beta-Diketo acid-containing compounds are a promising class of human immunodeficiency virus type 1 (HIV-1) integrase (IN) inhibitors. Starting from the hypothesis that these inhibitors are able to coordinate ions in solution before interacting on the active site, a series of potentiometric measurements have been performed to understand the coordination ability of the diketo acid pharmacophore toward the biologically relevant Mg(2+). Moreover, by using beta-diketo acid/ester as model ligands with a set of divalent metal ions (Mg, Mn, Ni, Co, Cu, and Zn), we obtained a series of complexes and tested them for anti-HIV-1 IN activity. Results demonstrate that the diketo acid functionality chelates divalent metal ions in solution, and complexes with metals in different stoichiometric ratios are isolated. We postulate that the diketo acids act as complexes in their active form. In particular, they predominantly form species such as Mg(2)L(2+) and Mg(2)L(2) (derived from diketo acids, H(2)L), and MgL(+) and MgL(2) (derived from diketo esters, HL) at physiological pH. Furthermore, the synthesized mono- and dimetallic complexes inhibited IN at a high nanomolar to low micromolar range, with metal dependency in the phenyl diketo acid series. Retrospective analysis suggests that the electronic properties of the aromatic framework influence the metal-chelating ability of the diketo acid system. Therefore, the difference in activities is related to the complexes they preferentially form in solution, and these findings are important for the design of a new generation of IN inhibitors.
Apparent and partial molar enthalpies at 298 K of the aqueous solutions of cationic gemini surfactants 1,1'-didodecyl-2,2'-dimethylenebispyridinium dimethanesulfonate (12-Py(2)-2-(2)Py-12 MS); 1,1'-didodecyl-2,2'-trimethylenebispyridinium dimethanesulfonate (12-Py(2)-3-(2)Py-12 MS); 1,1'-didodecyl-2,2'-tetramethylenebispyridinium dimethanesulfonate (12-Py(2)-4-(2)Py-12 MS); 1,1'-didodecyl-2,2'-octamethylenebispyridinium dimethanesulfonate (12-Py(2)-8-(2)Py-12 MS); 1,1'-didodecyl-2,2'-dodecamethylenebispyridinium dimethanesulfonate (12-Py(2)-12-(2)Py-12 MS) were measured as a function of concentration and are here reported for the first time. They show a very peculiar behavior as a function of the spacer length, not allowing for the determination of a -CH 2- group contribution when this group is added to the spacer. The curve of the compound with a four-carbon-atom-long spacer lies between those of the compound with a spacer of 2 and 3 carbon atoms, instead of that below the latter, as expected. This surprising behavior, never found before in the literature and different from that found for the more popular m- s- m-type bisquaternary ammonium gemini surfactants, could be explained by a conformation change of the molecule, caused by stacking interactions between the two pyridinium rings, mediated by the counterion and appearing at an optimum length of the spacer. The hypothesis is also supported by the data obtained from the surface tension vs log c curves, showing that A min, the minimum area taken at the air-water interface by the molecule, is significantly lower for 12-Py(2)-4-(2)Py-12 MS than that of the other compounds of the same homologous series, and that the same compound has a greater tendency to form micelles instead of adsorbing at the air/water interface. The evaluation of the micellization enthalpies, by means of a pseudophase transition model, agrees with the exposed trends. These results confirm the great crop of information that can be derived from the study of the solution thermodynamics of aggregate systems and in particular from the curves of apparent and molar enthalpies vs concentration.
[reaction: see text] In this work, we report the synthesis of a new series of glucocationic surfactants, a class of surfactants we introduced very recently. The preparation of the surfactants is based on the synthesis of the 2-bromoethyl-2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside, whose preparation was studied in order to improve yields and stereoselectivity of this key intermediate. These glucocationic amphiphiles were prepared and studied as a model of cationic surfactants marked with a carbohydrate moiety. The use of carbohydrates as markers on cationic lipids was recently introduced to induce recognition by specific receptors, present on the surface of cell membranes. The chemicophysical characterization of these model structures can give more insight on the aggregation behavior. Conductivity and surface tension measurements were performed in order to characterize the compounds from the amphiphilic point of view. The results showed a different effect of the glucosidic moiety on the cmc value with respect to the glucopyridinium cationic surfactants. The surfactants also showed the tendency to form premicellar aggregates in solution when the hydrophobicity is raised.
The critical micelle concentration (c.m.c.) for four cationic surfactants, alkyl-trimethyl-ammonium bromides, was determined as a function of temperature by conductivity measurements. The values of the standard free energy of micellisation DeltaG degrees(mic) at different temperatures were calculated by using a pseudo-phase transition model. Then, from the diagram (-DeltaG degrees(mic)/T)=f(1/T), the thermodynamic functions DeltaH(app) and DeltaS(app) were calculated. From the plots DeltaH(app)=f(T) and DeltaS(app) = f(ln T) the slopes DeltaC(p) = n(w(H))C(p,w) and DeltaC(p)=n(w(S))C(p,w) were calculated, with the numbers n(w(H)) and n(w(S)) negative and equal and therefore defined simply as n(w). The number n(w)<0, indicating condensed water molecules, depends on the reduction of cavity that takes place as a consequence of the coalescence of the cavities previously surrounding the separate aliphatic or aromatic moieties. The analysis, based on a molecular model consisting of three forms of water, namely W(I), W(II), and W(III), respectively, was extended to several other types of surfactants for which c.m.c. data had been published by other authors. The results of this analysis form a coherent scheme consistent with the proposed molecular model. The enthalpy for all the types of surfactant is described by DeltaH(app)= -3.6 + 23.1xi(w)-xi(w)C(p,w)T and the entropy by DeltaS(app)= +10.2+428xi(w)-xi(w)C(p,w) ln T where xi(w)= |n(w)| represents the number of molecules W(III) involved in the reaction. The term Deltah(w)= +23.1 kJ mol(-1) xi(w)(-1) indicates an unfavourable endothermic contribution to enthalpy for reduction of the cavity whereas the term Deltas(w)= +428 J K(-1) mol(-1) xi(w)(-1) represents a positive entropy contribution for reduction of the cavity, what is the driving force of hydrophobic association. The processes of non polar gas dissolution in water and of micelle formation were found to be strictly related: they are, however, exactly the opposite of one another. In micelle formation no intermolecular electronic short bond is formed. We propose, therefore, to substitute the term "hydrophobic bond" with that of "hydrophobic association".
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