Acta Pharm. 67 (2017) 15-33
Original research paper
Synthesis and antitumor
activity of some novel thiophene, pyrimidine,
coumarin, pyrazole and
pyridine derivatives
MOHAMMED ALBRATTY, KARAM AHMED EL-SHARKAWY and SHAMSHER ALAM
karamsyn@yahoo.com
1 Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, P.O. Box 114, Jazan
45142, Saudi Arabia
2 Department of Organic Chemistry, Faculty of
Biotechnology, October University for Modern Sciences and Arts (MSA), El-Wahat Road, 6 October City, Egypt
Accepted September 17, 2016
Published online September
26, 2016
2-Cyano-N-(thiazol-2-yl) acetamide (2a) and 2-cyano-N-(oxazol-2-yl) acetamide
(2b) were obtained via the reaction of ethyl cyanoacetate
with either 2-aminothiazole (1a) or 2-aminooxazole (1b). The
formed products were directed toward the reaction with cyclopentanone
and elemental sulfur in the presence of triethylamine to give cyclopenta[b]thiophene
derivatives (3a,b). The latter products were
reacted with either ethyl cyanoacetate or malononitrile to form compounds 4a,b
and 5a,b, respectively. Compounds 4a,b
were aimed at synthesizing some heterocyclic compounds; thus internal cyclization reactions were introduced to form compounds 6a,b.
Also, compounds 4a,b reacted with salicylaldehyde, hydrazine derivatives and either urea or thiourea to produce coumarin
derivatives (7a,b), pyrazole
derivatives (8a-d) and pyrimidine derivatives
(9a-d), respectively. Reaction of either benzaldehyde
or benzene diazonium chloride (11) with compounds
4a,b afforded compounds 10a,b
and 12a,b, respectively. On the other hand, compounds 5a,b underwent internal cyclization
to form pyrimidine derivatives 13a,b.
Also, when compounds 5a,b reacted with
either ethyl cyanoacetate or malononitrile,
they gave pyridine derivatives (15a-d) through the formation of
intermediates (14a,b,c,d). Finally, formation of
fused pyrimidine derivatives (17a,b) was achieved through the reaction of compounds 5a,b
and salicylaldehyde applying two different pathways. The
first pathway used a catalytic amount of piperidine
to form compounds 16a,b; the latter
products underwent cyclization to give compounds 17a,b.
The second pathway, using a catalytic amount of sodium ethoxide
solution directly in one step, afforded compounds 17a,b. Structures of the newly synthesized compounds were
established using IR, 1H NMR, 13C NMR and mass
spectrometry and their antitumor activity was
investigated. Some of these compounds showed promising inhibitory effects on
three different cell lines. However, fused pyrimidine acetonitrile
derivatives 6a and 6b exerted the highest inhibitory effect, comparable to
that of doxorubicin.
Keywords: thiophene, pyrimidine,
coumarin, pyrazole,
pyridine, antitumor activity