IMC 02: Understanding Functional Groups in Medicinal Chemistry

Question 1

What are the most common functional groups in drug-like molecules and proteins?

Answer 1

• carboxylic acid
• amine

Question 2

What results in interesting chemical and biological properties?

Answer 2

presence of pi bonds or other non-carbon or hydrogen atoms (heteroatoms)

• while sp3 to sp3 carbon-carbon bonds, and sp3 to s carbon-hydrogen bonds are found in nearly all organic compounds and drug molecules, these bonds do not generally play a major role in chemical reactions or have particularly strong roles in interactions between drug molecules and their molecular targets

Question 3

What is a functional group?

Answer 3

can consist of several atoms that may change the chemical or biological properties at a particular site of a molecule

Question 4

Alkanes

Question 5

Alkenes and Alkynes

Question 6

Aromatics (Benzene, Naphthalene)

Question 7

Alkyl and Aryl Halides (F, Cl, Br, I)

Question 8

Alcohols (1º, 2º, and 3º)

Question 9

Esters (cyclic esters = lactones)

Question 10

Ethers (and cyclic ethers)

Question 11

Aldehydes and Ketones

Question 12

Amides (cyclic amide = lactam)

Question 13

Carboxylic Acids (aliphatic and aromatic)

Question 14

Phenol

Question 15

Sulphonamides

Question 16

Thiol Amines (1º, 2º, and 3º, piperidine, piperazine)

Question 17

Pyridine

Question 18

Purine, Adenine, Guanidine

Question 19

Pyrimidines (cytosine, thymine, uracil)

Question 20

What is an L-a-Amino acid?

Answer 20

molecule containing single sp3-hybridized carbon between amino group and carboxylate group

• categorized based on their side chains (R groups) – 20 natural variations

Question 21

What are the 20 amino acids?

Answer 21

• alanine (ALA)
• glycine (GLY)
• isoleucine (ILE)
• leucine (LEU)
• proline (PRO)
• valine (VAL)
• phenylalanine (PHE)
• tryptophan (TRP)
• tyrosine (TYR)
• aspartic acid (ASP)
• glutamic acid (GLU)
• arginine (ARG)
• histidine (HIS)
• lysine (LYS)
• serine (SER)
• threonine (THR)
• cysteine (CYS)
• methionine (MET)
• asparagine (ASN)
• glutamine (GLN)

Question 22

Alanine

Answer 22

ALA
aliphatic

Question 23

Glycine

Answer 23

GLY
aliphatic

Question 24

Isoleucine

Answer 24

ILE
aliphatic

Question 25

Leucine

Answer 25

LEU aliphatic

Question 26

Proline

Answer 26

PRO aliphatic

Question 27

Valine

Answer 27

VAL aliphatic

Question 28

Phenylalanine

Answer 28

PHE aromatic

Question 29

Tryptophan

Answer 29

TRP aromatic

Question 30

Tyrosine

Answer 30

TYR aromatic

Question 31

Aspartic Acid

Answer 31

ASP acidic

Question 32

Glutamic Acid

Answer 32

GLU acidic

Question 33

Arginine

Answer 33

ARG basic

Question 34

Histidine

Answer 34

HIS basic

Question 35

Lysine

Answer 35

LYS basic

Question 36

Serine

Answer 36

SER has alcohol

Question 37

Threonine

Answer 37

THR has alcohol

Question 38

Cysteine

Answer 38

CYS has sulfur

Question 39

Methionine

Answer 39

MET has sulfur

Question 40

Asparagine

Answer 40

ASN has amide

Question 41

Glutamine

Answer 41

GLN has amide

Question 42

What does aliphatic mean?

Answer 42

include the alkanes, alkenes, and alkynes and substances derived from them

Question 43

What are the aliphatic amino acids? (6)

Answer 43

- alanine (ALA) - glycine (GLY) - isoleucine (ILE) - leucine (LEU) - proline (PRO) - valine (VAL)

Question 44

What are the aromatic amino acids? (3)

Answer 44

- phenylalanine (PHE) - tryptophan (TRP) - tyrosine (TYR)

Question 45

What are the acidic amino acids?

Answer 45

- aspartic acid (ASP) - glutamic acid (GLU)

Question 46

What are the basic amino acids? (3)

Answer 46

- arginine (ARG) - histidine (HIS) - lysine (LYS)

Question 47

What are the amino acids that have alcohol?

Answer 47

- serine (SER) - threonine (THR)

Question 48

What are the amino acids that have sulfur?

Answer 48

- cysteine (CYS) - methionine (MET)

Question 49

What are the amino acids that have amide?

Answer 49

- asparagine (ASN) - glutamine (GLN)

Question 50

Alkanes, Alkenes, Alkynes, Aromatics What are the key properties?

Answer 50

- hydrophobic - mostly scaffolding for appending functional groups - aromatics can participate in cation-pi and pi-pi stacking interactions

Question 51

An alkane as a functional group is referred to as ________.

Answer 51

alkyl group - note: it is NOT an alkyne

Question 52

Alkanes vs. Alkenes vs. Alkynes

Answer 52

- alkanes: single bonds - alkenes: double bond - alkynes: triple bond - aromatics: cyclic

Question 53

What are the 3 types of branched hyrdocarbons?

Answer 53

(pentane C5H12) - normal-butyl (n-butyl) - iso-butyl (i-butyl) - tert-butyl (t-butyl)

Question 54

What are the 3 types of aromatic hydrocarbons?

Answer 54

- ortho: CH3 at 1,2 positions - meta: CH3 at 1,3 positions - para: CH3 at 1,4 positions

Question 55

What are properties of alcohols, ethers, and carbonyls?

Answer 55

- polar covalent bonds - lone pairs on oxygen and nitrogen atoms - alcohols and esters may have poor pharmacokinetic properties due to oxidation or hydrolysis (respectively)

Question 56

What are alcohols classified based on?

Answer 56

number of carbons that are attached to the carbon that the alcohol is attached to - special (0º) – ie. water - primary (1º) – ie. ethanol, methanol - secondary (2º) – ie. 2-propanol - tertiary (3º) – ie. t-butanol

Question 57

What are amines classified based on?

Answer 57

number of carbons attached to nitrogen atom - special (0º) – ie. ammonia - primary (1º) – ie. methylamine - secondary (2º) – ie. dimethylamine - tertiary (3º) – ie. trimethylamine - quaternary (4º) – ie. tetramethylamine

Question 58

What are lactones?

Answer 58

cyclic esters

Question 59

What are lactams?

Answer 59

amides in ring

Question 60

What are the key properties of halogenated alkanes and aromatics?

Answer 60

- can improve aqueous or lipid solubility (depending on which halogens are used) - can be chemically inert or highly reactive - introduces polar covalent bonds and can change electron density in aromatic rings

Question 61

What are ionizable groups?

Answer 61

functional groups that carry + or - charge under physiological conditions

Question 62

What are the general properties of weak acids?

Answer 62

- H-bond donors - can be metabolically labile - may lose proton to form anions

Question 63

Weak Acids What are the key properties of carboxylic acids (and benzoic acids)?

Answer 63

- good water solubility - acidic, negatively charged at pH 7.4 - conjugate base is resonance stabilized - pKa range 2-6 (depends on R) - make ionic interactions and hydrogen bonds with biological targets

Question 64

Weak Acids Why is carboxylic acid so acidic?

Answer 64

because of the stability of the conjugate base it forms - lose proton - negative charge is delocalized between two oxygens

Question 65

Weak Acids What are the key properties of phenols?

Answer 65

- conjugate base is resonance stabilized - good solubility – has dipole - pKa around 10 (depends on R)

Question 66

What is piperidine?

Answer 66

- cyclic amine - weak base

Question 67

What is piperazine?

Answer 67

- cyclic amine - weak base

Question 68

Are anilines charged (protonated) at physiologic pH?

Answer 68

NO

Question 69

Are pyridines charged (protonated) at physiologic pH?

Answer 69

NO

Question 70

Are imidazoles charged (protonated) at physiologic pH?

Answer 70

yes if pKa is around 7.5

Question 71

Describe pyridines.

Answer 71

- looks like benzene, but with a nitrogen atom in the ring - has permanent dipole – contributes to solubility