This review summarizes the multifaceted aspects of antioxidants and the basic kinetic models of inhibited autoxidation and analyzes the chemical principles of antioxidant capacity assays. Depending upon the reactions involved, these assays can roughly be classified into two types:  assays based on hydrogen atom transfer (HAT) reactions and assays based on electron transfer (ET). The majority of HAT-based assays apply a competitive reaction scheme, in which antioxidant and substrate compete for thermally generated peroxyl radicals through the decomposition of azo compounds. These assays include inhibition of induced low-density lipoprotein autoxidation, oxygen radical absorbance capacity (ORAC), total radical trapping antioxidant parameter (TRAP), and crocin bleaching assays. ET-based assays measure the capacity of an antioxidant in the reduction of an oxidant, which changes color when reduced. The degree of color change is correlated with the sample's antioxidant concentrations. ET-based assays include th...

The Chemistry behind Antioxidant Capacity Assays

Room temperature ionic liquids as novel media for ‘clean’ liquid–liquid extraction

The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.

Synopsis of some recent tactical application of bioisosteres in drug design.

Scales of solute hydrogen-bonding: their construction and application to physicochemical and biochemical processes

Artificial Organic Host Molecules for Anions

A scale of solute hydrogen-bond acidity has been constructed using equilibrium constants (as log K values) for complexation of series of acids (i) against a given base in dilute solution in tetrachloromethane, equation (A). Forty-five such equations have been solved to yield LB and DB, log Ki=LB log KAHI+DB(A) values characterising the base, and log KAH values that characterise the acid. In this analysis, use has been made of the novel observation that all the lines in equation (A) intersect at a given point where log K= log KAH=–1.1 with K on the molar scale. Some 190 log KAH values that constitute a reasonably general scale of solute hydrogen-bond acidity have been obtained. It is shown that there is no general connection between log KAH; and any proton-transfer quantities, although certain family dependences are obtained. A number of acid-base combinations are excluded from equation (A), and alternative log KAHE values have been determined for such cases. The general log KAH values may be transformed into α2H values suitable for use in multiple linear-regression analysis through the equation α2H=(log KAH+ 1.1)/4.636.

Hydrogen bonding. Part 10. A scale of solute hydrogen-bond basicity using log K values for complexation in tetrachloromethane

Hydrogen bonding equilibrium constants have been measured for a large and varied selection of proton donors against a common acceptor (N-methylpyrrolidinone) and of proton acceptors against a common donor (4-nitrophenol). Together these have been used to create the log Kα and log Kβ scales of proton donor and acceptor ability which are explicitly targeted to the needs of the medicinal chemist in the context of potential drug–receptor interactions. To this end they have been measured in 1,1,1-trichloroethane, a solvent never before used for hydrogen bonding studies but whose high dipolarity is considered a much better model for real biological membranes than the very non-polar solvents that have previously been employed. It is shown that this solvent imposes significant ranking changes on the solutes, since the charge transfer element in hydrogen bonding is reinforced at the expense of the purely electrostatic component. Nevertheless it is possible to scale previous data in such a way that over 80 functional group log Kα and log Kβ values become available to the medicinal chemist (Table 4). In addition, data are given for a large number of parent heterocycles, most of which have never before been studied. We note that heterocycles are uniquely able to ‘fine-tune’ these scales, so providing at least one justification for their special interest to the medicinal chemist.In addition to equilibrium constants we have measured the spectroscopic quantities ΔνCO(for donors) and βsm(for acceptors). On various lines of evidence we suggest that these are enthalpy-related quantities and, following previous arguments, may function as alternative parameters suitable for use by the medicinal chemist under conditions of severe steric constraint.Cross-comparisons of these data allow conclusions to be drawn which considerably illuminate the factors that influence hydrogen bond strength, and some of which have no precedent. A selection follows. Where a level comparison can be made, the donor order is OH > NH > CH and the acceptor order is N > O > S. However, within each category there are various sorts of family relationship. For example, phenols and alkanols lie on separate lines of log Kαvs. pKa, and a similar separation for log Kβ is shown by 5- and 6-membered ring heterocycles. By contrast, OH and NH donors show a single relation between log Kα and ΔνCO, negative deviations from which are satisfactorily accounted for in terms of steric and stereoelectronic factors. The most important of the latter is lone-pair repulsion: ‘α-effect’ heterocycles are anomalously strong acceptors, whereas certain classes of donor, notably sulphonamides and carboxylic acids, are much weaker than would be expected from their pKa values. More subtle anomalies attach, inter alia, to heterocycles as donors, CH donors generally, and amines and sulphonamides as acceptors; all however can be rationalised.The extremes of both scales are charted. Alkyl thiols and amines are negligible as proton donors; correspondingly, π-donor hetero-atoms as e.g. in esters and amides are negligible acceptors. At the opposite extreme, heterocycles such as tetrazole and 4-quinolone figure prominently. Based on these results, some structural criteria are suggested that might lead to the synthesis of stronger proton acceptors than any so far known.

Hydrogen bonding. Part 9. Solute proton donor and proton acceptor scales for use in drug design

A general treatment of hydrogen bond complexation constants in tetrachloromethane

An LSER analysis of log P for the ‘critical quartet’ of solvent systems has been carried out using, as initial variables, VI for volume, µ2 for dipolarity, and proton donor ∑α and proton acceptor βf scales based on log Kα and log Kβ respectively A common data matrix and an unprecedented range of functionalities have been employed By making the analysis stepwise, starting with the simplest solutes and adding more in order of increasing complexity, we have been able to identify hitherto unrecognised variables and ‘fine-tune’ established ones in such a way as to derive self-consistent proton donor and acceptor values applicable to the whole range of solvent systems By this ‘LSER in reverse’ we have established, inter alia, the following new facts: (a)βf possesses a constant effective zero whereas that for ∑α is solvent-sensitive; (b) a new term nβf is required for acceptor solutes with two or more available lone pairs; (c) when neither lone pair is available, the acceptor strength of carbonyl is sharply reduced; (d) a second term specific to NH2 is required for ∑α in alkane and chloroform; (e) there is mutual shielding of XH and one lone pair in structures such as CO2H and CONH2; (f) ureas and other structures with parallel NH functions are proton donors of exceptional strength; (g) the acceptor ability of dipolar bases (PO and SO) varies with the solvent systemCooperativity in solute–solvent bonding exists but takes complex forms, and does not appear strong enough to account eg for the hydrogen bonding properties of bulk water and the alcohols, for which mass action appears a likelier explanation We present evidence (see Appendix) that mass action will most probably explain certain well known anomalies in the apparent proton acceptor ability of water as revealed by partitioning studiesThe present results throw new light on previously anomalous octanol–water log P values and can predict f-values for other solvent systems Most importantly, they provide new information not only on the strength of hydrogen bonding for more than 60 functional groups, but also on its directionality: we are able to predict, with reasonable certainty, which XH groups and lone pairs are actually available for bonding This information is applicable to water, other solvents, and by implication to the biophase, so should find direct and immediate use in rationalising and quantifying drug–receptor interactions

Model solvent systems for QSAR. Part 3. An LSER analysis of the ‘critical quartet.’ New light on hydrogen bond strength and directionality

Antiandrogenic activity is observed in anilides containing a tertiary hydroxyl group, and these compounds are used to define a pharmacophore in terms of their physicochemical properties. Infrared spectroscopy shows that these anilides exist in a single conformation, which exerts a powerful influence on the hydrogen-bond donor ability of the hydroxyl group in a model system. Arguments are presented which suggest that hydrogen-bonding ability is an important contributor to biological activity. Compounds were synthesized that reproduced these properties in series not containing an amide bond. Such compounds were found to exhibit good antiandrogen activity. We suggest that quantitative information on hydrogen bonding might also be useful in other systems.

Non-steroidal antiandrogens. Design of novel compounds based on an infrared study of the dominant conformation and hydrogen-bonding properties of a series of anilide antiandrogens.

Jeffrey J. Morris

Papers

Hydrogen bonding. Part 10. A scale of solute hydrogen-bond basicity using log K values for complexation in tetrachloromethane

Hydrogen bonding. Part 9. Solute proton donor and proton acceptor scales for use in drug design

A general treatment of hydrogen bond complexation constants in tetrachloromethane

Model solvent systems for QSAR. Part 3. An LSER analysis of the ‘critical quartet.’ New light on hydrogen bond strength and directionality

Non-steroidal antiandrogens. Design of novel compounds based on an infrared study of the dominant conformation and hydrogen-bonding properties of a series of anilide antiandrogens.