Page 167 - Medicinal Chemistry Self Assessment

156 Medicinal Chemistry Self Assessment

4. The mechanism of action of this class of to interact with the ATP-sensitive potassium groups.
Answer
Answer

B
A D
C

Tolbutamide

Amino Acids Capable of Forming
5. Tolbutamide has a half-life of 4.5 to 6.5 hourssignificantly longer half-life than tolbutamide.
Functional Group Types of Binding Interactions Specific Bond
Answer
A Phenyl ring; aromatic ring; van der Waals; Hydrophobic Tyr, Phe, Trp (better bond*); Val, Leu, Ile, Met, Ala
aromatic hydrocarbon
Sulfonylurea
B
Metabolism of Tolbutamide (1) Ionic (1) Lys, Arg, His**
(2) Ion–Dipole (as the Ion) (2) Ser, Thr, Tyr, Cys, Asn, Gln, His**
C Nitrogen atom of sulfonylurea (1) Ion–Dipole (as the Dipole) (1) Asp, Glu (with the hydrogen); Arg, Lys, His**
not involved in resonance Z oxidation (with the nitrogen)
(2) Dipole–Dipole (2) Ser, Thr, Tyr, Cys, Asn, Gln, His**
(3) Hydrogen Bond (Donor and/or Acceptor) (3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His**
D Alkyl group; alkyl chain; van der Waals; Hydrophobic Val, Leu, Ile, Met, Ala (better bond*); Tyr, Phe, Trp
aliphatic chain
Z-1 oxidation
*Due to steric fit, stronger van der Waals interactions occur when aromatic rings interact with aromatic
rings and when aliphatic chains interact with aliphatic chains; however, all of the listed amino acids could
Benzylic
possibly interact with the boxed functional group.
oxidation
**Histidine is primarily unionized at a pH=7.4. The small fraction that is ionized could participate in
an ion–dipole interaction with a partially negative atom, while the unionized fraction can serve as a
hydrogen bond donor or acceptor. It can also serve as the dipole in an ion–dipole bond.

1. Alcohol
dehydrogenase
5. Tolbutamide has a half-life of 4.5 to 6.5 hours, whereas chlorpropamide has a half-life of 36 hours.
2. Aldehyde
Propose a chemical/structural reason why chlorpropamide has a significantly longer half-life than
tolbutamide. dehydrogenase

Answer
As discussed in question 2, there are two structural differences between tolbutamide and chlor-
propamide: the length of the aliphatic chain and the para substituent on the phenyl ring. Both drug
Metabolism of Chlorpropamide
molecules can undergo π and π-1 oxidation of their respective aliphatic chains. Metabolism at these
sites would be expected to be similar; however, the additional carbon atom present in tolbutamide
may cause the butyl side chain to be less sterically hindered and more susceptible to oxidation than
Z oxidation
the propyl chain present in chlorpropamide. The more significant difference is metabolism of the
para substituent. The para methyl group present within the structure of tolbutamide can undergo
benzylic oxidation followed by two additional oxidative transformations to convert the benzylic
hydroxyl group into a para carboxylic acid. The para chloro group present within the structure of
chlorpropamide deactivates oxidation of the aromatic ring due to its electron withdrawing effects.
Z-1 oxidation
As a result, tolbutamide has a much shorter half-life than chlorpropamide.

Electron withdrawing
halogen prevents
aromatic oxidation