Structural Properties 2 Lecture

Question 1

What does a carboxylic acid do on a drug?

Answer 1

Strong hydrogen bonds with water ensure the solubility
Acids that strength depends on the stability of the carboxylate anion
React with bases to form salts that have high water solubility

Question 2

What decreases acidity for carboxylic acid groups? What does the opposite?

Answer 2

Electron donating R groups stabilize the carboxylate anion

Opposite is true for EWG due to resonance stabilization of the anion

Question 3

What are esters?

Answer 3

Is a combination with a polar alcohol and polar acid to produce less polar ester (lack of hydroxyl groups)
ONLY HBA!!

Question 4

Ester hydrolysis?

Answer 4

By esterases in the blood and other organs
Can be protected from this via electronic and steric factors
- Advantage as a prodrug
- Only important if the ester is involved in binding

Question 5

What are amides?

Answer 5

Results of polar carboxylic acid and a weakly polar primary or secondary amine or ammonia

• Reasonably soluble due to hydrogen bonding and ion-dipole interactions
• More stable to acid/base hydrolysis than esters but are also more neutral than basic (unable to form acid salts)
• N can’t participate in HBA because lone pair is involved in resonance with carbonyl

Question 6

What are amines?

Answer 6

Act as HBD and HBA and when protonated in electrosatic interactions
When protonated and carrying a positive charge, cannot be HBA (still be HBD and form stronger interactions)

Question 7

What are ketones and aldehydes?

Answer 7

Ketones can exist as an equilibrium mixture of keto- and enol- forms
- Carbonyl group is permanently polar (H bond with water –> good water solubility)

Aldehydes are very reactive and are quickly metabolised

Question 8

What is ketone binding?

Answer 8

Planer groups that participate in hydrogen bonding and dipole-dipole interactions

Question 9

What are alcohols?

Answer 9

Participate in inter- and intramolecular hydrogen bonding due to electronegative oxygen and positive hydrogen (permanent dipole)

• Form H bonds with water (dipole-dipole)
• Solubility decreases with length and position of OH

Question 10

What are phenols?

Answer 10

Hydroxyl group attached directly to the aromatic ring

With a carboxylic acid, phenols are the only organic acid (even though they are weak)

Question 11

What is the binding mode for alcohols and phenols?

Answer 11

Orientation is key for orbital overlap and bonding

Steric hindrance is key to pay attention to in order to see the orientation

Question 12

H bond strength is affected by what?

Answer 12

Length, charge, and angle (likes 180)

Question 13

What are alkanes and alkenes?

Answer 13

Cannot form ionic, hydrogen or ion-dipole bonds with itself or water; ONLY van der Waals and hydrophobic interactions

• Larger or more branched the alkyl chaines the less hydrophilic or more lipophilic the group becomes
• Alkenes are rigid

Question 14

What are halogenated hydrocarbons?

Answer 14

Less hydrophilic than the alkyl form due to the lack of an electron deficient region of the halide that prevents water bonding
- Anethestics

Question 15

Fluorine can effectively block ?

Answer 15

A metabolically labile site having the same size but different electronegatively as hydrogen

Question 16

Chlorine, bromine and iodine are ??

Answer 16

Very good leaving groups but usually lead to a bunch of nucleophilic substitution that cause toxicity

Question 17

What are aromatic hydrocarbons?

Answer 17

Significant in binding to proteins via van der Waals forces
Very rigid, do not rotate so they maintain their conformation really well
- Back bond of drugs and solubility is based on functional group attachment

Question 18

What is pi pi stacking?

Answer 18

2 phenol rings or 2 aromatic systems that can orient themselves on top of each other because you have a slightly positive charge and a slightly negative charge

Question 19

What are aromatic rings?

Answer 19

Flat, can fit into spaces that cyclohexane rings can’t

- Axial hydrogen’s block interaction

Question 20

What are heterocycles?

Answer 20

Rigid: fixed where they are because of double bonds
Can add in N, O, S
All fine tuning of drug by additional HBD, HBA, and VDW, ionic and hydrophobic interactions
Can be aromatic or aliphatic
- Exact positions can be controlled by synthesis (SAR)
Easier admin

Question 21

What is template hop?

Answer 21

Takes advantage of a known active template in a new drug–> copy and change

Question 22

What is Sterics?

Answer 22

Size matters –> size, shape and bulkiness will influence receptor binding
Bulky groups can be used to increase selectivity or to completely block and remove activity
- Potentially remove side effects

Question 23

Define pharmacophore

Answer 23

Active constituent of the drug

- Collection of functional groups and carbon backbone orientated into the optimal position ot maximize binding

Question 24

Function of carboxylic acid in aspirin?

Answer 24

ionization, solubility and administration

Forming ionic bonds and hydrogen bonds

Question 25

Function of ester in aspirin?

Answer 25

Pro-drug

Masking the phenol

Question 26

Function of the phenol in aspirin?

Answer 26

Hydrophobic interactions

Orient those other groups

Question 27

What is the MOD of aspirin?

Answer 27

Inhibit COX –> prevent arachidonic to PGs –> activates platelet activation and aggregaiton
- Donates acetyl group onto COX enzyme to form a covalent bond (which can be hydrolyzed off because it is part of an ester)
Works for 4-6 hours