DESIGNING DRUG MOLECULES TO FIT RECEPTORS 139exception of lipophilicity, which increases with the addition of “inert” hydrocarbon
groups. The degree of lipophilicity — so important in drug action and quantitative SAR
(QSAR) investigations — is otherwise subject to change together with the Hammet
σ-constant, a descriptor of the electron–donor or electron–acceptor capability of a
substituent.
3.4.1.6 Isosteric Variations
Theisosteric replacement of atoms or groups in a molecule is widely used in the design
of antimetabolites or drugs that alter metabolic processes. Isosteric groups, according
to Erlenmeyer’s definition, are isoelectronic in their outermost electron shell. However,
since their size and polarity may vary, the term isostere is somewhat misleading.
Isosteres are classified according to their valence (i.e., the number of electrons in the
outer shell):
Class I: halogens; OH; SH; NH 2 ; CH 3
Class II: O, S, Se, Te; NH; CH 2
Class III: N, P, As, CH
Class IV: C, Si, N+,P+,S+,As+
Class V: -CH=CH-, S, O, NH (in rings)
Thus, for instance, the exchange of OH for SH in hypoxanthine gives the antitumor
agent 6-mercaptopurine (3.17). Fluorine, the smallest halogen, replaces hydrogen well,
giving, for instance, fluorouracil (3.18), which is also an antitumor antimetabolite.
Interchanges of -CH- and nitrogen are common in rings, as seen in the antiviral agent
ribavirin (3.19).
The oldest example of the use of “nonclassical” isosteres involves the replacement
of the carboxamide in folic acid by sulfonamide, to give the sulfanilamides.
Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addi-
tion to the exploitation of auxiliary binding sites on dihydrofolate reductase. This con-
cept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the
same number of atoms or identical electron structure — is really the classical structure
modification approach.