Figure 1-2. Bioactivity as a function of pH.

a high proportion of polar functional groups. The opposite situation, where the ionized form may still have appreciable lipid solubility, where the drug has few polar groups but a relatively large hydrocarbon skeleton, is a possibility. Methyl prednisolone sodium succinate would be an example.

Although lipid solubility at physiological pH enhances a drug's penetrability of a membrane, too much may not necessarily result in increased activity. Many antibacterial sulfonamides exhibit their peak effectiveness at pH values at which they are only approximately half-ionized. These sulfonamides have pKa values in the 6-8 range. The apparent reason is that even though the molecular form can readily penetrate the bacterial membrane, only the anionic form is bacteriostatic once inside. Thus approximately 50% ionization appears to be optimal. Nevertheless, several highly active sulfonamides exist with a pKa considerably outside of this optimal range. Other factors are also presumably involved.

In summary, if bioactivity is caused by ionic forms of drugs, activity will increase as the degree of ionization increases. On the other hand, if undissociated molecules are the active species, then increased ionization will necessarily reduce this activity.

1.2.2. Chemical Structural Aspects

One of the long-term objectives of medicinal chemistry is the establishment of relationships of a drug's structural features to its pharmacological properties [i.e., structure-activity relationships (SARs)]. Although qualitative linkages, often on an intuitive basis, have sometimes been assigned, a quantitative foundation is the goal. Attempts to express pharmacological activity by mathematical means are being made, with some success. Both classical qualitative concepts and the newer more numerical ideas must be taken into consideration to understand drug activities better and, equally important, more rationally to design and then develop new, more effective, and safer drugs. Both aspects will be briefly described here. Some concepts will be developed in somewhat greater detail in subsequent chapters. Resonance and Inductive Effects

Resonance is a concept stating that if we can represent a molecule by two or more structures that differ only in their electron, but not atomic, arrangement then neither (or any) of the representations is satisfactory since the molecule is a hybrid of these possible structures. Each structure as depicted contributes to the "real" structure. One advantage of this idea is that it forces us to think of a drug molecule from additional mental angles rather than just those normally printed on a page. Electron density and electron distribution patterns help explain a drug's reactivity.

Unlike the theoretical resonance concept, inductive effects are measurable electrostatic phenomena. Inductive effects are caused by actual electron shifts, or displacements, along bonds. These shifts result from attractions exerted by certain groups because of their electronegativity. Thus groups or atoms that attract electrons more strongly than hydrogen have a negative inductive effect and tend to displace electron density toward themselves. The halogens are prime examples. Groups with positive inductive effect tend to push electrons into the rest of the molecule. These are usually alkyl groups such as methyl and iso-propyl. The electronic consequences are a strong influence on physicochemical properties such as acidity. Table 1-1 illustrates this effect. Using formic acid as the prototype, we

BASIC CONSIDERATIONS OF DRUG ACTIVITY Table 1-1. Inductive Effects on Acid Strength

Acid Formula pKa

Formic HCOOH 3.76

Acetic CHjCOOH 4.76

Chloracetic CICH2COOH 2.81

Fluoroacetic FCH2COOH 2.66

note that the positive inductive effect of the methyl group in acetic acid causes an increase in the pKa by a whole unit, which is a 10-fold decrease in acid strength. Conversely, in chloroacetic acid we find the strongly electronegative element chlorine withdrawing electron density from the carboxyl function, which results in a drop of almost two pKa units, or a 100-fold increase in acidity. It stands to reason that differences in bioactivity would also occur.

Electronic effects in compounds containing aromatic rings are especially pronounced since inductive effects are readily transmitted through such conjugated systems. An interesting example is found in a pair of carcinolytic nitrogen mustard compounds in which the intensity of activity is dependent on the degree of nucleophilic halogen displacement. In Structure II, the p-amino group pushes electrons into the system, resulting in facile chlorine displacement by a nucleophilic species it encounters in a biological environment, therefore exhibiting a cytotoxic effect. The negative induction of the p-chloro atom in Structure III has the opposite effect, reducing halogen displacement to less than 10% of that exhibited by Structure II. The result is a decreased bioactivity.

A group of local anesthetics related to procaine (Novocaine) illustrates several of the concepts discussed, particularly the influence of substitutents of the aromatic portion of the molecule on pharmacological effects. The local anesthetic effectiveness of this p-aminobenzoic acid ester is believed to be related to the degree of polar character possessed by the ester carbonyl function. Structures IV and V are two resonance forms of procaine, neither of which, as explained, represents the drug. Rather, a hybrid structure, wherein the carbonyl function is partially ionic (not totally as in V), would be a more correct representation. To test this hypothesis it should be possible to vary the anesthetic potency by changing the nature of the para substituent on the benzene ring and relate it to the bond order of the ester carbonyl by measuring its infrared stretching frequency. Such a study was done with interesting results, and is summarized in Table 1-2.

Amino and alkoxy groups are considered electron donors by resonance and thus enhance the dipolar (ionic) character of the C = O group, as can be seen by the infrared frequency values (Table 1-2). Para substituents having a strong electron-withdrawing effect


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