ROLE OF FUNCTIONAL GROUP DETERMINATION IN BIOLOGICAL ACTIVITY

BY

CHINNAMSETTI VISHNU BABU

1702-11-881-056

B PHARMACY IV year

GOKARAJU RANGARAJU COLLEGE OF PHARMACY

HYDERABADUNDER THE GUIDANCE OF

M. AKHILA

MS PHARM

Asst. Professor

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FUNCTIONAL GROUP CHEMISTRY

INTRODUCTION:

Drug molecule can be viewed as a collection of functional group

Functional groups: atoms present within the drug that confers specific

chemical & physical properties.

Eg. Ibuprofen.

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Functional groups determine such characteristics as follows:

1. Ionization

2. Solubility in aqueous &lipid environments

3. Reactivity

4. Chemical stability

5. Drug shelf life and storage

6. In vivo stability and the duration of drug action

7. The susceptibility towards drug metabolism

a. Drugs with a large number or percentage of hydrophilic functional groups are often

eliminated from the body unchanged & minimal metabolism.

b. Drugs with large number or percentage of Iipophilic functional groups often require

extensive metabolism.

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Types

Fucntional groups

Acidic

Basic

Hydrophilic Intermediate

polarity

Lipophilic

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CONCEPTS:

1. Hydrophilicity - increase the drug’s water solubility.

2. Lipophilicity -increase the drug’s tendency to cross cellular membranes through passive diffusion.

3. Acidic and basic functional groups -drug ionization and Impart enhanced water solubility to the molecule.

Exception is amphoteric drugs can form zwitterions, or internal salts. It has a net overall charge of zero,

it has difficulty dissolving in aqueous environments such as the gastrointestinal (Gi) tract.

4. Neutral functional groups can enhance either water or lipid solubility depending on their ability to form

hydrogen bonds with water.

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1. Acidic functional groups

1.1. Types.

• The six most common acidic functional groups : In general, carboxylic acids lend to be

more acidic than any of the other five functional groups.

• The tetrazole ring provides the best charge delocalization since resonance allows the

charge to be equally shared among five atoms in the ring.

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1.2. Common attributes for acidic functional group

a. Hydrophilicity to a drug molecule due to their potential for ionization.

b. Can form ionic , ion dipole, and hydrogen bonding with receptors, enzymes, transport

proteins, and other macromolecules& can form salts with bases.

c. Acidic functional groups can form salts when combined with bases.

d. Carboxylic acids are often esterified for the purposes of prodrug formation . They can

also undergo acid-or enzymecatalyzed decarboxylation reactions.

e. Metabolism. glucuronic acid, glycine and glutamine.

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2. Basic functional groups

2.1.Types

a. Aliphatic and alicyclic amines are the most common basic functional groups.

These amines can be primary, secondary & tertiary, depending on the number

of substituents attached to the nitrogen.

b. Aromatic amines, such as that seen in procainamide , are much less basic and

for all intents and purposes can be considered neutral.

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c. Aromatic heterocyclic nitrogens vary in their basicity, but in general are much less basic

than aliphatic and alicyclic amines . 9

d. Additional basic functional groups include imines, hydrazines , amidines , and

guanidines Imines tend to be less basic than aliphatic and alicyclic amines, whereas

guanidines tend to be much more basic.

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2.2 Common attributes for basic functional group

a. Hydrophilicity to a drug molecule due to their potential for ionization and their ability

to form hydrogen bonds.

b. Can form ionic, ion-dipole, and hydrogen bonds with receptors, enzymes, transport

proteins, and other macromolecules.

c. Can form salts when combined with acids.

d. Metabolism.

Primary amines - oxidative deamination, acetylation and N-oxidation.

Secondary& Tertiary amines- acetylation (secondary amines only) oxidative

N-dealkylation, and N-oxidation.

Aromatic amines -acetylation.

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3. Hydrophilic functional groups

3.1. Hydroxyl groups:

Hydroxyl groups may be classified as primary, secondary and tertiary, depending on the

number of substituents attached to their respective carbons. A good example of this is

seen with the glucocorticoid fludrocortisone

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a. Can form ion; dipole and hydrogen bonds with receptors, enzymes, transport

proteins and other macro molecules.

b. Increases water solubility due to their ability to form hydrogen bonds with

water.

c. Esterified in order to produce prodrugs.

d. Metabolism-Primary hydroxyl groups -oxidized to aldehydes and then to

carboxylic acids. Secondary hydroxyl groups are oxidized to ketones, while

tertiary hydroxyl groups are not usually oxidized. Hydroxyl groups may also

undergo phase II glucuronide or sulfate conjugation.

Characteristics of hydrophilic hydroxyl groups:13

3.2. Phenols, as exemplified by estradiol , are hydroxyl groups that are directly attached to an

aromatic ring

Due to resonance stabilization of the aromatic ring, phenols can be ionized in basic

environments ; however, most phenols are primarily unionized at physiological PH and as

such should be treated as neutral.

Similar to alcohols, phenols primarily form ion-dipole and hydrogen bonds. They can

also enhance water solubility and be esterified to form prodrugs .

Drug molecules containing phenols or catechols are susceptible to air oxidation and to

oxidation on contact with ferric ions.

Metabolism. Phenols undergo sulfation, glucuronidation, aromatic hydroxylation, and

O-methylation.

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3.3.Quaternary ammonium salts, as exemplified by ipratropium bromide, are neither

acidic nor basic but contain a permanent positive charge.

These salts enhance water solubility ; Due to positive charge, compounds containing

this functional group often have difficulty passing through lipid membranes.

Similar to amines, quaternary ammonium salts can participate in ionic and, ion-dipole

bonds.

Quaternary ammonium salts are generally not metabolized

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4. Functional groups with intermediate polarity

4.1. Ketones are less prevalent than alcohols and phenols in the structures of drug molecules.

One example is seen in the oral hypoglycemic agent, acetohexamide.

Ketones are Primarily lipid soluble :Form hydrogen bonds with alcohols and certain

amines, They can also form ion-dipole bonds.

Metabolism. Ketones are very stable. Their primary route of metabolism is reduction to

an alcohol.

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4.2. Compounds containing esters, amides and their respective cyclic forms,

lactones, and lactams can be seen below figure.

a. Capable of forming hydrogen bonds with receptors, enzymes, transport

proteins, other macromolecules, and water.

b. Metabolism. Esters and lactones are hydrolyzed to alcohols and carboxylic

acids, while amides and lactams are hydrolyzed to amines and carboxylic

acids.

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5. Lipophilic functional groups

5.1. Alkyl groups are saturated hydrocarbon chains, links, and rings that can vary

in size from single-carbon methyl and methylene groups to large chains. Similar to

amines, the designation alicyclic - alkyl groups - nonaromatic ring, while the

designation aliphatic refers to those that are part of a side chain or that function to

connect, or bridge, other functional group.

a. Alkyl groups can participate in van der Waals interactions .

b. Metabolism. Oxidation is the major route of metabolism. Alkyl slide chains are

usually oxidized at either the terminal (w) or penultimate (w- 1) carbon atoms.

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5.2. Alkenes.

a. The binding ability of alkenes is similar to that of saturated alkyl groups.

b. Metabolism. Alkenes are somewhat more reactive than alkyl groups and are

subject to metabolic hydration, epoxidation, peroxidation, and reduction.

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5.3. Most aromatic. Hydrocarbons are analogs of either benzene or naphthalene .

a. Aromatic hydrocarbons can participate in van der Waals interactions and

hydrophobic bonding. Aromatic rings can participate in charge-transfer

interactions.

b. Metabolism. Oxidation is the primary route of metabolism for aromatic

hydrocarbons, with hydroxylation, epoxidation, and diol formation comprising

the three most common pathways.

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5.4. Ether - They can be present as either a terminal functional group, such as the methoxy

group of naproxen, or as part of a central chain/backbone, such as that seen in gemfibrozil.

a. Drug binding is minimal , it can participate in dipole-induced dipole interactions and can

serve as hydrogen-bond acceptors.

b. Metabolism. Methyl and ethyl ethers can undergo O-dealkylation, while those larger do

not generally undergo metabolism.

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5.5. Alkyl and aromatic halides are electron-withdrawing

They are often used to 'lock" a drug molecule in a desired conformation and/or to decrease

aromatic Oxidation of the drug. Fluorine is the smallest halogen, with its size very similar to that

of hydrogen.

a. With the exception of fluorine, which can serve as a hydrogen-bond acceptor, halides do

not directly participate in the binding of drugs to their receptors or other macromolecules.

b. Metabolism. Aromatic halides are not normally metabolized. Alkyl halides can

undergo oxidative dehalogenation to form aldehydes.

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Conclusion :

Functional groups determine the ability of the drug to absorb, distribute,

metabolize along with the desired biological activity through their receptor

interactions.

The presence of a particular functional group may be crucial for a drug to

perform its desired role.

Novel drugs can be designed by thorough understanding of nature of

functional groups to predict their biological functions.

Knowledge on different varieties of functional groups aid in novel drug

discovery and development.

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BIBLIOGRAPHY :

1.Leon shargel, Alan H. Mutnick , Paul F. Souney, Larry N. Swanson ,

Comprehensive Pharmacy Review, page no:144-151,5th edition,2004,

Lippincott Williams & Wilkins.

2. Richard B. Silverman, Mark W. Holladay, The Organic Chemistry of

Drug Design and Drug Action , page no:57, 3rd edition, 2004, Elsevier .

3.Marc w. Harrold , Robin M. zavod , Basic concepts of medicinal

chemistry , page no:15-82,1st edition, 2010, American society of

health–system pharmacists

(www.ashp.org/DocLibrary/Bookstore/P2661/Sample-Chapter.pdf)

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