14 Basic Concepts in Medicinal Chemistry
In the acidic environment of the stomach, penicillin G undergoes significant acid-
catalyzed degradation. The key mechanistic step involves the lone pair of electrons
present on the side chain carbonyl group. In an acidic environment, these electrons
attack the carbonyl carbon of the -lactam ring. The ultimate effect is destruction
of the -lactam ring in the stomach and inactivation of penicillin G. In contrast, the
presence of the ether oxygen, withdraws the lone pair of electrons from the side chain
carbonyl as discussed above. This decreases the availability of the lone pair of elec-
trons to attack the carbonyl carbon of the -lactam ring, thus allowing penicillin V
to be much more stable in the acid environment of the stomach. From a therapeutic
standpoint, both of these drugs have a similar spectrum of antibiotic activity; how-
ever, penicillin V can be used orally, while penicillin G must be administered either
intravenously (IV) or intramuscularly (IM).
::
::
Electon flow in an acidic
environment for Penicillin V
Electon flow in an acidic
environment for Penicillin G
O
O
N
H
S
N
O
COOH
O
N
H
S
N
O
COOH
Solubility Effects
The overall water and/or lipid solubility of a drug molecule affects its route(s) of
administration, distribution within the body, metabolism, duration of action, and
route(s) of elimination. This overall solubility is a composite sum of the contributions
of each functional group present within the drug structure. The primary purpose of
this section is to identify those functional groups that confer water solubility and those
that confer lipid solubility. Similar to electronic effects, the overall solubility contribu-
tion of a specific functional group can vary depending upon adjacent groups. Further
explanations with respect to the importance of water and lipid solubility, partition
coefficients, the ability to analyze a drug molecule and identify its water soluble and
lipid soluble components, the need for a balance between water and lipid solubility,
the advantages of increasing either water or lipid solubility, and common strategies
to alter solubility in a desired direction are discussed in detail in Chapter 5.
Water Soluble Functional Groups
Functional groups that enhance the water solubility of a drug molecule are often referred
to as hydrophilic functional groups. The two major properties that contribute to the
water solubility of a functional group are its ability to ionize and/or its ability to form
hydrogen bonds. Let us examine each of these properties separately. Acidic and basic
functional groups are capable of ionization and can become negatively or positively
charged, respectively. A permanently charged quaternary ammonium group can also
provide a positive charge; however, this functional group is only seen in a small number