Background: Thiophene, thiazole, and isoxazole derivatives are present in a wide range of natural
and synthetic compounds with heterogeneous pharmacological activity. Due to their structural diversity, they are
some of the most versatile classes of compounds for anticancer drug design and discovery.
Objective: Thiophene, thiazole, and isoxazole derivatives were herein designed with a dual purpose: as antiproliferative
agents and kinase inhibitors.
Methods: The test compounds were synthesized in moderate to high yields through a simple methodology.
Tetrahydrobenzo[b]thiophen-5-one derivatives 5a-f were prepared from the reaction of 2-arylidencyclohexan-
1,3-dione 3a-c with elemental sulfur and either of malononitrile (4a) or ethyl cyanoacetate (4b) in 1,4-dioxan in
the presence of triethylamine. Compounds 5a,b were used for the synthesis of thiophene, thiazole, and isoxazole
derivatives through their reactions with different chemical reagents.
Results: Antiproliferative evaluations, c-Met kinase, and Pim-1 kinase inhibitions were performed where some
compounds revealed high activities. In all cases, antiproliferative activity and the kinase inhibitions were performed
against six cancer cell lines and five tyrosine kinases, respectively. Where the most cytotoxic compounds
were 3c, 5d, and 16c with IC50’s 0.29, 0.68, and 0.42μM, respectively, against the A549 cell line.
Conclusion: The anti-proliferative activities of the newly synthesized compounds were evaluated against the six
cancer cell lines (A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460). The most potent compounds
toward the cancer cell lines (3a, 3c, 5d, 7c, 11c, 16a, and 16c) were further investigated towards the five tyrosine
kinases (c-kit, FIT-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5d, and 16c were selected for testing
of their inhibition for the Pim-1 kinase due to their anti-proliferation activities against the cancer cell lines
and their high activities against the tyrosine kinases.