13 – MOLECULAR VARIATIONS BASED ON ISOSTERIC REPLACEMENTS

The replacement in an active molecule of an atom or a group of atoms by another one, presenting a comparable electronic and steric arrangement is based on the concept of isosterism. The development of the concept of isosterism has its roots in the attempts to extend to entire molecules the knowledge acquired for elements, especially the knowledge that two elements possessing an identical peripheral electronic distribution also possess similar chemical properties. The first example in the chapter clearly demonstrates that isosterism does not inevitably imply “isoelectric” structures, but it becomes evident that isoelectronic isosteres show the closest analogies. The main criterion for isosterism is that two isosteric molecules must present similar, if not identical, volumes and shapes. Ideally, isosteric compounds should be isomorphic and able to co-crystallize. Among the other physical properties that isosteric compounds usually share, one can cite boiling point, density, viscosity, and thermal conductivity. However, certain properties must be different: dipolar moments, polarity, polarization, size, and shape. It became evident to the physicists that the concept of isosterism, developed before quantum mechanical theories, could not provide, at the molecular level, the same results as those that the periodic classification had provided for the elements: a correlation between electronic structure, and physical and chemical properties. In the field of medicinal chemistry the isosterism concept, taken in its broadest sense, has proved to be a research tool of the utmost importance. The main reason for this is because isosteres are often much more alike in their biological than in their physical and chemical properties.