Classical bioisosteres[ edit ] Classical bioisosterism was originally formulated by James Moir and refined by Irving Langmuir [2] as a response to the observation that different atoms with the same valence electron structure had similar biological properties. For example, the replacement of a hydrogen atom with a fluorine atom at a site of metabolic oxidation in a drug candidate may prevent such metabolism from taking place. Because the fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the drug candidate may have a longer half-life. Procainamide , an amide , has a longer duration of action than Procaine , an ester , because of the isosteric replacement of the ester oxygen with a nitrogen atom.

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Swapnil R. Bhalerao M. Pharm II — Sem. Guided by- Prof. Amrutkar Department of Pharmaceutical Chemistry M. Drug discovery, Design and modification. Introduction to Lead compound. Method of Lead discovery.

Optimization of Lead. Bioisosterism and isosterisn. Classification of Bioisostere. Application of Bioisosterism in Drug design. It involves the study of effects of biologically active compounds on the basis of molecular structures or its physico-chemical properties. Lead discovery- Random Screening. Non-random Screening. Drug Metabolism Studies. Clinical approach. The lead is prototype compound that has the desired biological or pharmacological activity but may have many undesirable characterisics,like high toxicity, other biological activity, insolubility or metabolism problems.

Optimization of Lead: 6 Drug Development. Optimization of Lead -Identification of the active part. Alferrd Burger Bioisosteric Replacement. All lily of the valley flower 13 Why Bioisosterism? Classical bioisosteres- a. Univalent atoms and groups.

Bivalent atom or groups. Trivalent atom and groups. Tetravalent atoms. Non classical bioisosteres: 16 2. Non classical bioisosteres Do not have same number of atom and do not fit the steric and electronic rules of classical isosteres, but they produce similar biological activity Examples- a. Halogens- Cl,F,Br b. Ethers- R-O-R,-S- c. Hydroxy group- -OH d.

Catechol- 16 PowerPoint Presentation: 17 Changes resulting from bioisosteric replacements. Size, shape, electronic distribution, lipid solubility, water solubility, p K a , chemical reactivity, hydrogen bonding Effects of bioisosteric replacement: 1. Structural size, shape, H-bonding are important 2. Pharmacokinetics lipophilicity, hydrophilicity, p K a , H-bonding are important 17 Bioisosterism allows modification of physicochemical parameters: 18 Bioisosterism allows modification of physicochemical parameters -Multiple alterations may be necessary: -If a bioisosteric modification for receptor binding decreases lipophilicity, modify a different part of the molecule with a lipophilic group 18 PowerPoint Presentation: 19 Examples Of Bioisosteric Replacement 19 PowerPoint Presentation: 20 Adrenergic Drug.

The OH group is replaced by other group having ability to undergo H-bonding. Hence alkylsulphonamido derivative of phenylepherine was found to retain activity.

Bioisostere increase target interaction and selectivity: 21 Bioisostere increase target interaction and selectivity 21 Sultopride DU -Pyrrole ring has used as a non-classical isostere for an amide -Sultopride Dopamine antagonist leads to its antagonist activity as selectivity towards the D3 receptor over the D2 receptor. Bioisosteres for polar group: 22 Bioisosteres for polar group For example carboxylic acid is a highly polar group which can ionize and hindered the absorption of any drug containing it.

To overcome this problem, replacement of carboxylic acid with bioisostere which has similar physicochemical properties.

Tetrazole anaion is 10 times more lipophilic than a carboxylic acid and drug absorption is enhanced as a result 23 Carboxylic acid 5-Substiuted tetrazole H- acidic proton Bioisostere to increase absorption: 24 Bioisostere to increase absorption -Biphenyl structure a. Alpha tocopherol —reduce cardiac damage due to myocardial infraction. Bothara K. Varghese Publication.









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