Bioisosterism concept

Many compounds have been identified that comply with the "biology" aspect of the bioisostere concept but that do not fit the strict chemical (steric and electronic) definition of... 

F. The bioisosterism concept F. Reversal of functional groups C. Bioisosteries involving... 

Indeed scaffold hopping can be interpreted as the broadest expansion of the bioisosterism concept. The idea of scaffold hopping is indeed not new, it is rather a new term to designate known experimental evidences. A retrospective analysis of the marketed drugs and/or of the ligands acting... 

In this paragraph two applications of the bioisosterism concept that imply unusual behaviors of commonly encountered atoms or groups are discussed. 

The oldest example of the use of nonclassical isosteres involves the replacement of the carboxamide in foUc acid by sulfonamide, to give the sulfanilamides. Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addition to the exploitation of auxiliary binding sites on dihydrofolate reductase. This concept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the same nnmber of atoms or identical electron structure — is really the classical structure modification approach. 

The concept of bioisosterism is at the heart of drug design. As a concept, it existed in the minds of medicinal chemists long before the term was introduced (Friedman, 1951). 

The concept of bioisosterism has been used to theoretically evaluate structural variation Organophosphorous Agrochemicals within the lead structures of synthetic or natural origin prior to and during the preparation Insecticides (Tables 17.3a,b). Oiganophorous of molecules of specified efficacy, safety, sta- insecticides bind to Acetylcholinesterase (AchE),... 

In the optimisation process, we realized that the concept of bioisosterism and the available data for quantitative structure-physical property relationships were potentially a great help to pursue the optimisation effectively. But at the same time I should mention that even if comprehensive lists of bioisosteres and physicochemical parameters of... 

The concept of bioisosterism derives from Langmuir s (l)observationthat certain physical properties of chemically different substances (e.g., carbon monoxide and nitrogen, ketene and diazomethane) are strikingly similar. These similarities were rationalized on the basis that carbon monoxide and nitrogen both have 14 orbital electrons and, similarly. 

Other interesting new chemistry using bioisosteres is presented in the benzylnitramines of American Cyanamid, the vinylogous ureas of Stauffer, the tetrahydrofuranes of Chevron, and triazinones of FMC. The nitramines of this current example seem to function as a bioisostere of a carboxylic acid. The vinylogous ureas are another example of a possible homologous bioisostere at work. And finally, the triazinones appear to behave as imide bioisosteres. These certainly are concepts which merit wider attention. 

Recognizing the usefulness of the isosterism concept in the design of biologically active molecnles, Friedman proposed to call bioisosteres componnds... 

The apparent failure of the isosterism concept for the inactive thiophene, inversed furan and pyrimidine is thus interpretable on a rational basis. In Table 15.10 are listed some more exotic examples of bioisosteric replacements of cyclic systems. 

In this section we describe some exotic applications of the bioisostery concept implying the utilization of unusual elements such as silicon, boron, selenium, arsenic, and antimony. The use of those elements as bioisosteres of carbon in existing drugs is a different approach enabling the introduction of a new drug-like chemical space into the drug discovery and development process. 

Transition state isostere Enzymes catalyze reactions by lowering the energy barrier that separates the substrate from the product. L. Pauling and others postulated that a substrate intermediate, the transition state, fits the enzyme better than both the substrate and the product, thereby favoring the conversion. This concept led to the design of enzyme inhibitors that resemble this transition state (bioisosteres) in order to better compete with the substrate, because of their higher affinity for the enzyme. 

The rationale applied in miniaturizing renin inhibitors to achieve clinically useful compounds by eliminating their protein nature and increasing inhibitory potency has, of course, wider ramifications. Judicious use of bioisosteric replacements and the relevancy of the transition-state analogy concept can also be applied with similar success to polypeptide neurotransmitters. 

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