MEDICINAL CHEMISTRY

Structure-activity Relationship
All of the cournarin derivatives are water insoluble lactones. Though coumarin is a
neutral compound, the clinically utilized derivatives are weakly acidic due to a 4-hydroxy
substitution. Therefore, reaction of 4-hydroxycoumarin derivatives with an appropriate
base yields water-soluble salts. Because of the acidity of the proton on the 4-hydroxy
group of warfarin and the proximity of the side chain carbonyl six atoms away, the
possibility of' another ring closure exists. If the acidic 4-hydroxy proton is removed, the
resulting oxyanion can act as a nucleophile and attack the electrophilic carbonyl carbon
forming a hemiketal called cyclocoumarol, which is neutral.
Structure-activity relationship (SAR) requirements are typically based on substitution of
the lactone ring, specifically, in positions 3 and 4. Initial investigation into the,
anticoagulant activity requirements of coumarin derivatives led link to suggest that a 3substituent,
a 4-hydroxy group and a bis molecule were all necessary. Though a bis
compound (bis-hydroxycoumarin, dicoumarol) fits these requirements, it is no longer
used clinically. Additional studies have concluded that the methoxy group addition to
position 8 increases anticoagulant activity. The conformation of warfarin has been
studied by nuclear magnetic resonance spectroscopy. These studies suggest that there are
three conformations of the drug in solution, two diastereomeric cyclic hemiketals and one
open form. Since it has been suggested that vitamin K forms an active hemiketal in vivo,
vitamin K antimetabolite compounds such as warfarin may well be active as the cyclic
hemiketal
Warfarin is a chiral compound. Though the clinically utilized preparation is racemic, the
enantiomers are not equipotent. In fact, (S)-warfarin is at least 4-fold more potent as an
anticoagulant than the (R)-warfarin. The difference in the activities and metabolism of
the enantiomers is the key to understanding several stereoselective drug interactions
including those with zileuton, miconazole, sulfinpyrazone and cimetidine.
Derivatives of 1,3- indanedione are also known to cause anticoagulation through
mechanisms similar to warfarin in that they inhibit the synthesis of active clotting factors
VII, IX, X and plasma prothrombin.
3. Anti-hypertensive Agents
Introduction
Hypertension or High Blood Pressure is the name of a pathological condition in which
blood pressure is persistently elevated (i.e. it stays high for a long period of time). The
blood pressure is a measurement of the pressure of the blood against the blood vessel
walls. The persistent high blood pressure puts undue stress on the heart, blood vessels and
other organs. In fact, hypertension is a major public health problem of largely unknown
cause. Unfortunately, at present, it is yet a great concern of modern medical practice due
to its doubtful and uncertain etiology (even in the 90 % of cases) and its faulty cure
management. The people suffering from this disorder are not only at high risk of
abnormally elevated blood pressure, but also they gradually come under the phenomena
of secondary complications that may produce other vital-organ diseases. It is single