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The acid–base equilibria of six ACE inhibitors (ACEIs), captopril, cilazapril, enalapril, lisinopril, quinapril, and rami- pril, were investigated in the presence of micelles of nonionic surfactant Brij 35. The pKa values were potentiometrically determined at 25 °C and at a constant ionic strength (0.1 M NaCl). The obtained potentiometric data were evaluated in the computer program Hyperquad. On the basis of the shift in the pKa values (ΔpKa ) determined in micellar media in relation to the pKa values previously determined in “pure” water, the effect of Brij 35 micelles on ACEIs ionization was estimated. The presence of nonionic Brij 35 micelles caused a shift in the pKa values of all ionizable groups of the investigated ACEIs (ΔpKa from − 3.44 to + 1.9) while shifting the protolytic equilibria of both acidic and basic groups toward the molecular form. The Brij 35 micelles expressed the most pronounced effect on the ionization of captopril among the investigated ACEIs and stronger effect on the ionization of amino than on the ionization of carboxyl groups. The obtained results suggest that ionizable functional groups of ACEIs are involved in interactions with palisade layer of nonionic Brij 35 micelles, which potentially can be considered in physiological conditions. Distribution diagrams of the investigated ACEIs equilibrium forms as a function of pH indicate that the change in distribution is most strongly expressed in pH range 4–8, which includes biopharmaceutically important pH values.

Diseases of infection, of neurodegeneration (such as Alzheimer’s and Parkinson’s diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists.

The electrochemical response of two biologically important benzopyrazine derivative, Quinoxaline and Brimonidine (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxaline-6-amine) was studied at glassy carbon electrode. Investigations were performed in acetate buffer at pH 3.6 where both compounds undergo complex electrode process which begins with quasi reversible redox process at pyrazine ring forming di-hydro derivative, which is further irreversible oxidized to hydroxyl-derivative. Cyclic voltammetry at different scan rates was employed for the determination of heterogeneous electron transfer rate constant and diffusion coefficient of the compounds. The values of electron transfer rate constant at different temperatures were used for the evaluation of thermodynamic parameters like enthalpy, entropy and Gibbs free energy changes, as well as apparent energy of activation. Computational study has been performed in order to evaluate some useful quantum chemical parameters with the aim to confirm and explain the difference in experimentally obtained kinetic and thermodynamic parameters of the investigated QUI and BRIM redox process. Results were compared with studies of similar compounds and pointed out the observed similarities and differences.

The ionization order of sartans in aqueous media and possible way of interactions between their equilibrium forms and surfactant micelles have been theoretically investigated. The examined sartans are ampholytes (irbesartan and losartan) and a diacid (valsartan) with the close values of ionization constants. In order to get a better insight in the overlapped protolytic equilibria of sartans and to predict an affinity of the equilibrium forms interacting with micelles as biomembrane mimetic systems, the theoretical study was performed. Energy calculation of the optimized structures of the equilibrium forms was performed at the B3LYP/6-31G (d,p) level of the Density Functional Theory (DFT). The results of the theoretical study helped to assign the experimentally determined pK(a) values to the corresponding ionizable centers and confirmed that in all examined compounds, the higher pK(a) values can be attributed to ionization of tetrazole. The molecular descriptor values showed that sartans interact predominantly with the micelle surfaces. The equilibrium forms of ampholytes demonstrate higher affinity to the micelles, as compared to the forms of the diprotic acid. Additionally, it was shown that the uncharged molecular forms of ampholytes are more lipophylic then their zwitterionic forms.

The acid-base equilibria of rupatadine fumarate were investigated in the absence and the presence of differently charged anionic (sodium dodecyl sulfate), cationic (cetyltrimethylammonium bromide), and nonionic (4-octylphenol polyethoxylate) surfactants. The pK(a) values of rupatadine and fumaric acid were potentiometrically determined at 25 degrees C and at a constant ionic strength (0.1 M NaCl). The obtained potentiometric data were evaluated with use of the computer program Hyperquad. Ionization in the surfactant-free media was defined, and the effects of surfactants on protolytic equilibria of rupatadine were estimated, based on a shift of the apparent ionization constants determined in micellar solutions against the pK(a) values in water. The anionic SDS micelles caused an increase in the pK(a) values of all the rupatadine ionization centers (Delta pK(a) up to +1.44), while the shift of protolytic equilibria in different directions was observed in the case of the cationic CTAB (Delta pK(a) from -1.99 to +0.14) and the nonionic TX -100 (Delta pK(a) from -0.72 to +0.38) micelles. Distribution diagrams of the equilibrium forms as a function of pH indicate that the change in distribution is most strongly expressed in the pH range 4-8 which includes biopharmaceutically important pH values.

Protolytic equilibria and solubility of verapamil were investigated in the presence and in the absence of nonionic surfactant Brij 35 at a constant ionic strength (0.1 mol/L NaCl) and temperature 25 degrees C. In surfactant free media the intrinsic solubility, S-o = 4.51 X 10(-5) mol/L (only the neutral form is present in the solution) and pH dependent solubility, S (neutral and ionized form in solution) of verapamil were determined. On the basis of the solubility data, the apparent pK(a) value 9.15 of verapamil was indirectly obtained. In micellar media (10(-3) mol/L Brij 35) the solubility of verapamil free base (S-0,S-s = 2.76 X 10(-3) mol/L) and the apparent pK(a,s) = 6.35, were determined. The shift in the protolytic equilibria (Delta pK(a) = -2.80) and the increased solubility of verapamil free base (approximately 60 times) caused by Brij 35 point out to specific interactions between verapamil and the inner part of Brij 35 micelles. The most significant changes in distribution of verapamil equilibrium forms were observed at biopharmaceutically important pH 7.4 which potentially indicates interactions with biomolecules in blood plasma.