IMC 02: Understanding Functional Groups in Medicinal Chemistry Flashcards
What are the most common functional groups in drug-like molecules and proteins?
- carboxylic acid
- amine
What results in interesting chemical and biological properties?
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
What is a functional group?
can consist of several atoms that may change the chemical or biological properties at a particular site of a molecule
Alkanes
Alkenes and Alkynes
Aromatics (Benzene, Naphthalene)
Alkyl and Aryl Halides (F, Cl, Br, I)
Alcohols (1º, 2º, and 3º)
Esters (cyclic esters = lactones)
Ethers (and cyclic ethers)
Aldehydes and Ketones
Amides (cyclic amide = lactam)
Carboxylic Acids (aliphatic and aromatic)
Phenol
Sulphonamides
Thiol Amines (1º, 2º, and 3º, piperidine, piperazine)
Pyridine
Purine, Adenine, Guanidine
Pyrimidines (cytosine, thymine, uracil)
What is an L-a-Amino acid?
molecule containing single sp3-hybridized carbon between amino group and carboxylate group
- categorized based on their side chains (R groups) – 20 natural variations
What are the 20 amino acids?
- 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)
Alanine
ALA
aliphatic
Glycine
GLY
aliphatic
Isoleucine
ILE
aliphatic
Leucine
LEU
aliphatic
Proline
PRO
aliphatic
Valine
VAL
aliphatic
Phenylalanine
PHE
aromatic
Tryptophan
TRP
aromatic
Tyrosine
TYR
aromatic
Aspartic Acid
ASP
acidic
Glutamic Acid
GLU
acidic
Arginine
ARG
basic
Histidine
HIS
basic
Lysine
LYS
basic
Serine
SER
has alcohol
Threonine
THR
has alcohol
Cysteine
CYS
has sulfur
Methionine
MET
has sulfur
Asparagine
ASN
has amide
Glutamine
GLN
has amide
What does aliphatic mean?
include the alkanes, alkenes, and alkynes and substances derived from them
What are the aliphatic amino acids? (6)
- alanine (ALA)
- glycine (GLY)
- isoleucine (ILE)
- leucine (LEU)
- proline (PRO)
- valine (VAL)
What are the aromatic amino acids? (3)
- phenylalanine (PHE)
- tryptophan (TRP)
- tyrosine (TYR)
What are the acidic amino acids?
- aspartic acid (ASP)
- glutamic acid (GLU)
What are the basic amino acids? (3)
- arginine (ARG)
- histidine (HIS)
- lysine (LYS)
What are the amino acids that have alcohol?
- serine (SER)
- threonine (THR)
What are the amino acids that have sulfur?
- cysteine (CYS)
- methionine (MET)
What are the amino acids that have amide?
- asparagine (ASN)
- glutamine (GLN)
Alkanes, Alkenes, Alkynes, Aromatics
What are the key properties?
- hydrophobic
- mostly scaffolding for appending functional groups
- aromatics can participate in cation-pi and pi-pi stacking interactions
An alkane as a functional group is referred to as ________.
alkyl group
- note: it is NOT an alkyne
Alkanes vs. Alkenes vs. Alkynes
- alkanes: single bonds
- alkenes: double bond
- alkynes: triple bond
- aromatics: cyclic
What are the 3 types of branched hyrdocarbons?
(pentane C5H12)
- normal-butyl (n-butyl)
- iso-butyl (i-butyl)
- tert-butyl (t-butyl)
What are the 3 types of aromatic hydrocarbons?
- ortho: CH3 at 1,2 positions
- meta: CH3 at 1,3 positions
- para: CH3 at 1,4 positions
What are properties of alcohols, ethers, and carbonyls?
- polar covalent bonds
- lone pairs on oxygen and nitrogen atoms
- alcohols and esters may have poor pharmacokinetic properties due to oxidation or hydrolysis (respectively)
What are alcohols classified based on?
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
What are amines classified based on?
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
What are lactones?
cyclic esters
What are lactams?
amides in ring
What are the key properties of halogenated alkanes and aromatics?
- 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
What are ionizable groups?
functional groups that carry + or - charge under physiological conditions
What are the general properties of weak acids?
- H-bond donors
- can be metabolically labile
- may lose proton to form anions
Weak Acids
What are the key properties of carboxylic acids (and benzoic acids)?
- 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
Weak Acids
Why is carboxylic acid so acidic?
because of the stability of the conjugate base it forms
- lose proton
- negative charge is delocalized between two oxygens
Weak Acids
What are the key properties of phenols?
- conjugate base is resonance stabilized
- good solubility – has dipole
- pKa around 10 (depends on R)
What is piperidine?
- cyclic amine
- weak base
What is piperazine?
- cyclic amine
- weak base
Are anilines charged (protonated) at physiologic pH?
NO
Are pyridines charged (protonated) at physiologic pH?
NO
Are imidazoles charged (protonated) at physiologic pH?
yes if pKa is around 7.5
Describe pyridines.
- looks like benzene, but with a nitrogen atom in the ring
- has permanent dipole – contributes to solubility
