Structural Properties 2 Lecture Flashcards
What does a carboxylic acid do on a drug?
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
What decreases acidity for carboxylic acid groups? What does the opposite?
Electron donating R groups stabilize the carboxylate anion
Opposite is true for EWG due to resonance stabilization of the anion
What are esters?
Is a combination with a polar alcohol and polar acid to produce less polar ester (lack of hydroxyl groups)
ONLY HBA!!
Ester hydrolysis?
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
What are amides?
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
What are amines?
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)
What are ketones and aldehydes?
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
What is ketone binding?
Planer groups that participate in hydrogen bonding and dipole-dipole interactions
What are alcohols?
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
What are phenols?
Hydroxyl group attached directly to the aromatic ring
With a carboxylic acid, phenols are the only organic acid (even though they are weak)
What is the binding mode for alcohols and phenols?
Orientation is key for orbital overlap and bonding
Steric hindrance is key to pay attention to in order to see the orientation
H bond strength is affected by what?
Length, charge, and angle (likes 180)
What are alkanes and alkenes?
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
What are halogenated hydrocarbons?
Less hydrophilic than the alkyl form due to the lack of an electron deficient region of the halide that prevents water bonding
- Anethestics
Fluorine can effectively block ?
A metabolically labile site having the same size but different electronegatively as hydrogen
Chlorine, bromine and iodine are ??
Very good leaving groups but usually lead to a bunch of nucleophilic substitution that cause toxicity
What are aromatic hydrocarbons?
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
What is pi pi stacking?
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
What are aromatic rings?
Flat, can fit into spaces that cyclohexane rings can’t
- Axial hydrogen’s block interaction
What are heterocycles?
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
What is template hop?
Takes advantage of a known active template in a new drug–> copy and change
What is Sterics?
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
Define pharmacophore
Active constituent of the drug
- Collection of functional groups and carbon backbone orientated into the optimal position ot maximize binding
Function of carboxylic acid in aspirin?
ionization, solubility and administration
Forming ionic bonds and hydrogen bonds
Function of ester in aspirin?
Pro-drug
Masking the phenol
Function of the phenol in aspirin?
Hydrophobic interactions
Orient those other groups
What is the MOD of aspirin?
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
