1) Barbiturates are derivatives of barbituric acid formed by the reaction of malonic acid with urea. Barbituric acid was first synthesized in 1864. 2) Barbiturates are classified based on their duration of action - long acting (>6 hrs), intermediate acting (3-6 hrs), short acting (<3 hrs), and ultra short acting. Their chemical structures determine duration of action. 3) Extensive testing of barbiturate structures has defined structure-activity relationships. Substitutions that increase lipid solubility, like lower alkyl groups at position 5 and N-methylation at position 3, decrease duration of action by enhancing brain penetration and liver metabolism. Replacing the

1. By;
AMJAD ANWAR
Department of Pharmacy, UOM

2.  All Barbiturates are the derivatives of Barbituric
acid, formed by the reaction of Malonic acid with
Urea.
 Barbituric acid was first synthesized on Dec 6,
1864 by German researcher Adolf Von Baeyeri, by
the reaction of Malonic acid with Urea.

3. GENERAL STRUCTURE
 Note:
◦ In Thiopental and Thiamylal (Ultra Short acting),
X = S while in rest of all X = O

4. CLASSIFICATION
1. Barbiturates with long duration of action (6
hrs or more)
NAME R5 R′5 R1
Mephobarbital C2H5 CH3
Metharbital C2H5 C2H5 CH3
Phenobarbital C2H5 H

5. 2. Intermediate duration of action (3-6 Hrs)
NAME R5 R′5 R1
Butabarbital -C2H5 H
Amobarbital -C2H5 H
Aprobarbital CH2=CH-CH2 H
Talbutal CH2=CH-CH2- H
Hexobarbital CH3- CH3
Butalbital CH2=CH-CH2- (CH3)2CHCH2 H
CH3 CH2 CH
CH3
CH
H3C
H3C
CH2 CH2
CH
H3C
H3C
CH3CH2 CH
CH3

6. 3. Short duration of action (less than 3 Hrs)
NAME R5 R′5 R1
Pentobarbital -C2H5 H
Secobarbital CH2=CH-CH2- H
CH3 CH2 CH2 CH
CH3
CH3 CH2 CH2 CH
CH3

7. 4. Ultra short acting
NAME R5 R′5 R1
Thiopenton or
Thiopental
-C2H5 H
Thiamylal CH2=CH-CH2- HCH3 CH2 CH2 CH
CH3
CH3 CH2 CH2 CH
CH3

8. Chemical Name
◦ 5-Ethyl, 5-Phenyl 2,4,6 pyrimidinetrione
Description:
 It occurs as white, odorless, glistering small crystals or as a white
crystalline powder, which may exhibit polymorphism
 M.P is about 176 oC
 Its PKa is 7.6
Solubility:
 1gm of it is soluble in;
◦ 1000ml of water
◦ 10ml alcohol
◦ 40ml of chloroform
◦ & 15ml of ether.

10. Chemical name
 5-(1-cyclohexene-1-yl) 1,5-dimethyl barbituric
acid
Description/physical properties:
 See Remington or google

12. ❑ Extensive synthesis & testing of barbiturates
over a long time span have produced well
defined SAR which is summarized below.

13. 1) Both H atoms at position # 5 should be replaced, if
a single H is present at position # 5, then it will give
rise to phenomena of tantomerism, the resultant
compound will be highly acidic. Tri-OH pyrimidine,
having Pka = 4 is largely in ionic form (anionic
form) at physiological PH with little unionized lipid
soluble portion to cross BBB.
2) Beginning with the lower alkyl group, there is an
increase of onset of action. % increasing of
hydrocarbon contents upto 7-9 carbon atom
substituted at position # 5, there is an increase in
onset of action & decrease in duration of action, so
for optimal activity the sum of carbon atoms at
position # 5 having substituents would be 7-9.
◦ Increase in onset of action may be due to enhanced
lipophilicity & ability of drug atom to penetrate brain &
◦ Decrease in duration of action may be due to its ability to
penetrate liver microsomes.

14. 3) N-methylation at position # 3 shortens
onset time & duration of action as compared
with the weaker acid (barbiturates without N-
methyl group i.e phenobarbitone with Pka 7.6).
The weaker acid (N-methylated derivative) is an
unionized lipid soluble form which can readily
cross CNS.

15. 4) Introduction of halogen atom to 5 alkyl
substituents will enhance the activity
5) Introduction of polar groups like OH, COOH,
NH2, SO3H, to 5-alkyl substituent gives derivatives
which are inactive.
6) Replacement of carbonyl oxygen at Carbon # 2
will results in Thiobarbital with quick onset &
shorter duration of action i.e Thiopental &
Thiamylal.
◦ Thiobarbiturates differs a little from barbiturates in acid
strength values, the Pka value of Thiopental is 7.4 as
compared with carbonyl barbiturates with Pka 7 which
may be due to lipophilic character of sulphur atom.