EXAM 2 - Functional Groups in Drug Molecules (part 1) Flashcards
What is the significance of the functional group in a drug molecule?
Individual functional groups determine many properties of molecule in chemical, biochemical, and pharmacological terms.
* chemical properties explain pharmacological properties
What factors may functional groups have on drug molecules? (5)
1) part of PHARMOCOPHORE - interact directly with the target
2) control PHYSIOLOGICAL PROPERTIES
3) part of SCAFFOLD - provide structural elements
4) part of PRODRUG - be lost prior to activation
5) NO CONTRIBUTION to overall pharmacological profile
What is a pharmacophore?
Anything that is neccessary for a drug’s interaction.
Name the key parameters for each functional group:
Basic chemical properties
- polarization
- reactivity
- acid-base behavior
- stability
Types of non-covalent interactions for binding
- van der Waals contacts
- ionic interactions
- H-bonding (accepting/donating)
- steric clashes
Physiological properties
- role of solubility
- metabolism
- potential toxicity
How are functional groups altered?
Through metabolism
Explain the process of metabolizing drugs.
Drugs are metabolized in the body as foreign substances
Involves increasing water solubility of drug –> so it can be excreted by the kidneys
* phase 1 (modification): carried out by CYPs, usually oxidation (makes more polar)
* phases 2 (conjugation): transfer of polar groups, usually nucleophilic attack (gluoronidation, sulfonation)
*key component of overall bioavailability
Where does most metabolism occur?
Mostly in the liver, but also the kidneys, GI tract, and lungs
Which of the following is not a key parameter to consider for functional groups?
A) key interactions
B) routes of metabolism
C) acid-base interactions
D) chemical reactivity
E) atomic number
Atomic number
Alkanes and alkenes
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
- linear or cyclic
- very common in many drugs (form basic scaffold of drug)
Key interactions: van der Waals (hydrophobic packing)
Role for solubility: increase lipophilicity
Metabolism: oxidation by CYP
Significant acid-base: none
Chemical reactivity: low (with exceptions)
Explain the difference between an alkane and alkene.
Both hydrocarbons
alkanes - only have single bonds
alkenes - have at least one double bond
What does it mean to be alipahtic?
Have full saturation; no double bonds
Identify the different alkyl chains
What effect does additional carbon (alkyl chain) have on logP?
Each additional carbon adds about 0.5 to logP (octanol/water)
Adding an isopropyl functional group to a drug scaffold will likely have what effect (most prominently)?
a) increase acidity
b) increase absorption through cell membranes
c) increase water solubility
d) increase reactivity
b) increase absorption through cell membranes
- more carbon = more hydrophobic
What are the two more common ring sizes in drug molecules? Why?
- cyclohexane
- cyclopentyl
* bc of their bond angles
* cyclohexane is able to form a conformation with almost no ring strain
What happens when we have an electron withdrawing group attached to an alkene?
- removes double bond
- adds a nucleophilic group
What can happen when you have a reactive electron poor alkenes (accepting groups)?
When an EWG is binded to an alkene?
BC of resonance form:
* The EWG (oxygen) will attract the electrons from the double bond and go to the oxygen group
* Result: makes the carbon (that used to have the double bond) electrophilic
How do strong donating groups affect alkenes?
Makes them very reactive
* removes the donating group from the alkene
Explain the overall enamine reaction. (electron rich alkenes)
When you have an acid present, you can remove a donating group and form a ketone or aldehyde (if terminal).
ex. loss of amine -NR
Explain the difference between aldehyde and ketone.
aldehyde - C=O binded to a -R and -H groups
ketone - C=O binded to 2 -R groups
What is a benzenoid?
Structure that MUST contain a benzene ring.
Describe benzenoid aromatics
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
- often have multiple rings
- very common in drugs
Key interactions: van der waals and pi-stacking
Role for solubility: increase lipophilicity (decrease hydrophobicity)
Metabolism: oxidation by cytochromes to give phenols (add OH group)
Significant acid-base: none
Chemical reactivity: fairly low, stable
Explain ortho, meta, and para
Identify these structures
Benzenoid: What are considered donors versus acceptors?
Donors - add electron density to ring (speeds up reaction)
Acceptors - withdraw electron density from the ring (slows reaction)
List the 5 groups that attach to benzene to make it a donor.
Benzene attached to…
- R
- Ar
- OR
- NHCOR
- SR
List the 5 groups that attach to benzene to make it an acceptor.
Benzene is attached to…
- X (X=Br, Cl, I, F)
- CO2R
- SO2R
- NO2
- CN
D. Para; donating
B. Van der Waals interactions
Describe alcohols and related functional groups
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
- inactivates drug
Key interactions: H-bond donor & acceptor (more willing to give up H+)
Role for solubility: increase water solubility (polar)
Metabolism: oxidation (form aldehyde/ketone or conjugation (phase II of metabolism)
Significant acid-base: slightly acidic
Chemical reactivity: reacts as nucleophiles (not important for drug-drug interaction)
Explain the difference between primary, secondary, and tertiary alcohol.
Primary - attached to 1 carbon
Secondary - attached to 2 carbons
Tertiary - attached to 3 carbons
Are enols stable? When are they stable?
No. Enols are very unstable and usually get converted to a ketone (favored;stable)
* enols can also be stablized when conjugated in large compound
What are phenols?
Phenols are a type of enol but in highly conjugated aromatic ring
* more favored than enols
C. more acidic; water solubility goes up
Describe amines and their properties.
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
-
Characterized by what the nitrogen is bound to.
primary amine - N bound to one carbon
Key interactions: H-bond acceptor or donor (as long as there is a hydrogen bound to it)
Role for solubility: increase water solubility (H-bonding)
Metabolism: complex; mainly oxidation (replace amine with oxygen)
Significant acid-base: weak base (significantly ionized)
Chemical reactivity: reacts as nucleophiles
