Fundamentals of Medicinal Chemistry

(a)

(b)

L M L E M

E

4 −C(CH 3 ) 3

or

3,4−dimethyl

L M

3 −Cl

3 −N(CH 3 ) 2 3 −CH 3

2 −Cl

4 −F 4−NO 2

3 −CF 3 and 3−Br and 3−I

3,5−dichloro and 3,5−(CF 3 ) 2

3 −NO 2

E

E

L

L

E M

3 −Cl 4 −N(CH 3 ) 2

4 −NH 2 3 −CH 3 , 4−N(CH 3 ) 2

or 3−CH 3

or 4−OH

or 4−CH 3 O

M

H

4 −Cl

4 −CH 3 −

L M

4 −CH 3 O− 3,4−Dichloro

E

4 −CF 3

2,4−dichloro

4 −NO 2

3 −CF 3 , 4−Cl

3 −CF 3 , 4−NO 2

CH 3

(CH 3 ) 2 CH−

E M

L

L M

L

M

or

C 2 H 5 −

E

Stop

−CH 2 Cl

or

−CH 2 CF 3

or

or

H

CH 3 OCH 2 −

or

CH 3 SO 2 CH 2 − −CF

3

−CH 2 SCH 3

Ph−

or

PhCH 2 −

(CH 3 ) 3 C− or

PhCH 2 −

PhCH 2 CH 2 −

E

Figure 4.7 The Topliss decision trees for (a) an unfused aromatic ring and (b) an aliphatic side

chain. (L¼significantly lower activity, E ¼about the same activity and M¼ significantly

greater activity). Reproduced by permission of Taylor and Francis Ltd. from theJournal of

Medicinal Chemistry15, No. 10 1006 (1972), http://www.tandf.co.uk/journals. Utilisation of

Operational Schemes for Analog Synthesis in Drug Design by J G Topliss

is followed and the appropriate analogue synthesized. This procedure is

repeated, the activity of each new analogue being compared with that of its

precursor in order to determine which branch of the tree gives the next ana-

logue. Suppose, for example, that a compound A (Figure 4.8) is active against

90 THE SAR AND QSAR APPROACHES TO DRUG DESIGN