Isosteric Replacement Pharmaceutical Chemistry

Source: Silverman, R. B.: The Organic Chemistry of Drug Design and Drug Action. New York, Academic Press, 1992.

Source: Silverman, R. B.: The Organic Chemistry of Drug Design and Drug Action. New York, Academic Press, 1992.

group to produce the dibenzodiazepine class of antidepressant drugs. The vinylene group in an aromatic ring system may be replaced by other atoms isosteric to sulfur, such as oxygen (furan) or NH (pyrrole); however, in such cases, aromatic character is significantly decreased (Fig. 2.27).

Examples of isosteric pairs that possess similar steric and electronic configurations are the carboxylate (COO") and sulfonamide (SO2NR") ions; ketone (C=O) and sulfone (O=S=O); chloride (Cl") and trifluoromethyl (CF3); hydrogen (—H) and fluorine (—F); hydroxy (—OH) and amine (—NH2); hydroxy (—OH) and thiol (—SH). Divalent ether (—O—), sulfide (—S—), amine (—NH—), and methylene (—CH2—) groups, although dissimilar electronically, are sufficiently alike in their steric nature to be frequently interchangeable in designing new drugs.48

Compounds may be altered by isosteric replacements of atoms or groups, to develop analogs with select biological effects or to act as antagonists to normal metabolites. Each series of compounds showing a specific biological effect must be considered separately, because there are no general rules that predict whether biological activity will be increased or decreased. Some examples of this type follow.

When a group is present in a part of a molecule in which it may be involved in an essential interaction or may influence

Figure 2.27


Examples of isosteric ring

Examples of isosteric ring

Methotrexate R1 = NH2; R2 = CH3 Antimetabolite

Figure 2.28 • Examples of how isosterism produces drugs that inhibit the activity of the native metabolite.

the reactions of neighboring groups, isosteric replacement sometimes produces analogs that act as antagonists. The 6-NH2 and 6-OH groups appear to play essential roles in the hydrogen-bonding interactions of base pairs during nucleic acid replication in cells (Fig. 2.28). Adenine, hypoxanthine and the antineoplastic 6-mercaptopurine illustrate how substitution of the significantly weaker hydrogen-bonding isosteric sulfhydryl groups results in a partial blockage of this interaction and a decrease in the rate of cellular synthesis. Similarly, replacement of the hydroxyl group of pteroylglutamic acid (folic acid) by the isosteric amino group and addition of the methyl group to the ^-aminobenzoate leads to the widely used methotrexate, a folate antimetabolite. Replacement of the hydrogen at the 5-position of uracil with the isosteric fluorine producing 5-fluorouracil blocks the methylation step leading to thymine.

As a better understanding of the nature of the interactions between drug-metabolizing enzymes and biological receptors develops, selection of isosteric groups with particular electronic, solubility, and steric properties should permit the rational preparation of drugs that act more selectively. At the same time, results obtained by the systematic application of the principles of isosteric replacement are aiding in the understanding of the nature of these receptors.

Are There Drugs Developed Using the Newer Computer-Aided Drug Design Methods?

The same question asked in the discussion of QSAR must be asked regarding the newer CADD methods. Are their commercial products that were discovered using these techniques?

Here, the answer is yes. The example of dorzolamide is one. Others include the ACE-inhibitor captopril and HIV protease inhibitors nelfinavir and amprenavir. In reality, modern CADD is used in combination with structure-based drug design and QSAR. These methods permit the medicinal chemist to focus more quickly on the structural components that enhance activity and provide receptor specificity.49,50


The field of drug design, particularly those aspects that are computer intensive, is increasingly being featured on Web pages. Faculty and students might find it instructive to search the Web at regular intervals. Many university chemistry departments have organized Web pages that provide excellent linkages. Listed are a small number of representative sites that feature drug design linkages. Some have excellent illustrations. These listings should not be considered any type of endorsement by the author, editors, or publisher. Indeed, some of these sites may disappear.

(Search terms: QSAR; molecular modeling)

(Search terms: QSAR; medicinal chemistry)

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  • lennon
    What is isoteric replacement?
    1 year ago
  • Levi
    What is isosteric substitution?
    6 months ago

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