الفهرس 
Chemistry of quinazolineOnly 14 pages are availabe for public view
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Abstract
Quinazoline nucleus possessed the potent pharmacodynamic
nucleus. In addition several quinazoline derivatives possess diverse
biological activities Viz. Anticonvulsant, Hyponotics, Thus in the present
work, we looking forward to synthesis of a series of new heterocyclic
rings containing the quinazoline nucleus. Construction of the starting material began by N-alkylation of
quinazolin-4(3H)-one 1 with ethyl bromoacetate in the presence of
potassium carbonate in stirring dimethylformamide at room temperature
yielding the desired ethyl 2-(4-oxoquinazolin-3(4H)-yl)acetate 2.
Hydrazinolysis of 2 at room temperature afforded the key intermediate 2-
(4-oxoquinazolin-3(4H)-yl)acetohydrazide 3. When the acetohydrazide
derivative was treated with carbon disulphide in ethanol in the presence
of potassium hydroxide, 3-[(5-mercapto-1,3,4-oxadiazol-2-yl)methyl]
quinazolin-4(3H)-one 4 was obtained. The treatment of 4 with
iodoethane, benzyl chloride, or ethyl bromoacetate under alkaline
conditions provided 3-[(5-substituted sulfanyl-1,3,4-oxadiazol-2-yl)
methyl]quinazolin-4(3H)-one 5, 6, and 7 respectively. On the other hand
the reaction of acetohydrazide 3 with Phenyl isothiocyanate in ethanol
gave the corresponding 2-[2-(4-oxoquinazolin-3(4H)-yl)acetyl]-Nphenylhydrazinecarbothioamide
8. Depending on the reaction medium,
thiadiazole or oxadiazole derivatives can be formed during the cyclization
reaction of the thiosemicarbazide derivative 8. Thus, stirring at 0 °C of 8
in the presence of sulfuric acid provided 3-{[5-(phenylamino)-1,3,4-
thiadiazol-2-yl]methyl}quinazolin-4(3H)-one 9. However, cyclization of
8 in the presence of HgO under reflux condition gave 3-{[5-
(phenylamino)-1,3,4-oxadiazol-2-yl]methyl}quinazolin-4(3H)-one 10.
The thiosemicarbazide derivative 8 was then reacted with ethyl romoacetate in the presence of anhydrous sodium acetate in absolute
ethanol to afford N’-(4-oxo-3-phenylthiazolidin-2-ylidene)-2-(4-oxoquinazolin-
3(4H)-yl)acetohydrazide 11 (scheme 1) .
Scheme 1. Synthesis of the target compounds 4-11.
The condensation of the acetohydrazide 3 with appropriate
aldehyde provided the corresponding benzylidene derivatives 12, 13, and
14. On the other hand, the reaction of acetohydrazide 3 with alkene
derivative diethyl ethoxymethylenemalonate in ethanol afforded 15.
When acetohydrazide 3 was reacted with ethyl chloroformate leads to the
corresponding ethyl-2-[1-(4-oxoquinazolin-3(4H)-yl)acetyl] hydrazine
carboxylate 16, on further condensation with hydrazine hydrate in ethanol
it afforded 17. The latter product was reacted with aromatic aldehyde or
cyclic ketones to give the corresponding arylidene 18, and cycloalkylidene derivatives 19 and 20 respectively. Compound 17 upon
treatment with carbon disulphide and potassium hydroxide in boiling
ethanol, provided the oxadiazole derivative 21 which undergo facile
alkylation with benzyl chloride under alkaline conditions to afford the
corresponding derivative 22 (scheme 2).
Scheme 2. Synthesis of the target compounds 12-22
The preparation of nitrile derivative 23 by treatment of quinazolin-
4(3H)-one with acrylonitrile in the presence of trimethylamine appeared
to be a practical starting point for the elaboration into compounds 24, 25,
26, and 27. The cyclisation of compound 23 using sodium azide and
ammonium chloride under reflux condition providing tetrazole derivative
24. The versatile nitrile derivative 23 was converted into acid 25 by
hydrolysis using sodium hydroxide. The treatment of 25 with N aminothiourea and phosphoryl chloride afforded 26 in low yield. The
methyl ester derivative 27, formed from 25 under standard conditions,
treated directly with hydrazine hydrate to give 28. The hydrazide
derivative 28 is a key intermediate, which give rise to a variety of
compounds by condensation with p-nitrobenzaldehyde, 3-chloro-4-
fluorobenzaldehyde, or acetone afforded 29, 30, and 31, respectively.
Alternatively, treatment of hydrazide derivative 28 with carbon
disulphide and potassium hydroxide at reflux condition for 4h gave 32.
The benzyl chloride was reacted with 32 in the presence of potassium
carbonate to give 33 (scheme 3) .
Scheme 3. Synthesis of the target compounds 24-33 A series of novel quinazolin-4(3H)-one derivarives were
synthesized by incorporating different moieties in the 3rd position of the
quinazolinone nucleus and their structures were established based on
spectroscopic data. The obtained compounds were evaluated for their
anticonvulsant activities using Picrotoxin model. The results of this study
demonstrated that, Compounds 4, 6, 11, 12, 14, 15, 18, 19, 22, 26, 29, 31,
and 32 proved to be inactive, while compounds 5, 7, 10, 21, 24, and 33
significantly prolonged the onset time for convulsions . The order in
prolonging the onset time for convulsions was 24 > 7 > 33 > 5 > 21 > 10.
Additionally compounds 7, 10, 21, 24 and 33 successfully protected
16.67% of animals from death and 5 protect 33.33% and all significantly
delayed the death latency in the remaining animals.
The pharmacological results obtained in the current studies proved
that incorporation of the oxadiazole moiety through a different linker in
the 3rd position of the quinazolinone nucleus for example 7, 10, 21, 24,
and 33 was essential for anticonvulsant activity in this series of
compounds. The present active compounds, especially 5 could be useful
as a template for further modifications to produce more active analogues.