Design, synthesis and biological evaluation of novel thiadiazoline-thiazolone hybrids as kinase inhibitors.
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Date
2017
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Abstract
Cancer is a leading cause of death globally, and it was responsible for 8.8 million deaths in
2015. It is predicted that there will be 22 million new cancer cases by 2030 worldwide.
Approximately, 70% of deaths from cancer occur in low- and middle-income countries.
Furthermore, breast cancer is the second most common cancer among South African women
and is reported to affect 1 in every 26 women. The social and economic burdens associated
with cancers are severe at national and international levels hence, there is an urgent need for
the development of more effective cancer therapeutics. To accomplish this aspect, in this
study, thiadiazole-thiazolone (TDT) hybrids were developed as dual inhibitors of cyclindependent kinase (CDK) and kinesin spindle protein (KSP), respectively. Twenty-two novel
TDT hybrid compounds (8a-v) were synthesized using multistep organic synthesis and were
characterized using thin layer chromatography (TLC), infrared spectroscopy (FT-IR), nuclear
magnetic resonance spectroscopy (1H and 13C NMR), and high-resolution mass spectrometry
(HR-MS). All the compounds (8a-v) were screened for their potential in vitro inhibition of
validated anticancer drug targets (CDK, Abl and KSP) and cancer cell lines (MCF-7 and K562). Results obtained from these evaluations suggested that the synthesized compounds
were potent inhibitors of CDK and KSP thus confirming the dual mode of action. Amongst,
8h was identified as the most potent compound with an IC50 value of 3.1 µM against CDK2
enzyme and exhibited good cytotoxicity (GI50 = 6.25 µM) against the tested cancer cell lines
(MCF-7 and K-562). A brief structure-activity relationship (SAR) analysis indicated that 2-
chloro and 4-nitro substituents on the phenyl ring of the thiazolone motif contributed
significantly to the inhibition of both of the anticancer drug targets (CDK and KSP). An in
silico molecular docking study using the crystal structures of the target enzymes (CDK-2 and
KSP) further supported the SAR and extrapolated the importance of crucial molecular
interactions in influencing the enzyme inhibitory activities
Description
Masters Degree. University of KwaZulu-Natal, Durban. 2017