Bioisosteric replacement classical

Note broadly similar biological properties. Bioisosteric replacement must allow a number of properties to remain, and some to be altered. Thus, one may allow selective binding to a receptor to remain, but alter an agonist to an antagonist. This is the classical approach to many drugs that was pursued long before the term bioisostere was invented. 

The thiocarbonyl group is a classic bioisosteric replacement for the carbonyl group which has been widely exploited in medicinal chemistry. This is illustrated with the preparation of thioketones derived from thiocolchicine283 and isothiocolchicine284 which exhibited high antitubulin activity (equation 38). 

Bioisosterism is a key concept in modern medicinal chemistry. This chapter has provided an in-depth overview of the types of classical bioisosteric replacements with real-world exemplars of successful bioisosteric replacements from the literature. 

The first part of this book covers the historical aspects of bioisosterism, from its founding principles of isosterism from Langmuir through defined sets of classical isosteres and bioisosteres, to the potential consequences of bioisosteric replacement in context. 

Figure 9.2 Structural analogs of classical bioisosteric replacement of antipsychotic drugs.

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. 

Structure-activity correlations in the P-lactam antibiotic field have required drastic re-evaluation in view of the novel structures described above. Apparently, only the intact P-lactam ring is an absolute requirement for activity. The sulfur atom can be replaced (moxalactam) or omitted (thienamycin), and the entire ring itself is, in fact, unnecessary (nocardicin). The carboxyl group, previously deemed essential, can be replaced by a tetrazolyl ring (as a bioisostere), which results in increased activity and lactamase resistance. The amide side chain, so widely varied in the past, is also unnecessary, as shown in the example of thienamycin. There is a considerable literature analyzing the classical structure-activity relationships of the penicillin and cephalosporin groups. 

Some non-classical isosteres are reported in Table 15.5 and from a brief glance it can be noticed that they do not obey the steric and electronic definition of classical isosteres. A second notable characteristic of non-classical bioisosteres is that they do not have the same number of atoms as the substituent or moiety for which they are used as a replacement. 

Table 2.9. Classical Bioisosteres (Groups Within the Row Can Replace Each Other)...

In order to calculate the similarity between fragments (substituents, spacers, or rings) that one wants to replace in the process of bioisosteric design, it is necessary to quantify somehow their properties and express them as a set of numerical values -descriptors. In the classical years of quantitative structure-activity relationship (QSAR), the properties of substituents were mostly characterized by experimentally derived parameters. Hammett sigma constants a (and several variations of this parameter) played a prominent role in characterizing the electron-donating or electron-accepting power of substituents 7], and the Hansch n parameter, defined... 

JMC5309). Phosphate function is known to be advantageously replaced by a phosphonate, and a-fluoromethylene- or a,a -difluoromethylene-phosphonates are considered as better bioisosteres of the phosphate group. Replacement of one or two hydrogens of a methylene group is classically used to modulate metabolism or off-target activity. 

The only structural difference between these two examples (Fig. 18.19) is represented by the heteroatom which makes them classical bioisosteres since both oxygen and sulphur have the same valence. Both may be classified as mixed 5-HT/NA reuptake inhibitors but replacement of the oxygen atom with sulphur appears to shift the selectivity from NAT to SERT. 

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