The concept of isosterism between relatively simple chemical entities was originally contemplated by James Moir in 1909, a notion further refined by H. G. Grimm’s hydride displacement law and captured more effectively in the ideas advanced by Irving Langmuir based on experimental observations. Langmuir coined the term “isostere” and, 18 years in advance of its actual isolation and characterization, predicted that the physical properties of the then unknown ketene would resemble those of diazomethane. The emergence of bioisosteres as structurally distinct compounds recognized similarly by biological systems has its origins in a series of studies published byHans Erlenmeyer in the 1930s, who extended earlier work conducted by Karl Landsteiner. Erlenmeyer showed that antibodies were unable to discriminate between phenyl and thienyl rings or O, NH, and CH2 in the context of artificial antigens derived by reacting diazonium ions with proteins, a process that derivatized the ortho position of tyrosine, as summarized in Figure 1 The term “bioisostere” was introduced by Harris Friedman in 1950 who defined it as compounds eliciting a similar biological effect while recognizing that compounds may be isosteric but not necessarily bioisosteric. This notion anticipates that the application of bioisosterism will depend on context, relying much less on physicochemical properties as the underlying principle for biochemical mimicry. Bioisosteres are typically less than exact structural mimetics and are often more alike in biological rather than physical properties. Thus, an effective bioisostere for one biochemical application may not translate to another setting, necessitating the careful selection and tailoring of an isostere for a specific circumstance. Consequently, the design of bioisosteres frequently introduces structural changes that can be beneficial or deleterious depending on the context, with size, shape, electronic distribution, polarizability, dipole, polarity, lipophilicity, and pKa potentially playing key contributing roles in molecular recognition and mimicry. In the contemporary practice of medicinal chemistry, the development and application of bioisosteres have been adopted as a fundamental tactical approach useful to address a number of aspects associated with the design and development of drug candidates. The established utility of bioisosteres is broad in nature, extending to improving potency, enhancing selectivity, altering physical properties, reducing or redirecting metabolism, eliminating or modifying toxicophores, and acquiring novel intellectual property. In this Perspective, some contemporary themes exploring the role of isosteres in drug design are sampled, with an emphasis placed on tactical applications designed to solve the kinds of problems that impinge on compound optimization and the long-term success of drug candidates. Interesting concepts that may have been poorly effective in the context examined are captured, since the ideas may have merit in alternative circumstances. A comprehensive cataloging of bioisosteres is beyond the scope of what will be provided, although a synopsis of relevant isosteres of a particular functionality is summarized in a succinct fashion in several sections. Isosterism has also found productive application in the design and optimization of organocatalysts, and there are several examples in which functional mimicry established initially in a medicinal chemistry setting has been adopted by this community.

Synopsis of some recent tactical application of bioisosteres in drug design.

Structure-based ligand design in medicinal chemistry and crop protection relies on the identification and quantification of weak noncovalent interactions and understanding the role of water. Small-molecule and protein structural database searches are important tools to retrieve existing knowledge. Thermodynamic profiling, combined with X-ray structural and computational studies, is the key to elucidate the energetics of the replacement of water by ligands. Biological receptor sites vary greatly in shape, conformational dynamics, and polarity, and require different ligand-design strategies, as shown for various case studies. Interactions between dipoles have become a central theme of molecular recognition. Orthogonal interactions, halogen bonding, and amide⋅⋅⋅π stacking provide new tools for innovative lead optimization. The combination of synthetic models and biological complexation studies is required to gather reliable information on weak noncovalent interactions and the role of water.

Molecular Recognition in Chemical and Biological Systems

Four-membered ring-containing spirocycles: synthetic strategies and opportunities.

Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3-position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3-substituted oxetanes. It also includes a discussion of the site-dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

The four-membered oxetane ring has been increasingly exploited for its contrasting behaviors: its influence on physicochemical properties as a stable motif in medicinal chemistry and its propensity to undergo ring-opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last five years up to the end of 2015. These methods are clustered by strategies for preparation of the ring and further derivatization of preformed oxetane-containing building blocks. Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally, examples of oxetane derivatives in ring-opening and ring-expansion reactions are described.

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Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry

Spirocyclic Oxetanes: Synthesis and Properties

Inside Cover: Spirocyclic Oxetanes: Synthesis and Properties (Angew. Chem. Int. Ed. 24/2008)

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Spirocyclic Oxetanes: Synthesis and Properties

Inside Cover: Spirocyclic Oxetanes: Synthesis and Properties (Angew. Chem. Int. Ed. 24/2008)