Summary:
In this work, novel bioactive, heterocyclic, α,β-unsaturated carbonyl compounds
were designed and synthesized and their anti – parasitic activity evaluated.
The powerful and diverse biological properties of quinolinones and chalcones,
in the field of the antioxidant, anti – parasitic, anticancer and antivirus
activities, were combined to a novel hybrid skeleton of Quinolinyl –
Chalcone.Among the methods employed in the synthesis of quinolinone analogues,
the C- acylation reaction of ethyl acetoacetate, by
2-methyl-3,1-benzoxazin-4-one and further cyclization of the C-acylated
intermediates under basic conditions, led to the formation of the starting
material 3-acetyl 4-hydroxyquinolin-2(1H)-one.
The new series of quinolinyl chalcones were prepared via a crossed aldol
coupling reaction between 3-acetyl-4-hydroxy-quinolinone and various aromatic
aldehydes using piperidine as a basic catalyst. Twelve novel compounds were
synthesized in total, bearing either a variety of electron – donating or
electron – withdrawing substituents or a conjugated system.
Moreover, as we were interested in investigating further the structure –
activity relationship of the new series of quinolinyl chalcones, we decided to
proceed to the modification of the two more important structural
characteristics of these molecules, i.e. the amide hydrogen of the heterocyclic
ring of the quinolinone and the α,β-unsaturated system of the chalcone.
The methodology which was developed for the substitution of amidic hydrogen
with electron donating goups, such as ethyl or benzyl, was realized via
reductive amination of methyl anthranilate by the appropriate substituted
aldehyde, acylation of the secondary amine and further cyclization under basic
conditions. The newly synthesized quinolinyl chalcones were prepared via a
crossed aldol coupling reaction, according to the initial method.
The first approach in the chemical modification of the α,β-unsaturated carbonyl
system of chalcones was realised by heating the corresponding quinolinyl
chalcone with hydrazine derivatives in the presence of acetic acid, as a
solvent, to give the novel heterocyclic pyrazoline analogues. Furthermore,
hydrogenation of the quinolinyl chalcones, using an appropriate organic
compound as a hydrogen donor, catalyzed by Pd/C, led to the synthesis of novel
dihydrochalcones.
In the present study, the newly synthesized compounds were evaluated for their
in vitro antiparasitic activity against Visceral leishmaniasis and Human
African Trypanosomiasis (ΗΑΤ). The compounds present efficient inhibitory
activity, encouraging us for further investigation of the structure activity
relationship.
The structure of all of the synthesized quinolinyl-chalcone analogues was
elucidated using spectroscopic techniques (1H and 13C-NMR, ESI/MS, HRMS).
Keywords:
Chalcones, Quinolinones, Hybrid, Leishmaniasis, Trypanosomiasis
