Determination of pK a Values of Some Benzoxazoline Derivatives and the Structure−Activity Relationship Hayati Celik,* ,† Mahmure Bü yü kağ a, ‡ Mustafa C ̧ elebier, § Ebru Turkoz Acar, † Melek Sirin Baymak, ∥ Nesrin Gö khan-Kelekc ̧ i, ⊥ Erhan Palaska, ⊥ and Hakkı Erdoğ an ‡ † Department of Analytical/Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey ‡ Department of Analytical/Pharmaceutical Chemistry, Faculty of Pharmacy, Near East University, Nicosia via Mersin 10, Turkey § Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey ∥ Department of Chemistry, Faculty of Arts and Science, Marmara University, Istanbul, Turkey ⊥ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey ABSTRACT: The acid ionization constant (pK a ) values of 2-(3H)- benzoxazolinone and its 17 derivatives were determined in buffered solutions by UV−vis spectrophotometry, potentiometry, and capillary zone electrophoresis techniques. The pK a values of the studied compounds are found to be in the range of 9.01 to 7.15. The advantages and limitations of each technique are discussed. The results suggest that the removal of a proton from the molecule occurred on the nitrogen atom of the 2-(3H)-benzoxazolinone ring and the analgesic/ anti-inflammatory activities of the benzoxazolinone derivatives decrease when the pK a values of the compounds increase. 1. INTRODUCTION Between the two main groups of analgesics for the treatment of inflammation and pain, the non-narcotic ones (nonsteroidal anti-inflammatory drugs (NSAIDs)) are generally used since they do not cause drug dependence. The first used NSAID with therapeutic benefits was acetylsalicylic acid (ASA, known as aspirin), which has now been used for more than a century. NSAIDs, by inhibiting cyclooxygenase enzymes (COX-1 and COX-2), prevent the biosynthesis of prostaglandins (PGs) thus showing antipyretic and anti-inflammatory properties. 1 The fact that no dependence develops against their therapeutic effects is another advantage of such drugs. However, administration of NSAIDs, in some cases, causes a lack of PGs that are necessary for physiological functions. 2−4 Therefore, long-term use of such drugs results in gastrointestinal irritation, gastrointestinal ulcers and bleeding, or renal disorders. 2,3 As a consequence, development of effective NSAIDs with minimal side effects has became the main goal of drug research. 4 Since today’s widely used NSAID drugs are announced to have hypnotic effects, 5,6 studies have intensified, and derivatives of such anti- inflammatory and analgesic drugs possessing the benzoxazoli- none main body have become important. 5−7 The first studies on 2-(3H)-benzoxazolinone derivatives started with the synthesis of 2-(3H)-benzoxazolinone from o- hydroxyphenylurethane. 8 Then, the new benzoxazolinone derivatives synthesized by structural modifications mostly made on the third, fifth, and sixth positions of the molecule (Figure 1) were shown to have analgesic and anti- inflammatory, 9−18 antifungal, 19−21 antirheumatic, 17 muscle relaxant, 22,23 and antibacterial properties. 24−26 Most pharmaceutical compounds are either protonated or deprotonated in aqueous solutions. 27,28 The ionization ability is measured by a parameter, the acid ionization constant (K a ), which is also called the protonation constant, equilibrium constant, or (acid) dissociation constant. Along with the partition coefficient, solubility, and reaction rate, the pK a (negative logarithm of the K a ) is also an important physicochemical property of a given compound to be formulated into a useful medicine. 29 Depending on a function of its pK a value(s) and the acidity of the solution, the extent of ionization of a drug controls its solubility and dissolution rate and, as a result, has great impact on gastrointestinal uptake into the bloodstream, distribution, cell permeability, drug-receptor binding, reaction kinetics, metabolism, and elimination. 30,31 Also, knowledge of the pK a is useful when forming a salt in order to obtain biopharmaceutical properties and solid-state characteristics that may be lacking in the free form of the compound in the preformulation stage. Hence, knowledge of the possible ionization states of a pharmaceutical substance by determining their pK a values is vital for drug development. 27 The pH at which 50 % of a compound (with only one ionizable group) is ionized defines its acid dissociation constant value. The ionization of the studied compound can be calculated at any chosen acidity after the pK a value is determined. The pK a value is an important parameter for a Received: November 30, 2012 Accepted: May 2, 2013 Published: May 15, 2013 Figure 1. Structure and numbering of 2-(3H)-benzoxazolinone. Article pubs.acs.org/jced © 2013 American Chemical Society 1589 dx.doi.org/10.1021/je3012919 | J. Chem. Eng. Data 2013, 58, 1589−1596