MEDICINAL CHEMISTRY

Structure - Activity Relationship: Since cardiac glycosides comprise of:
1. A genin or aglycone portion and
2. A sugar portion, the SAR studies of these agents are based on the separate SAR
investigations on these portions.
(1) Genin or aglycone portion
(A) C-17 Side chain: The substitutions at C- 17 of the genin portion cardiac glycosides
are generally of two types
Where A may be oxygen or nitrogen.
CH = CH - C (R) = A
C
17
(120)
(a) A five or six-membered lactone ring. In both these types of C-17 substituent, there is a
double bond conjugated with carbonyl oxygen.
O
C
17
O
Butenolides (121)
O
C
O
Pentadienolides (122)
(b) Reduction of C- 17 side chain double bond results into decreased activity.
(c) The compounds having
-CH = CH- CH = NH, side chain (A=N) at C-17, exhibit higher activity.
(d) If the conjugation system in C- 17 side chain is extended (i.e. - CH = CH – CH = CH
CH = A), activity abolishes.
(e) Since H-boning (which takes place between the side-chain and K + -binding site of
Na + , K + -ATPase enzyme) determines the degree of Na + , K + -ATPase inhibition, the
molecule's dipole is an important parameter.
(B) Steroid nucleus
(a) Lactone ring at C- 1 7, essential for activity.
(b) Since some compounds, not having C-14 hydroxyl group, have not shown activity,
therefore, C-14 hydroxyl group is not essential for activity.
(2) Sugar Portion
Though the sugars are not directly involved in cardiotonic activity, their attachment to the
steroid (at C3,) contributes greatly to both the pharmacodynamic and pharmacokinetic