Bioisostere classical

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. 

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). 

Table 4.3 Examples of isosteres. Each horizontal row represents a group of structures that are isosteric. Classical isosteres were originally defined by Erlenmeyer as atoms, ions and molecules with identical shells of electrons. Bioisosteres are groups with similar structures that usually exhibit similar biological activities...

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. 

FIGURE 15.10 Ligands for central cholinergic receptors with different non-classical bioisosteres of the pyridine ring. 

Examples from literature show that there are several non-classical bioisosteres for the pyridine system or the pyridazine system. Which is the rationale behind this in order to choose the most appropriate analog to start with An indication could be given by the comparison of the boiling points... 

FIGURE 15.21 An example of bioisosterism, or non-classical isoster-ism GABA, isoguvacine, and THIP are all agonists for the GABA-A receptor. The 3-hydroxy-isoxazole ring has a comparable acidity to that of a carboxylic acid function. ... 

The preceding discussion on isosterism dealt mainly with the types of isosteres that may be considered classic (i.e., that is where the molecule bears a more or less readily apparent structural relationship to the parent compound). If one interprets bioisosteric relationships more broadly, less readily apparent similarities may result in useful new drugs. These might aptly be considered nonclassic isosteres. 

The term non-classical isosterism is often used, interchangeably with the term bioisosterism, for example, when one has to deal with isosteres that do not possess the same number of atoms, but which have in common some key parameter of importance for the activity in a given series. Thus, the two GABAergic agonists isoguvacine and THIP (Fig. 13.3) possess similar pharmacological properties to GABA itself. The key parameters in these compounds are... 

In the histaminic H2 receptor antagonist series, the classical urea-thiourea-guanidine progression was successfully completed by the use of the V-nitro and V-cyanoguanidines and, later on, by l,l-diamino-2-nitroethylene groups (Fig. 13.19). Cyano amidines and carbamoyl amidines were also used, and structure-activity relationship patterns were rationalized in terms of dipole moment orientation of related bioisosteric groups. ... 

Functional moieties which either fulfil or satisfy the original conditionalities put forward by Langmuir and Grimm are termed as classical bioisosteres . More explicitely, in animals the occurrence of several hormones, neurotransmitters etc., having almost idential structural features and above all similar biological activities may be classified as bioisosteres. 

Table 2.1. Evidently shows the various classical bioisosteres with their appropriate examples ...

S.No. Types of Classical Bioisosteres Various suitable examples... 

Following are the various salient features of classical bioisosteres ... 

Importantly, the nonclassical bioisosteres are preeisely the replaeements of functional groups not falling within the regimen by classical definitions. Although, several of these functional moieties practically just behave as one of the following characteristic specific features, such as ... 

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

Figure 8.8 Classical and non-classical bioisosteres (Reprinted with permission from, Showell, G.A., Mills, J.S. Chemistry challenges in lead optimization Silicon isosteres in drug discovery. Drug Discov. Today, 8, 551-556, copyright 2003, Elsevier.)...

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