Abstract:
3,4-dihydropyrimidin-2(1H)-ones and their derivatives have attracted
increasing interest owing to their therapeutic and pharmaceutical
properties, such as antiviral, antibacterial, anti-inflammatory and
antitumor activities. Recently, functionalized dihydropyrimidinones have
been successfully used as antihypertensive agents, calcium channel
blockers, adrenergic and neuropeptide antagonists. Chapter one of this
thesis covers the different chemical reactions that were utilized in the
synthesis of dihydropyrimidines. A concise review of a wide range of
biological activities associated with dihydropyrimidine ring system was
covered and presented.
In this work, eighteen compounds of dihydropyrimidine moiety were
synthesized. The synthetic designing of these compounds was constructed
with retrosynthetic analysis and disconnection approach. Therefore the
prepared dihydropyrimidines in this work fall into three major categories
depending upon the synthetic route. The first of these synthetic routes is a
direct condensation reaction between a 1,3-dicarbonyl compound and
urea in presence of ethanol and acetic acid under reflux for long period of
time. This method suffered from some drawbacks concerning low yields,
long reaction period and deficiency in designing substituents. The second
synthetic route attempted in this work is the multi-component reaction
involving a 1,3-dicarbonyl derivative, an aromatic aldehyde and urea,
which is generally known as Biginelli reaction. The third synthetic route,
which was mainly followed in this thesis is the synthesis of the target
dihydropyrimidines through a Michaell type cyclization reaction between
α,β-unsaturated carbonyl derivative (chalcone) and urea. This reaction is
proved to be versatile and gave way to designed highly substituted
dihydropyrimidines. Accordingly, the readily available or synthetic 1,3-
dicarbonyl compounds and their corresponding diazotised derivatives
were allowed to react with benzaldehyde or p-N,N-dimethylbenzaldehyde
in ethanol and sodium hydroxide in cross aldol condensation, Claisen-
Schemidt reaction to furnish the corresponding α,β−unsaturated carbonyl
derivatives. The second step involves a cyclization reaction between the
synthesized α,β−unsaturated carbonyl derivatives and urea to furnish the
required dihydropyrimidine derivatives.
The reaction progress was followed by TLC and the purity of the
recrystallized compounds was checked by chromatographic means.
The different mechanistic pathways leading to intermediate and final
compounds were discussed and outlined. The structures of the different
synthesized compounds were elucidated and confirmed by full spectral
technique involving UV-Vis, IR, 1H and 13CNMR, MS and GC-MS.
The spectral data were interpretated and assigned for each compound.
The full range of the synthesized and intermediate compounds was
screened for their antimicrobial activity. The compounds were tested for
antibacterial activity against two gram-positive bacteria S. aureus and B.,
subtilis, two gram-negative bacteria E. coli and P. aeruginosa
Compound XIX in a concentration of 100 μg/ml in PRG was found to be
the most active derivative. This compound is characterized by the
presence of a benzoyl group in position 5- of the dihydropyrimidine ring
system.
Compounds XIX and XXI showed the higher efficacy in terms of %
reduction of parasitemia when tested against T. evansi in albino rats.