotonation. In general, experimentally obtained values agree with the in silico predicted data (ACD/Percepta RMSE: 0.552 and Marvin RMSE: 0.706, n = 88). However, for cephalosporins having imine and aminothiazole groups structurally close, Marvin presented problems in pKapredictions. For the biological and environmental fate and effect discussion, it is important to recognize that CEPA and CEF, as well as many other cephalosporins, are present as anionic species in the biologic and environmentally relevant pH values of 6-7.5.
authors.affiliation: Instrumental Analytical Chemistry and Centre of Water and Environmental Research (ZWU), University of Duisburg-Essen, Universitätsstraße 5, 45141, Essen, Germany. Electronic address: alyson.ribeiro@stud.uni-due.de.
authors.forename: Alyson R
authors.initials: AR
authors.lastname: Ribeiro
authors.affiliation: Instrumental Analytical Chemistry and Centre of Water and Environmental Research (ZWU), University of Duisburg-Essen, Universitätsstraße 5, 45141, Essen, Germany. Electronic address: torsten.schmidt@uni-due.de.
authors.forename: Torsten C
authors.initials: TC
authors.lastname: Schmidt
mesh_terms: D019342:Acetic Acid / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D002511:Cephalosporins / Q000737:chemistry*; D019343:Citric Acid / Q000737:chemistry; D006851:Hydrochloric Acid / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D015394:Molecular Structure; D011199:Potentiometry / Q000379:methods; D012995:Solubility; D013053:Spectrophotometry / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D019343:Citric Acid; C053503:ceftiofur; D019342:Acetic Acid; D006851:Hydrochloric Acid
keywords: Antibiotics; Cephalosporins; Potentiometry; Prediction; Spectrophotometry; pK(a) determination