Académique Documents
Professionnel Documents
Culture Documents
Dr. N. C. DESAI
(PROFESSOR IN CHEMISTRY)
Date : 17/05/08
Objective
A little more than half of this time is spent testing the drug in
the laboratory (known as 'pre-clinical' testing).
RCOCl
NH2 NHCOR
(i) (ii)
RCONHR'
(CH3CO)2O
O O
COOH R'
N H2NR' O
SOCl2 / DMF
Formamide
NH2 (R, R' =H) R N R
N
(i) (iii)
R' (A)
N
NH2
NO2
(v)
(vi)
N
H2NO2S
O
CH3
N N
NH NH
O O
Chemistry and Mechanism of
4-Oxo-thiazolidines
Most of the thiazolidines have been prepared by the
condensation of the required aldehydes with hydrazides and
2-sulfanyl acetic acid. Here, electronegative sulphur acquires
negative charge, which in turn is responsible for the attraction
between sulphur and the electropositive imino carbon. To maintain
the stability carbon breaks the π-Bond with nitrogen atom, leading
to the development of negative charge on nitrogen. This reactive
nitrogen attacks on the carbonyl carbon, which has positive charge
thus eliminating hydroxy group and forming the Thiazolidinone
ring. The hydroxyl group and the hydrogen atom released
combines together to give a water molecule.
O OH Ar O Ar
N N
H
S R R
H S
H
Pharmaceutical Importance of
4-Oxo-thiazolidines
N C Desai et al have synthesized several 4-
oxo-quinazoline and thiazolidine derivatives and
O tested them for their anti HIV, anticancer and
O S
antitubercular activities.
N
N
N C6H 5
COCl O NH 2
COOH
Pyridine O
+
+
0-4oC, 2 hrs.
NH 2 N
CH 3 COOC2H 5
CH 3
Compound A
Pyridine
8-9 hrs.
O
NH 2 COOC2H 5
O NH O
N NH 2NH 2H 2O N
Methanol, 6-7 hrs.
N N
CH 3 CH 3
Compound C Compound B
Reaction Scheme of 4-Oxo-thiazolidines
O
NH 2
O NH
CH 3
Compound C
O NH R
N
N
S
O
N
CH 3
Compound D
O
NaOMe, 8-9 hrs.
Ar H
O
O NH R
N
N
S
O
N
CH 3 Ar
Compound E
Where, Ar = Different aryl groups
Studies on 5-Imidazolone Derivatives
Many of the azoles comprise the ring system of several
natural and synthetic compounds which are important for the
living systems and also as important drugs, dyes and
agricultural chemicals.
R O O R1
R1-NH 2 R NH
N O O
NH
Ar Ar
Amides of acylamino acrylic acids
R O
R1-NH 2
K CO POCl3
Ethanol 2 3
N N
R1
Ar
4-arylidine-imidazolin-5-ones
Ar = -C6H 5, R = Different aryl groups, 1= R Alkyl or aryl groups
Sequence of Transformation of
Imidazolone From Oxazolone
(a) Cyclisation of hippuric acid and aromatic aldehydes to form Oxazolones.
(b)Proton abstract by base results in the generation of carbanion.
(c) Carbanion attacks on carbonyl carbon of aldehyde, followed by
dehydration .
(d)Ring opening by attack of amine.
(e) Ring closure results in the formation of imidazolone ring.
Ar O
H Ar O Ar O
N O .
N N N
H
N N Ar
.
H Ar OH Ar
Pharmaceutical Importance of
5-Imidazolone Derivatives
Imidazolone ring system is of biological and chemical interest since long. The
imidazolinones are associated with a wide range of therapeutic activities such as
anticonvulsant, sedative and hypnotic, potent CNS depressant, antihistamine,
antimalarial, bacteriocidal, fungicidal, anti-inflammatory, MAO inhibitory,
antiparkinsonian, antihypertensive and anthelmintic.
O
Ph
N CH 3 N
N
N NH
C6H 5
O
Reaction Scheme of 5-Imidazolone
CONHCH 2COOH
Ar H
+
N-benzoyl amino acetic acid
Anhydrous
(CH 3CO)2O
CH 3COONa
Ar O O
O
N O N
+H N NH N
2
R
Pyridine
150oC, 6-8 hrs.
O
Ar O O
N
N N NH N
R
1N N 3
a
The numbering refers to annular centers in 1,2,4-triazole.
Different Possible Route For Synthesis of
[1,2,4]-Triazole Moiety
Route (1) 1,3-dipolar cycloadditions
leading to a great variety of heterocyclic
systems are applicable to the synthesis of
triazoles and derivatives. Nitrilimines
formed by dehydro-halogenation of C-
halobenzylidenephenyl- hydrazones, which
react with phenylcyanide, phenyl
PhC NNHPh isocyanate and benzylidenephenylamine to
Cl afford triazoles derivatives.
C-halobenzylidenephenylhydrazones
Et3N
+ -
PhC N NPh
PhCN Nitrilimines PhCH NPh
Ph Ph
PhNCO H N
N
Ar N
N
Ph
N Ph N
Ph N Ph Ph
O N
N
Ph Ph
Route (2) Ring closure of acyl
derivatives of semicarbazides,
thiosemicarbazides or aminoguanidines
in alkaline solutions is a method widely
applied for the preparation of 1,2,4-
triazoles. Gehlen reported that 3-
hydroxy-5-alkyl–1,2,4-triazoles are
produced in 65-75% yield by this
method.
O
NH N
NH NH 2
N KHCO 3 OH
R' O N
Svensson et al synthesized Y X W
NH
2,4-dihydro-[1,2,4] triazole-3-thione. S
N
These compounds are inhibitors of the NH
enzyme myeloperoxidase (MPO) and Where W = H, CH
3, F, OH, CH2OH, Ph
are thereby particularly useful in the X = O, CH 3
2, NR . R3 = H/Cl/6 alkyl
treatment of prophylaxis of Y = phenyl, naphthyl
neuroinflammatory disorders.
CH 3 H
O HO O N
O N
H 3C N
N N
N N N O O NH
N N
N
HO OH NH 2
4. Itraconazole Cl Cl 5. Viramidine
N
N
N
N N O O
OH CH N
3
F
F O
Cl N
N Cl
N N CH 3
F
6. Voriconazole 7. Terconazole CH 3
Reaction Scheme of [1,2,4]-Triazole
O NH
NH 2
CS2
KOH
C2H 5OH
O NH
NH S- K +
R
Compound A
C2H 5OH
Ar-CONHNH 2
SH O
N Ar
N N NH
R
Where, Ar = Different aryl groups
R =Naphthalene , 4-Chloro-1-methoxybenzene,
Methoxynaphthalene , 1-Methyl-3-nitrobenzene
Biological Evaluation
ANTIBACTERIAL AND ANTIFUNGAL ACTIVITIES OF THE
COMPOUNDS
SYNTHESISED IN PART - I , II & III.
H 2N O O CH 3
Gentamycin K. Nystatin
HO OH
NH 2
SECTION : 8
SH O
N Ar
PIX -06 Where Ar = -2-Cl-C6H4
N N NH
C. albicans (FBC) = 50 µg/ml