MedChem2 Exam 1: Fletcher Content

What is an acid?

Proton Donor

What is a base?

Proton Acceptor

The pKa of an acid is the pH where is is exactly ______ dissociated

half

Acidic functional groups

Imide, phenol, sulfonamide

Carboxylic acid, acylfulfonamide

Sulfonic acid, HCl

Acid strength and pKa

Acid strength comes from the stability of the conjugate base

The more the negative charge can be delocalized and over more electronegative atoms, the more stable is the conjugate base and hence the stronger is the parent acid (the power it's pKa)

Which is more acidic? Alcohol or Phenol? Why?

Phenol (pKa 10) is more acidic than alcohol (pKa 15), this is because phenol has 4 resonance structures, whereas alcohol only has 1 anion structure

Which is more acidic: Imide or Amide? Why

An Imide is more acidic than an amide. Amides have 2 resonance structures with a pKa of 15; whereas Imides have 3 resonance structures and a pKa of 10

Why are carboxylic acids so acidic if they only have 2 resonance structures?

They are more acidic due to the charge being delocalized onto 2 electronegative atoms (oxygen), which helps stabilize the conjugate base

Which is more acidic: sulfonamides or acylsulfonamides? Why?

An acylsulfonamide is more acidic than a sulfonamide, due to the conjugate base being more stable with 4 resonance structures, sulfonamides only have 3 resonance structures

Basic functional groups

Aniline, pyridine, imidazole

primary, secondary, and tertiary amines

Guanidine

Why are amides not basic?

Amides are neutral due to the long pair of electrons being delocalized into the adjacent carbonyl (not available for acid/base reactions)

Why are pyrroles not basic?

The lone pair of electrons is pulled into (delocalized) the conjugated ring to contribute to the aromaticity

Hydrochlorothiazide "N" group

HCTZ contains a secondary amine group with electrons being delocalized into an aromatic ring

This is an aniline derivative with a pKa of 5

Soluble at pH 3 and below

Do benzoic acid and sodium benzoate make good injectables? (in blood pH buffer system)

Yes, both species are ionized/soluble at pH 7+

This is due to both are soluble at the same buffered pH because the same equilibria are established in each case

Do tertiary amines and HCl salts make good injectables? (in buffered solution)

Yes, both are soluble at pH 6 and below and the same equilibria are established allowing for complete dissolution

T/F: water acts as a buffer and a species dissolved in water will not affect pH

False!! Water is NOT a buffer, the species dissolved in water will affect pH

How do you determine the pH of the resulting solution upon dissolution of a salt in water?

Add pKa values of the parent and base of the salt and then divide by 2

What is the pH of a solution of NaCl in water?

NaCl (salt) = HCl + NaOH

HCl pKa = 0, NaOH pKa = 14

(0+14)/2 = 7

How do you know if two salts in an admixture dissolve completely (i.e. compatible) in BUFFER?

If both salts (look at the parent compound) are independently soluble in the buffer, then they will also be soluble as an admixture

Look at parent structure of each salt, determine what pH it will be soluble at, then compare to given buffer

How do you know if two salts in an admixture dissolve completely (i.e. compatible) in WATER?

Add the pKa values of the parent acid and base of the salt and divide by 2 (do for each salt)

Then add these 2 salt pH's together and divide by 2 to determine the resulting pH of the solution

Last, determine if the parent compound of each salt is soluble in the resulting pH

No -> incompatible; Yes -> compatible

Bioisosteres for Carboxylic Acids

Chemical substituents or groups with similar physical and/or chemical properties that produce broadly similar biological properties

Reasons to use bioisosteres

Reduce toxicity

Change bioavailability

Modify activity

Alter metabolism

Why might someone opt to use tetrazole as a bioisostere for a carboxylic acid?

Carboxylic acid has a negative charge making it poorly cell permeable and is prone to metabolism

Tetrazole is more cell permeable as the charge can be delocalized, additionally, it is more resistant to metabolism and has the same pKa as a carboxylic acid

Bioisosteres for carboxylic acids:

tetrazole

acyl sulfonamide

3-hydroxyisoxazole

Drug Incompatibility

Interactions between two or more substances, which leads to changes in therapeutic, physical, and chemical properties of the pharmaceutical dosage form

Therapeutic Incompatibility

Modification of the therapeutic effect of one drug by another drug (drug-drug interactions) i.e. synergism/antagonism

Physical Incompatibility

Interaction between two or more substances, which leads to a change in color, odor, taste, viscosity and/or morphology (often called pharmaceutical incompatibilities)

Often occurs as a result in pH

Chemical Incompatibility

A chemical reaction between two or more substances, which leads to a change in chemical properties of the drug

Chemical Incompatibilities: Types

Oxidation

Hydrolysis

Factors leading to oxidation:

oxygen

light

temperature (higher)

pH (basic)

dosage form

unsaturated bonds

How do we protect drugs from oxidation?

Addition of anti-oxidants

Addition of chemicals that form complexes with metals

Protection from light

Pharmaceutical dosage forms (solid vs solution)

Storing at low temperature

Storage under inert (nitrogen) atmosphere

What are some indications that a drug has undergone oxidation?

Change in color, odor, viscosity of dosage form

Pink and stinks!

What chemical groups are prone to oxidation?

phenols

catechols

pyridines

thiols

sulfides

thiophenes

Factors leading to hydrolysis

water

faster at pH extremes

accelerated by high temperatures

How do we protect drugs from hydrolysis?

storage in a dry place

use buffered solution ( close to 7) if must be aqueous solution

package with materials that absorb water

What chemical groups are prone to hydrolysis?

Esters

Amides

Factors leading to drug-drug reactions

Combination of electrophilic and nucleophilic drugs

What is drug metabolism?

When a drug enters the body and is altered by metabolic enzymes to be more easily excreted

May be metabolized into an active, inactive, or toxic metabolites

Phase I Metabolism

Drug metabolism where the drug is converted into more polar (water-soluble) molecules that can be excreted

Often done by CYP450 enzymes

Generally involve oxidation, reduction and hydrolysis

Mostly occurs in the liver

Chemical groups prone to oxidation in phase I metabolism

N-methyl groups

Aromatic rings (para position is preferred)

Alkyl groups (terminal positions)

Alicylic rings (most exposed position)

Chemical groups prone to reduction in phase I metabolism

Nitro groups

Azo groups

Aldehyes

Ketones

Chemical groups prone to hydrolysis in phase I metabolism

Esters

Amides

How can you block N-oxidation (i.e. of a pyridine/amine)

Lower the pH and block the N lone pair (proton will now be bonded to lone pair so oxidation is no longer possible, or at least now much slower

Heteroatom Dealkylation

Requires abstraction of an alpha H radical

Then a-hydroxylation can occur

N groups become semi-aminals, O groups become hemi-acetals (both are unstable groups)

These further break down into formaldehyde and their respective O/N groups

Phase II Metabolism: Conjugation Reactions

A polar molecule is attached to a suitable polar "handle" that is already on the drug or was attached during phase I

Generally occurs in the liver

Resulting conjugate has greatly increased polarity

Phenols, alcohols, and carboxylic acids undergo glucuronidaiton reactions

Sulfation is another type of Phase II reactions

Types of conjugates added during phase II reactions

Glucuronyltransferases for phenols, alcohols, and carboxylic acid gorups

Sulfotransferases for phenols, alcohols, and amines

How do we block Para-Hydroxylation?

By using fluorine (versus H) to inhibit hydroxylation from occuring

This works due to H and F being roughly the same size

How do we block metabolism of an aromatic alkyl group?

By replacing CH3 with CF3 or Cl, these are isometric in size with CH3 and reduce metabolism

Why does barbituric acid have a low pKa of 4?

Tautomerism

When deprotonated the aromatic anion is stabilized

Barbituric Acid Pharmacophore

Important SAR pieces for Barbiturates: 5' substituents

The combined number of carbon atoms of the 5' substituents should be between 6-10

Unsaturation (double bonds) is better than saturated

Branched is better than unbranched

Important SAR pieces for Barbiturates: Acidic NH

At least one acidic NH is required for activity at t=0

If no acidic NH, then the molecule is not active at t=0

If an acidic H can be formed via time-delay metabolism then the molecule can be active (via N-alkylation)

Important SAR pieces for Barbiturates: 2' substituents

Replacement of the 2-substituted oxygen with sulfur increases lipid solubility

Since maximal thiobarbiturate levels are quickly reached, onset of activity is rapid

Why do we need prodrugs of Barbiturates?

They are poorly water-soluble

We can utilize the N-dealkylation mechanism of N-methylated barbiturates to make them water-soluble prodrugs (inactive)

What are the two ways to activate an Succinate Ester Barbiturate Prodrug?

Ester hydrolysis

Intramolecular decomposition

How are Phosphate Ester Barbiturate Prodrugs activated?

Ester hydrolysis

Pharmacophore of an Amphetamine

Aromatic ring

2-C linker

Basic amine

Amphetamine Pharmacophore: Beta Position

Beta -OH: reduces potency

Beta =O: retains potency

Amphetamine Pharmacophore: Aromatic Substitution

Unsubstitution of the aromatic ring is preferred (can be H/F, these are isosteric)

Amphetamine Pharmacophore: Chiral Center

S is preferred over R

Amphetamine Pharmacophore: Terminal Amine

NHMe > NH2 > NHR > NR2

Amphetamine Pharmacophore: alpha-methyl group

Homologation decreases potency, replacement by H decreases potency

Requirements for N-dealkylation

Nitrogen in the alpha position

Abstractable hydrogen radical

Internal Salt

A molecule with both an acidic and basic group that allows the molecule to be soluble in water, but is insufficient having one of those groups alone for water-solubility

How do we determine if an internal salt is soluble in water?

Calculate molecules resulting pH by adding the pKa's of the acid and basic group and divide by 2.

Then see if one of these groups is completely ionized at this pH

If one is soluble, then it is soluble in water

T/F: an HCl salt of an amino acid-based compound is more resistant to oxidation than is a sodium salt

True

Why are HCl salts more resistant to oxidation compared to sodium salts?

HCl salts can protonate amino groups and make the electrons less available to oxidation processes

Anticonvulsant General Pharmacophore

Barbiturates: X= CONH

Hydantoins: X= NH

Oxazolidinediones: X = O

Succinimides: X= CH2

Barbiturates: X= CONH: Receptors + Drugs

Work on GABA receptors and Na+ channels

Drugs: phenobarbital and mephobarbital

Hydantoins: X= NH: Receptors + Drugs

Works on Na+ channels

Drugs: phenytoin, mephenytoin, and ethotoin

Oxazolidinediones: X= O: Receptors + Drugs

Works on Ca2+ channels

Drugs: trimethadione and paramethadione

Succinimides: X= CH2: Receptors + Drugs

Works on Ca2+ channels

Drugs: ethosuximide, phensuximide, and methsuximide

Is Vibagatrin water soluble? (internal salt)

NO!

Resulting pH: 6.5

Neither a carboxylic acid nor primary amine is ionized at this pH

Is Tiagabine water soluble (internal salt)

NO!

Resulting pH: 6.5

Neither a carboxylic acid nor primary amine is ionized at this pH

Is a HCl Salt soluble in water? (tertiary amine + HCl)

Yes!

Resulting pH: 4

Both groups will be ionized

NSAID Definition

A drug that exerts analgesic, antipyretic, anti-inflammatory, (and anti-platelet) properties

Example: Aspirin

Is acetaminophen an NSAID?

No, it doesn't have anti-inflammatory effects

It does have analgesic and antipyretic affects

Aspirin Structure

Acetaminophen Structure

Ibuprofen Structure

How do NSAIDs work?

NSAIDs inhibit PG synthesis through binding the active site of COX-1 and COX-2

T/F: Aspirin is a reversible COX(1/2) inhibitor

False, it is irreversible (but is more potent against COX-1 than COX-2)

COX-1

Constitutive enzyme

Responsible for maintenance and protection of the GI tract

COX-2

Inducible enzyme

Synthesized for inflammation and pain

Active sites of COX enzymes

Oxidation of arachidonic acid (AA) to PGG2

Reduction of PGG2 to PGH2

Pharmacophore of Salicyclates

Groups needed for salicylate anti-inflammatory activity

CO2H and OH groups ortho/next to one another

What diminishes/abolishes salicylate activity

No OH group ortho to COOH

Strongest-Weakest: Order of salicylate strength

Aspirin > Salicylic acid > Benzoic acid

Aspirin: why is it so potent?

Aspirin is potent due to the acetyl group which allows it to irreversibly inhibit COX1/2

Why is Salicylamide as effective as aspirin, but exhibits no anti-inflammatory properties?

Has a CONH2 group instead of a CO2H group

How can you increase anti-inflammatory properties of a salicylate?

First it requires the CO2H and OH groups ortho

Then substitution at the 5-position increase anti-inflammatory properties

Addition of the OH meta to the COOH also increases potency

How do NSAIDs inhibit COX?

They reversibly inhibit COX via a salt bridge (electrostatic interaction) using the Arg120 residue

Blocks the channel so AA cannot access, which temporarily inhibits PG synthesis

How does Aspirin irreversibly inhibit COX?

Aspirin irreversibly inactive the enzyme via covalent modification of Ser-530 (COX-1) and Ser-516 (COX-2)

Cannot react with AA to make PGs after this occurs

Also binds reversibly as salicylate (Arg120 salt bridge)

NSAIDs cause gastric damage by Dual-Insult mechanisms, what are they?

1: ion trapping/direct acid damage

2: inhibition of PG synthesis especially PGE2

Primary NSAID Insult: Ion Trapping

When a neutral molecule is permeable and crosses into a different pH causing it to become ionized, resulting in it being trapped, allowing for accumulation and toxicity

Secondary NSAID Insult: COX1/2 Inhibition

NSAIDs generally inhibit PG formation, this includes cytoprotective PGE2 and PGI2 which inhibit gastric secretion (both) and secretion of alkaline mucus (PGE2)

Causes vomiting, heartburn, GERD, and PUD

Which drug is the most toxic: acetanilide, phenacetin, or acetaminophen?

Acetaminophen due to the formation of a Michael acceptor -> NAPQI

How is APAP metabolized?

Major: sulfation

Minor: glucuronidation

<5% CYP450 -> NAPQI

Metabolism of APAP: 3 Routes

(normal dosage- small amounts of NAPQI made; high doses- larger amounts of NAPQI

Route 1: toxic metabolite is excreted after conjugation with glutathione

Route 2: if followed with antidote NAC, is metabolized and excreted renally

Route 3: No NAC, hepatic necrosis, renal failure, and death