Classical Bioisosteres

5.1. Classical Bioisosteres

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.

Example : Insulins isolated from various mammalian species are found to differ by a substantial quantum of ‘aminoacid residues’ but surprisingly they do exert the same biological effects (i.e., lowering of blood-sugar). However, if this did not occur ; the actual usage of ‘insulin’ to treat, control and manage diabetes might had to wait for another half-a-century for the development and recognition of recombinant DNA technology to allow production of human insulin****.

Actual applications of ‘bioisosteres’ in the successful design of a specific given molecule interacting with a particular ‘receptor’ in one glaring example, very often either fails or negates the biological characteristics in another environment (system). Therefore, it is pertinent to state at this juncture that the logical use of biological replacement (classical or nonclassical) in the design of a ‘new target- drug molecule’ is solely and significantly dependent on the specific biological system under critical investigation. Hence, there are no predetermined, well-established, predictable hard and fast guidelines or laid-out generalized rules that may be useful to a ‘medicinal chemist’ to affect biosteric replacement gainfully towards improved biological activity. The wisdom, intuition, skill, experience and creative imagination of a ‘medicinal chemist’ contribute a major role to zero-down or pin-point or hit the bull’s- eye to obtain the best possible results towards ‘new target-drug’ molecules.

Table 2.1. Evidently shows the various ‘classical bioisosteres’ with their appropriate examples : * Burger, A., ‘Isosterism and Bioisosterism in Drug Design’, Progress in Drug Research, 37, 288–371, 1991.

** Langmuir, I. J., Amer. Chem. Soc., ; 41 : 868 ; ibid, 41, 1543, 1919. *** Grimm, H.G., Z. Elekrochemie., ; 31 : 474, 1925. ****A Danish recombinant-DNA-technology based firm has produced ‘insulin’ from the yeast cells that almost

meets all the stringent requirements of human insulin [Humulin (R) ].

PHYSICAL-CHEMICAL FACTORS AND BIOLOGICAL ACTIVITIES

Table 2.1 : Classical Bioisosteres*

S.No. Types of Classical Various suitable examples Bioisosteres

C HAPTER

1 Monovalent atoms and

2 Divalent bioisosteres

– C = S, – C = O, – C = NH, – C = C – ,

3 Trivalent atoms

=, – N = ; – P =, – AS = ;

and groups

4 Tetrasubstituted atoms

5 Ring equivalents

* Groups within the row can replace each other conveniently. Salient Features : Following are the various salient features of ‘classical bioisosteres’ : (1) Hydrogen replaced by Fluorine : It is regarded as one of the commonest monovalent

isosteric replacements. Both H and F are fairly identical with their Van der Waal’s radii being 1.2 Å and 1.35 Å respectively. Fluorine being the most electronegative element in the periodic table ; therefore, the augmentation in the biological profile of drugs containing F may be attributed to this specific characteristic.

Example : [1] 5-Fluorouracil from uracil, obtained by replacement of H with F gives rise to the formation of an extremely therapeutically potent antineoplastic drug :

[2] Aminopterin (I) mimicks the tautomeric forms of folic acid (II), thereby giving rise to the formation of suitable H-bondings to the corresponding enzyme active site, as illustrated below :

MEDICINAL CHEMISTRY