Ring equivalent

The importance of chemical rings in drug discovery is never overstated. Looking at the best selling drugs in 2006 reported in Table 15.9, it can be noticed that 8 out of 10 molecules are small molecules and that all of them have a chemical ring in their strnctnre. This trend is reflected 

The ADME (absorption, distribution, metabolism, excretion) profile as well as the toxicity of biologically active molecules can rely on the nature of a given ring such 

CHAPTER 15 Molecular Variations Based on Isosteric Replacements 

In all these cases no essential activity difference is found between the original drug and its isostere. However, 

FIGURE 15.9 The thiophene isostere of zonisamide is practically inactive as an anticonvulsant. 

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The reciprocal lattice of single crystal is a system of points. In the case of a plate texture, the axis of the reciprocal lattice is perpendicular to the specimen support. When a plate texture specimen is perpendicular to the electron beam, the diffraction pattern becomes a system of concentric rings (equivalent to the rotation of single crystal about the texture axis). 

The data in Table VII reveal that 2-, -11(N), 3-, -17(N), and 4-, -21(N), aromatic-ring compounds account for 23, 28, and 15% of the anthracene-oil bases. The ring equivalent -12, -18, and -22 hydrocarbons account for 14, 24, and 26% or a total of 64% of the anthracene-oil hydrocarbons. Thus, both the distribution and total percentage of 2-, 3-, and 4-ring aromatic compounds is similar for the bases and hydrocarbons. In contrast, the 2-, 3-, and 4- ring-aromatic compounds account for only 9,... 

The fact that aromatic hydrogens are deshielded compared to their vinyl cousins is a direct consequence of the magnetic anisotropy of the aromatic it system. Below is a depiction of the toluene molecule showing how the three ti bonds (six 7t electrons) are conjugated, that is, all the p orbitals (one on each sp2 ring carbon) are parallel. This makes all C-C bonds in the ring equivalent, halfway between single and double... 

Asymmetric reductions of prochiral ketones with (R,R)- or (5, 5 )-2,5-dimethyl-borolanes proceed with high enantioselectivity. The C(2) symmetry, which makes both faces of the borolane ring equivalent, is an important feature of these reagents. In the majority of cases, the presence of a C(2) symmetry axis within the chiral auxiliary can serve the very important function of dramatically reducing the number of competing diastereomeric transition states. 

To the ring equivalents the equivalence between —CH=CH— and —S— explaiiung the well-known analogy between benzene and thiophene (Table 15.3). 

There are many examples of ring equivalents and so far it seems impossible to rationalize a method that could give a reliable indication which heterocycle could be the best substitute of another one. The best approach is to look at the examples reported in the literature and learn from those. 

FIGURE 20.25 Acetylenic groups as aromatic ring equivalents. 

In order to estimate the magnitude of this secondary field, Pople replaced the induced current by a point dipole (at the centre of the ring) equivalent to the magnetic moment of the current loop (see Fig. 4). The magnetic moment, it will be recalled, is proportional to the current flowing in the loop (for which Pople used the Pauling 25> free electron value),... 

The substitution of —CH= by — N= in aromatic rings has been one of the most successful applications of classical isosterism (see following paragraph on ring equivalents). Aminopyrine and its isostere are about equally active as antipyretics (Fig. 13.5). 

The concept of ring equivalents has been generahzed to any possible heterocyclic system and represents a huge number of possible variations. Table 13.6 lists some less well-known studies on ring equivalents in aromatic series. 

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