Site‐Specific Acid–Base Properties of Tenoxicam

Abstract

The Hammett approach, as a new deductive tool, was introduced to characterize the otherwise inaccessible minor protonation pathway of tenoxicam (1), the non-steroidal anti-inflammatory drug. A total of eight compounds, constituting a systematic series of side chain-substituted analogues of tenoxicam and piroxicam (2), were synthesized and studied in terms of acidÀbase properties and Hammett constants to identify the ideal replacement of the unprotonated pyridin-2-yl group, a key moiety in both molecules. Hammett constants of the phenyl substituents have been found to be in a linear correlation with the experimental log K values of the enolate sites, the basic moiety of the extended conjugated system in this family of piroxicam derivatives. Then, a similar correlation was observed for the analogous tenoxicam derivatives. After identifying the 2-aza Hammett constant of the pyridin-2-yl group and the corresponding log K value, the site-specific acid -base properties of tenoxicam could be quantitated. This novel method is assessed to be a fine-tuning tool to find the ideal substituent by using analogue-based deductive method to obtain site-specific constants of the minor protonation/deprotonation pathway in drugs and biomolecules. The tenoxicam microconstant values indicate that the enolate moiety is of extremely low basicity (reflected by the log k O ¼ 3.70 and log k O N ¼ 1.09 values), which can, however, be interpreted in terms of the peculiar ring system and the overwhelming electron-withdrawing effects of the adjacent heteroatoms. A diagram depicting the pH-dependent distribution of 1 microspecies is also presented.

First-Principles Prediction of the pKas of Anti-inflammatory Oxicams

“… a Signed errors are shown in brackets. b Reference . c Reference . d Reference . e Reference . f Reference . …”

“…The experimental pK a s of these compounds have been measured using a variety of techniques, including spectrophotometric, capillary zone electrophoresis, and potentiometric methods in aqueous and aqueous-organic solvent mixtures. [4][5][6][7][8][9][10] Most oxicams were designed under the isosteric replacement principle where molecular fragments are replaced for other molecular moieties with similar stereoelectronic features with the view to optimizing their pharmacological activities. Earlier studies have found that such substitutions can have a profound influence on the physicochemical properties of these compounds such as partition constants, lipophilicity, and acid-base behavior.…”

“…The acid−base character of these compounds are particularly important for their biological activity because the ionization states of these compounds are directly determined by their p K a values at a given pH, and this in turn controls their binding to certain enzymes as well as uptake into cells. The experimental p K a s of these compounds have been measured using a variety of techniques, including spectrophotometric, capillary zone electrophoresis, and potentiometric methods in aqueous and aqueous−organic solvent mixtures. − …”

Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

“…In some cases the choice between possible derivatives of the main compound to mimic one of the microspecies is not straightforward. In order to solve this problem, the Hammett approach, as a new deductive tool, was introduced to characterize the minor protonation pathway of the non-steroidal anti-inflammatory drug tenoxicam [42]. A total of eight compounds, constituting a systematic series of side chainsubstituted analogues of tenoxicam and piroxicam, were synthesized and studied in terms of acidbase properties and Hammett constants to identify the ideal replacement of the unprotonated pyridin-2-yl group, a key moiety in both molecules.…”

Estimating the Bias of Model Compounds for the Determination of Species-Specific Protonation Constants

“…To solve this problem, the Hammett approach, as a new deductive tool, was introduced to characterize the minor protonation pathway of the nonsteroidal anti-inflammatory drug tenoxicam. 20 However, these small structural differences between the model compound and the investigated compound may result in differences between the intrinsic protonation constant values of the neighboring moieties as well; that is, to some extent the underlying assumption is necessarily violated. This question is still unanswered.…”