Isosteric Substitution as a Strategy for the Design of Safer Chemicals

A discussion on how to derive a QSAR regression equation is beyond the scope of this chapter. However, in addition to the paper by Grogan et al. [8], a number of books are available on QSAR, and most provide many different descriptors and QSAR regression equations that correlate the specific biological activities (e.g., acute toxicity) of various classes of substances with physicochemical properties. Books that are more suited for the beginner are listed in the reference section [63-66]. The reader is encouraged to examine these books for detailed discussions on the development and applications of QSAR equations. 

Isosteric Substitution as a Strategy lor the Design of Safer Chemicals 

Substances that have similar molecular and electronic characteristics but are not necessarily structurally related often have similar physical or other properties. Langmuir called this phenomenon isosterism, and coined the term isostere [67]. According to Langmuir s definition, isosteres are substances or substituents that have the same charge, caused by the same number and arrangement of electrons and the same number of atoms. 

Benzene (33) is isosteric with pyridine (34) and thiophene (35) because the -CH=CH- group is isosteric with -N= and -S- atoms. Although these substances are structurally different, some of their chemical properties are nonetheless similar. All of them are aromatic, all are liquid, and all are about equal in molecular size and volume. In fact, both 33 and 35 boil at about 81 °C. 

Substances that are isosteric equivalents of substances that are toxic or pharmacologically active may also possess these biological properties. It is also possible that biological properties may be bestowed, exacerbated, or attenuated when isosteric modifications are made. This point is illustrated by the following examples. 7-Methyl-benz[a]anthracene (36) is a known carcinogen, whereas 7-methyl-l-fluorobenz[o] 

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