Isosteric relationships

The isosteric relationship of benzene and thiophene has often led medicinal chemists to substitute the sulfur containing heterocycle for benzene drugs in biologically active molecules. That this relationship has some foundation in fact is attested by the observation that the resulting analogs often possess full biologic activity. Alkylation of the diamine, 71 (obtained from aniline and the chloroethylamine), with 2-chloromethylthiophene affords the antihistamine methaphenylene (72) The correspond-... 

As may be expected from the isosteric relationship between the two ring-systems, 1,2,4-thiadiazoles and the corresponding pyrimidine derivatives show certain similarities in their physical properties. Thus, the boiling points of the parent compounds are strikingly similar5 (see Table V). 

SAR of Diphenhydramine. The antihistaminic drug may be viewed as possessing an isosteric relationship with adiphenine an antispasmodic i. e., the latter has an additional carbonyl moiety to give it the status of the ester compound as given below ... 

Classical medicinal chemistry has often recognized the isosteric relationship of sulfur and the vinylene group. Accordingly, we have prepared several 13-thia-15-hydroxy analogs, which in isosteric terms also may be considered congeneric to the i3-i5-deoxy-16-hydroxy series. These 13-thia congeners were... 

The isosteric relationship of sulfur and vinylene has often been recognized, and on occasion an exchange of one for the other has provided analogs of interest. However, this concept has not proven useful in the prostaglandin series, the 13-thia derivatives (see Scheme 35) having less than 1% the activity of the parent A -15-deoxy-16-hydroxy (or A 3 i5 hy(jroxy) compound (91). 

Although isoelectronic and isosteric relationships are usually attributed to Langmuir, they were extended by Grim and Erlenmeyer. Grimm [121-123] considered all molecules with the same number of valence electrons regardless of the number of atoms involved and used isomorphism as a criterion. Erlenmeyer concluded that only the outer number of electrons should be counted in proposing iso-sterism and applied it widely to organic molecules [124],... 

Five novel carbonates/ designed as suicide (mechanism-based) inhibitors of acetylcholinesterase, were synthesized and evaluated against the enzyme in vitro and screened for insecticidal activity. The design strategy of inhibition was based on the isosteric relationship of carbonates to the ester of the natural substrate acetylcholine, and on the release of electrophilic quinone methides or alpha-chloroketones at the active site after enzymatic carbonate hydrolysis. Most coirpounds were inhibitory in vitro, with good specificity for acetylcholinesterase. Some showed modest insecticidal activity. Results of kinetic studies on one analog were consistent with mechanism-based inhibition. 

It is generally assumed that isosteric thermodynamic heats obtained for a heterogeneous surface retain their simple relationship to calorimetric heats (Eq. XVII-124), although it may be necessary in a thermodynamic proof of this to assume that the chemical potential of the adsorbate does not show discontinu-... 

Figures la and lb are typical curves found for the heat of immersion of polar solids in water (and are also foimd for polar and nonpolar solids in organic liquids). An example of Fig. la is found in the immersion of chrysotile asbestos having known and increasing amounts of physically adsorbed water on its surface (S ). The linear relationship between the heat of wetting and the volume adsorbed up to about a monolayer is significant and indicates surface homogeneity since the heat evolved is proportional to the amount of bare surface present. In accord with this finding, the isosteric heat values calculated from adsorption isotherms increased with coverage to a maximum near the monolayer as expected for adsorption on a surface possessing nearly uniform sites.

Equation (90) shows that the isosteric heat of adsorption is evaluated by comparing the equilibrium pressure at different temperatures for samples showing the same amount of surface coverage. The data of Figure 9.7 may be used as an example to see how this relationship is applied. 

What is isosteric heat of adsorption How is it related to the pressure-versus-temperature relationship at constant surface coverage ... 

The data shown in Table 2 illustrate the general paucity of comparative toxicity data within an isosteric series of chemicals. In this Table a variety of toxic end-points observed for benzene and naphthalene have been compared with those of their simple heterocyclic analogues, and it is clear that it is almost impossible to derive chemical structure-biological activity relationships from the published literature for even such a simple series of compounds. Even basic estimates of mammalian toxicity such as LD50 values cannot be accurately compared due either to the absence of relevant data or the noncomparability of those available. Thus in a field where there are little comparative data on the relative toxicity to mammals of pyrrole, thiophene and furan for example, it is difficult to relate chemical structure to biological activity in historical heterocyclic poisons such as strychnine (3) and hemlock [active agent coniine (4)]. 

Table 3 Structure-Activity Relationships Reported for Structural Analogues and Isosteres of 2,3,7,8-TetrachIorodibenzo-p-dioxin (TCDD) ... 

Alternatively, an appropriate isotherm expression may be substituted in Equation 1 to obtain an explicit relationship between the isosteric heat of adsorption and the adsorbent loading (3). The validity of these calculated heats is based upon the assumptions that the differential adsorption... 

The ability to obtain isotherms on individual groups also enable the calculation of the isosteric heat of adsorbtion on that site (as distinct from the heats of adsorption averaged over the whole surface which are normally obtained from adsorption isotherms). Relationships between the OH frequency shifts and heats of adsorbtion have been obtained this way (18). A relationship between the frequency shift and the ionisation potential of the adsorbing molecules has been demonstrated by several authors (20-22) and a theoretical explanation based on the Mullikan-Puranik approach to H-bonding has been given by Low and Cusamano (23). 

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