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Principles of Medicinal Chemistry Review of Organic Functional Groups II

September 16/2002.

Zbigniew J. Witczak, Ph.D.


Principles of Medicinal Chemistry PHA 421: Dr. Zbigniew J. Witczak

Learning Objectives After completion of theses lectures students should be able to: 1. Predict the effect on water solubility of various functional groups within a drug molecule. 2. Should be able to describe hoe the structures of drug molecules influence their pharmacological activity. 3. Should be able to explain the principle of bioisosterism and be able to modify drug molecules using this principles. 4. Should be able to relate the principle of pharmacophore and how it is used to develop new drugs.


Important Functional Groups on Drugs II 1.Phenols Metabolism OH

OH OH

Hydroxylation

and/or OH

OH

COOH Conjugation HO

O

OH OH

Conjugation

O

O S OH O

Methylation OCH3

Metabolic Reactions of the Phenol Functional Groups


1.Ether Metabolism

OCH3

Dealkylation

Metabolic dealkylation of anisole

O OH

+H

C

H


Aldehydes and Ketones H

C

O

O

O CH 3

H

Formaldehyde

C

H

CH 3

O

C

CH3

CH 3

C

acetaldehyde

dimethyl ketone methyl phenyl ketone ( acetone) (acetophenone) • Ketones can exist as an equilibrium mixture of keto- and enol- froms • Carbonyl group is permanently polar and thus can hydrogen bond

with water to exhibit good water solubility O CH 3

C

OH CH 3

CH3

Keto-from

C

CH2

enol-form

Minor oxidation of aldehydes O

O R

C

H

Oxidation

R

C

OH

Oxidizing enzymes: Xanthate oxidase, aldehyde oxidase, aldehyde dehydrogenase


Amines •Primary and secondary amines have weaker dipole moments than hydroxyl groups thus poorer hydrogen bonding capacity***** •The amines do have one pair of unshared electrons, which is able to provide hydrogen bonding with water hydrogen and thus reasonable solubility. • Solubility trends primary> secondary> tertiary • Amines also have basic nature due to availability of the two unshared electrons on the nitrogen • Aromatic amines are generally less basic due to electron-withdrawing nature of phenyl and thus the unshared electrons are resonance stabilized. • Amines can react with acids to from conjugate salts which would be watersoluble provided the conjugate is dissociable. Can from salts with hydrochloric, sulfuric phosphoric, succinic citric maleic and tartaric acids. • Addition of base to the conjugate salts will liberate the free amine which can precipitate out of solution due to poor water solubility. Thus bases are chemically incompatible with amine salts. ****** • Quarternary amines cannot be converted to free amine by base treatment and positive charge on the nitrogen allows good ion-dipole interaction with water and thus exhibit good water solubility


Carboxylic Acids

• Strong hydrogen bonds with water ensure the solubility of this group • Behave as acids strength depends on stability of carboxylate anion which is influenced by electronic character of R group : electron-donating R groups stablize the carbonylate anion and decrease acidity. The opposite is true for electron – withdrawing groups due to resonance stablization of the anion. • Carboxylic acids will r4eact with bases to from salts that have high water solubility.Chemical incompatibility of carboxylate salt conjugate with acids is due to formation of free carboxylic acid which can precipitate out of solution. 2 1

COOH HO

F C

COOH

F 4 COOH 3

Which group on the compound is most & least acidic.


Functional derivatives of Carboxylic Acids A. • • •

Esters Similar physicochemical properties to ethers: is a combination of polar alcohol and polar acid to produce less polar ester –due to lack of hydroxyl groups. Can be hydrolyzed by acid or base to an alcohol and acid Esters are incompatible with strong bases due to above reaction O

O R

C

OR' + OH-

R HO

O

C

R

C

OH

+ ROH

OR'

B. Amides • Amides results from a polar carboxylic acid and weakly polar primary or secondary amine or ammonia: have reasonable solubility due to hydrogen bonding and ion-dipole interactions. • Amides are more stable to acid/base hydrolysis than esters but are also more neutral than basic and thus being unable to from acid salts.


Structure –Activity Relationships in Drug Action • Pharmacological agents generally mimic the structural properties of endogenous substances

SO2NHR H2 N

N O CH3


Neurotransmitters OH HO

HO

NHR

NH2

HO

HO

R = H, Noradrenaline R = Me Adrenaline

Dopamine

COOH

NH2

HO NH2

HO

NH

OH O

3-hydroxytryptamine

C

Serotonine

Glycine

O CH3

NH

NH2

OH O

Acetylocholine

NMe3

O

C

NH2

Îł-aminobutiric acid (GABA)


Structures of Clinically Useful Sulfonamides Sulfacytine

Sulfadiazine

R = pKa = 6.9 O

N

R=

R = pKa = 5.45

N N

N

N

Sulfamethizole

S

N

SO2NHR

CH3

H2 N

Sulfamerazine R=

Sulfamethazine

R=

R=

N

CH3

N O

N

N

CH3

Sulfamethoxazole

N

CH3

CH3


Schematic Actions of Sulfonamides and Trimethoprim COOH H2 N

p- Aminobenzoic acid Dihydropteroate synthetase

Sulfonamides (compete with PABA)

Dihydrofolic acid Dihydrololate reductase

Trimethoprim NH2

Tetrahydrofolic acid H2N

Purines DNA

OCH3

N N

OCH3 OCH3


How prodrugs are made


Chemical Delivery Systems: Pharmacologically inactive molecules that require several steps of chemical and/or enzymatic conversion to the active drug and enhance drug delivery to particular organs or sites. Example: Brain-specific chemical delivery system


New approaches Soft Drugs: Biologically active, therapeutically useful chemical molecules (drugs) characterized by a predictable and controllable in vivo deactivation, after achieving the therapeutic objective, to nontoxic, inactive compounds


Examples: 2. Improving drug delivery The pro-drug by its improved characteristics gets closer to the receptor site for a longer period of time, and conversion to the parent drug takes place at the site of action.



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