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.

2.5. Ionic Liquids Presented in This Review 2020 3. Cyclocondensation Reactions 2020 4. Synthesis of Three-Membered Heterocycles 2022 4.1. Aziridines 2022 5. Synthesis of Five-Membered Heterocycles 2022 5.1. Pyrroles 2022 5.2. Furans 2022 5.3. Thiophenes 2023 5.4. Pyrazoles 2024 5.5. Imidazoles 2025 5.6. Isoxazoles 2027 5.7. Oxazoles, Oxazolines, and Oxazolidinones 2027 5.8. Thiazoles and Thiazolidinones 2028 6. Synthesis of Six-Membered Heterocycles 2030 6.1. Pyridines 2030 6.2. Quinolines 2031 6.3. Acridines 2033 6.4. Pyrans 2033 6.5. Flavones 2035 6.6. Pyrimidines and Pyrimidinones 2035 6.7. Quinazolines 2037 6.8. -Carbolines 2038 6.9. Dioxanes 2039 6.10. Oxazines 2039 6.11. Benzothiazines 2040 6.12. Triazines 2040 7. Synthesis of Seven-Membered Heterocycles: Diazepines 2041

Ionic liquids in heterocyclic synthesis.

The therapeutic journey of benzimidazoles: a review.

Alpha-fluorinated ethers, thioethers, and amines: anomerically biased species.

Squaramides are remarkable four-membered ring systems derived from squaric acid that are able to form up to four hydrogen bonds. A high affinity for hydrogen bonding is driven through a concomitant increase in aromaticity of the ring. This hydrogen bonding and aromatic switching, in combination with structural rigidity, have been exploited in many of the applications of squaramides. Substituted squaramides can be accessed via modular synthesis under relatively mild or aqueous conditions, making them ideal units for bioconjugation and supramolecular chemistry. In this tutorial review the fundamental electronic and structural properties of squaramides are explored to rationalise the geometry, conformation, reactivity and biological activity.

Squaramides: physical properties, synthesis and applications

Synthetic entries to 6-fluoro-7-substituted indole derivatives

The synthesis and structural characterization of way-120,491; a novel potassium channel activator

3-hydroxy-3-cyclobutene-1,2-dione: Application of novel carboxylic acid bioisostere to an in-vivo active non-tetrazole angiotensin-II antagonist

There are disclosed compounds of general formula (I) wherein X is H, NR?12R13, OR14?, CN, F, Cl, I, Br, perfluoroalkyl, alkyl, alkoxy, alkyl-OH, alkoxyalkyl, -(CH?2?)nCO2R?14?, -(CH?2?)nCONR?12R13?; Y is NR?15, NR18CR16R17, CR16R17NR15; R1? is 5-tetrazolyl, CO?2?R?14, SO?3H, NHSO2CH3, NHSO2CF3; R2, R3 is H, alkyl, alkoxy, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, CN, NO?2?, SO2R?19?, -(CH?2?)nCO2R?14?, -(CH?2?)nCONR?12R13, OR14?, F, Cl, Br, I, NR?12R13; R4-R11? is H, F, alkyl, alkoxy, alkoxyalkyl, -OCOR14, alkyl-OH, perfluoroalkyl, aralkyl, aryl, CN, NO?2?, SO2R?19?, -(CH?2?)nCO2R?14?, -(CH?2?)nCONR?12R13?, OH, OR?14, -NR12R13?, any two geminal groups can be O or CH?2?; R?12, R13? is H, alkyl, aralkyl; R14 is H, alkyl, aralkyl, alkoxyalkyl; R16, R17 is H, alkyl, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, CN, NO?2?, SO2R?19?, -(CH?2?)nCO2R?14?, -(CH?2?)nCONR?12R13; R18? is H, alkoxyalkyl, alkyl-OH, perfluoroalkyl, aralkyl, OR14, -(CH?2?)nCO2R?14?, -(CH?2?)nCONR?12R13?, alkyl, -COR?14, -CONR12R13; R19? is alkyl, aralkyl; n is 0, 1, 2 or 3; m is 1-5; wherein alkyl is defined as 1-8 carbons, branched or straight chain; perfluoroalkyl is defined as 1-6 carbons; aralkyl is defined as 7-12 carbons or 7-12 carbons substituted with fluorine, bromine or chlorine; aryl is defined as 6-10 carbons or 6-10 carbons substituted with fluorine, bromine or chlorine and the pharmaceutically acceptable salts thereof, which by virtue of their ability to antagonize angiotensin II are useful for the treatment of hypertension and congestive heart failure. The compounds are also useful for reducing lipid levels in the blood plasma and are thus useful for treating hyperlipidemia and hypercholesterolemia. Also disclosed are processes for the production of said compounds and pharmaceutical compositions containing said compounds.

Pyrimidocycloalkanes as angiotensin ii antagonists

N-sulfonamides of benzopyran-related potassium channel openers: Conversion of glyburide insensitive smooth muscle relaxants to potent smooth muscle contractors

Richard M. Soll

Papers

Synthetic entries to 6-fluoro-7-substituted indole derivatives

The synthesis and structural characterization of way-120,491; a novel potassium channel activator

3-hydroxy-3-cyclobutene-1,2-dione: Application of novel carboxylic acid bioisostere to an in-vivo active non-tetrazole angiotensin-II antagonist

Pyrimidocycloalkanes as angiotensin ii antagonists

N-sulfonamides of benzopyran-related potassium channel openers: Conversion of glyburide insensitive smooth muscle relaxants to potent smooth muscle contractors