Fundamentals of Medicinal Chemistry

4.6 Questions

(1) State the full wording of the abbreviation ‘SAR’. Describe the general way in

which SAR is used to develop a drug. Illustrate the answer by reference to the

changes in the activities of 4-alkylresorcinols caused by changes in the chain

length of the 4-alkyl group.

(2) (i) How would the introduction of a chloro group be expected to affect the

character of the resulting analogue?

(ii) What alternative halogen containing group could be used in place of

chlorine? Give one reason for the use of this group.

(3) Explain the meaning of the terms (i) isostere and (ii) bioisostere.

(4) Suggest how the introduction of each of the following groups into the struc-

ture of a lead could be expected to affect the bioavailability of the resultant

analogue: (i) a sulphonic acid group, (ii) a methyl group and (iii) a hydroxy

group. Assume that these groups are introduced into the section of the lead’s

structure that does not contain its pharmacophore.

(5) Outline the fundamental principle underlying the QSAR approach to drug

design.

(6) Lipophilicity, shape and electron distribution all have a major influence on

drug activity. State the parameters that are commonly used as a measure of

these properties in the QSAR approach to drug design.

(7) (a) Describe the approach to drug design known as Hansch analysis.

(b) Phenols are antiseptics. Hansch analysis carried out on a series of phenols

with the general structure A yielded the Hansch equation

log 1=C¼ 1 : 5 p 0 : 2 sþ 2 : 3

n¼23,s¼ 0 :13,r¼ 0 : 87

(A) R OH

What is (i) the significance of the termsn,sandr, (ii) the relative significance

of the lipophilicity and electronic distribution of a phenol of type A on its

activity and (iii) the effect of replacing the R group of A by a more polar

group?

92 THE SAR AND QSAR APPROACHES TO DRUG DESIGN