SAR

Question 1

strategies for struc modifications

Answer 1

1. variation of substituents
2. chain extension/ cotnraction
3. ring expansion/ contraction
4. ring variation
5. ring fusion
6. isosteric replacement
7. simplification of structure
8. stereoisomers

Question 2

alkyl sub

Answer 2

used to probe binding site for size and hydrophobicity

probe: depth and width of pocket
- binding interaction and incr binding affinity

Question 3

substituent

on aromatic ring as probe

Answer 3

• vary the position of substituents on aromatic ring to probe for better interaction at binding site
• alkyl grp, OH, Halogen grps
• receptors binding site

Question 4

vinyl grp and vinylogues

Answer 4

double bond conjugated with (C=O) or (O-H) grp can impart diff chemical properties to mole

(a,b unsaturated ketone, enol, enone): strongly acidic

Question 5

struc extension

Answer 5

explore new int outside binding site

another functional grp to lead to probe for extra binding interactions

• alkyl (hydrophobic int)
• OH, phenol, amine, COOH (H, ionic interaction)

Question 6

ring expansion/ contraction

Answer 6

by 1 unit qt a time, see how it affects biological activity

(when too big > receptor binding site, cannot withhold the substrate)

Question 7

ring fusion

Answer 7

incr interaction or incr selectivity

recognise area for better hydrophobic int = better binding affinity

Question 8

ring fusion to probe

Answer 8

eg: benzologues – benzene ring inserted by fusion into structure for exploration of potential enhancement in hydrophobic int

linear and angular benzologues

Question 9

bioisosteric replacement

Answer 9

using atoms. grps believed to have similar physical and chemical prop

evaluate whether analogues will have better/ weaker biological activity

Question 10

classic bioisosteres

Answer 10

monovalent:
F,H
OH, NH
F, OH, NH, CH3 –> H
SH, OH
CL, Br, CF3

divalent
C=S, C=O, C=NH, C=C

trivalent
CH=, -N=, -P=, -As=

tetrasub
N+, C, P+, As+

Question 11

ring variation:

rings in lead compound replaced

Answer 11

with equivalent rings to investigate if ligand affinity can be enhanced/ reduced SE

aromatic carbocylic or aromatic heterocyclic ring
- diff ring size/ heteroatoms
- extra H bonding int

Question 12

eg of ring equivalents to substitute with

Answer 12

carbocyclic: cyclohexane, cyclopropane, steroid, triterpene
- not conjugated

aryl rings: benzene, napthalene, phenathrene

heterocyclic rings: pyridine, pyrimidine, thiophen, furan, quinoline, indole

Question 13

simplification of lead compound

Answer 13

natural sources as lead

simplified structure carry essential grps that interact with the target

non -essential parts are removed by struc modifications

Question 14

disadv of oversimplification

DLSS

Answer 14

1) binds diff to target
2) lose desirable pharm activity
3) SE/ toxicity
4) less target selectivity

Question 15

stereo-selectivity leads with chiral centres

Answer 15

need to be evaluated if stereoisomers give diff biological activity

chiral centres should be avoided

1) aceeptor-donor/ hydrophobic intr
2) H bond
3) ionic bond (Asp, Glu COOH grp of receptor)

Question 16

3 approach of SAR

Answer 16

1) analoguing - similar complexity
2) simplification - key int retained
3) adding grp (conjunctive) - create new int, MW, clogP