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

The estradiol pharmacophore: Ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site

A continual challenge in the field of chemical detection is the development of approaches to designing microsensors and microsensor-based detectors with high selectivity. No single science exists to unite all sensor technologies with a common set of principles and a common approach to achieving selectivity. Nevertheless, in the area of vapor detection, sorption phenomena and solubility interactions can be identified as common features of many sensors. In designing microsensors for vapor detection, interactive coating materials must be chosen that will collect and concentrate analyte molecules at the sensor's surface. The sensitivity and selectivity of each individual sensor is controlled by tailoring the chemical and physical properties of the coating material to maximize particular solubility interactions. The selection of coatings for the complete sensor array is logically made through a systematic variation of the solubility properties of the coating materials, so that each sensor is selective for a different balance of solubility interactions. This account discusses solubility in great detail. Parameters and methodologies for characterizing analyte solubility properties, sensor coating material solubility properties, and their interactions are presented. Specific functional groups are recommended for inclusion in sensor coating materials in order to maximize particular interactions. In addition, the treatment of coating material properties is integrated with consideration of the factors that influence chemical selectivity in sensor arrays. Methods for choosing coatings inteligently for sensor arrays, and for optimizing sensor arrays for particular analytes are considered.

https://apps.dtic.mil/sti/pdfs/ADA224957.pdf

Solubility interactions and the design of chemically selective sorbent coatings for chemical sensors and arrays

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

Hydrogen-bonding. Part 6. A thermodynamically-based scale of solute hydrogen-bond basicity

A novel calorimetric method has been derived for the simultaneous determination of equilibrium constants and enthalpies of complexation of monomeric carboxylic acids with bases in an inert solvent. The method requires a knowledge of the corresponding equilibrium constants and enthalpies for the monomer/dimer equilibrium in the same solvent. Both sets of K° and ΔH° values have been obtained for a number of carboxylic acids (and some other hydrogen-bond donors) in 1,1,1-trichloroethane at 298 K, using N-methylpyrrolidinone as a standard base. For the first time, it is possible to evaluate the relative hydrogen-bonding strength of monomeric carboxylic acids and other hydrogen-bonding species in an inert solvent. It is shown that unactivated carboxylic acids are no stronger than simple phenols: equilibrium constants for hydrogen bonding towards N-methylpyrrolidinone are acetic acid (109), benzoic acid (118) and phenol (137). It is further shown that the monomeric carboxylic acids are ca. 20 times as strong as the dimeric acids towards N-methylpyrrolidinone (NMP) in 1,1,1-trichloroethane, with respect to the formation of the species RCO2H·NMP in each case.

Hydrogen bonding. Part 1.—Equilibrium constants and enthalpies of complexation for monomeric carboxylic acids with N-methylpyrrolidinone in 1,1,1-trichloroethane

Enthalpies of solution of seven phenols and of NMP have been determined in 1,1,1-trichloroethane and in tetrachloromethane at 298 K. Combination with our previously determined enthalpies of complexation, ΔH°, of the phenols with NMP leads to enthalpies of transfer of the hydrogen-bond complexes ArOH ‥ NMP from 1,1,1-trichloroethane to tetrachloromethane. The substituent-dependent behaviour of values of ΔH° in the two solvents arises exclusively from the effect of the solvents on the reactant phenols and not on the complexes themselves. This finding confirms the suggestion that the ΔH° values in 1,1,1-trichloroethane contain a contribution from association of the phenols with the solvent itself, probably of the dipole–dipole type.

Hydrogen bonding. Part 3.—Enthalpies of transfer from 1,1,1-trichloroethane to tetrachloromethane of phenols, N-methylpyrrolidinone (NMP) and phenol–NMP complexes

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

Hydrogen-bonding. Part 6. A thermodynamically-based scale of solute hydrogen-bond basicity

Hydrogen bonding. Part 1.—Equilibrium constants and enthalpies of complexation for monomeric carboxylic acids with N-methylpyrrolidinone in 1,1,1-trichloroethane

Hydrogen bonding. Part 3.—Enthalpies of transfer from 1,1,1-trichloroethane to tetrachloromethane of phenols, N-methylpyrrolidinone (NMP) and phenol–NMP complexes