Abstract
Griseofulvin, an antifungal drug, has also shown good antiproliferative activity previously. This study was aimed to synthesize heterocyclic extension derivatives of griseofulvin and test them against cancer cell lines. Griseofulvin was hydrolyzed to afford griseofulvic acid (
) followed by hybridization with important heterocyclic moieties. Initially, the active methylene group of the 1,3-cyclohexanedione moiety in
was utilized to synthesize fused thiophene derivatives (
and
) by reacting with malononitrile or ethyl cyanoacetate together with elemental sulfur. Compounds
and
were further converted to fused pyrimidine derivatives (
) using ethyl isothiocyanate or phenyl isothiocyanate. Compound
was also reacted with aryldiazonium chlorides to synthesize compounds
and
, which were used to prepare fused thiophene derivatives (
). The resulting thiophenes (
) underwent cyclization to produce fused pyridazine derivatives (
). In addition, fused pyridine derivatives (
and
) were also prepared by the reaction of
and
with ethyl cyanoacetate using two different catalytic bases. The first was triethylamine to form
and
in two steps via
and
, and the second was sodium ethoxide to afford
and
in one step. Finally,
and
underwent cyclization in the presence of acetylacetone to yield compounds
and
. The structures of synthesized compounds were confirmed using IR,
H NMR,
C NMR, and mass spectrometry techniques. The synthesized compounds were subjected to cytotoxic screening against three tumor cell lines and presented good to excellent cytotoxic profiles. Compounds
and
showed significant inhibitory activity against the three cell lines compared to the standard drug doxorubicin.