The rationale for incorporation of the sulfur atom into the cyclic moieties of druglike compounds is multifold. Modulation of local or overall molecule polarity or other physical properties, adjustment of substituent trajectory in order to fine tune their placement in a ligand binding site to maximize complimentarity, and capitalization upon the larger size, yet greater polarizability, of the sulfur atom compared to carbon are but a few of the reasons for the prevalence of sulfur-containing rings in pharmaceutical agents. More recently, examples within the medicinal chemistry community have emerged featuring an additional, yet still underappreciated, role of sulfur in cyclic systems-- the ability of sulfur to serve as means of conformational control. Whereas examples of strategies such as cycle formation (e.g. amide to imidazole), intramolecular hydrogen bonding, use of macrocycles, etc. to enforce a particular, bioactive conformation are widespread, significantly less common from a medicinal chemistry perspective is the rational incorporation of sulfur into a ring system in order to bias a particular core or substituent orientation. Moreover, the electronic characteristics inherent to cyclic (particularly aromatic) sulfur compounds, from which these particular conformational characteristics arise, may also be at play to some extent in an intermolecular sense. This presentation discusses the structural and electronic characteristics of cyclic sulfur species, combining literature examples with theoretical and experimental data, in order to provide the physical basis, scope, and potential applications of sulfur-containing heterocycles beyond their use as straightforward carbocycle or non-sulfur heterocycle mimics.

Sulfur-containing heterocycles in drug design

249th National Meeting (2015)

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