A facile one-pot four-component reaction was utilized to construct 2-oxo-1,2-dihydropyridine-3-carbonitrile as a scaffold for the synthesis of many fused heterocyclic systems, namely, furopyridine, pyridothiadiazepinthione, and pyridotriazine, as well as non-fused heterocyclic systems such as phthalazin-2(1H)-ylnicotinonitrile, pyridin-2-yl-1H-pyrazole, and pyrazol-1-ylnicotino-nitrile,1-(3-cyanopyridin-2-yl)-1H-pyrazole. The new compounds were evaluated as antimicrobial and antiviral agents.
Background:
In a continuous combat against cancer, which is one of the leading causes of mortality
now, chalcone and Schiff bases moieties have been incorporated and their antiproliferative activities and associated
mechanisms against liver (HepG2) and breast (MCF-7) cell lines in addition to normal fibroblasts (WI-38)
have been examined.
Methods:
Derivatives 4 and 5 of Schiff bases only and chalcone derivatives of Schiff bases 1 and 2 were devoid
of any antiproliferative activity. All three compounds (3, 6, and 7) with significant antiproliferative activity were
selective and caused no growth inhibition in normal fibroblasts. Derivative 3 was a chalcone only with IC50 of
~20 µM and has a very interesting signature where it enhanced apoptosis in HepG2 by stimulating the expression
of downstream execution caspase 3 without affecting neither p53 nor initiator caspase 9. In spite of the
structural similarity between compounds 6 and 7, compound 6 discerned itself with a unique IC50 of ~ 10 µM.
Results:
The antiproliferative activity of derivative 6 could be attributed to its unique capability of formation of
free radicals such as phenoxide radicals which arrested the cell cycle through enhancing the expression of p53
and induced apoptosis by induction of both caspases 9 and 3. It was the only investigated derivative that inhibited
the tyrosine kinase activity by 89%.
Conclusion:
The antiproliferative activity of the compounds under investigation considerably depended on the
nature of the substituent at position 4 in phenyl rings of both chalcone and Schiff base fragments. Derivative 6
with electron withdrawing chlorine substitution on the phenyl ring of Schiff base fragment and an electron donating
methoxy group on the phenyl ring of chalcone fragment was the most active member.
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