Abstract
Herein, we report an environmentally friendly, rapid, and convenient one-pot ultrasound-promoted synthesis of 5-amino-2-(4-chlorophenyl)-7-substituted phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α)pyrimidine-6-carbonitrile derivatives. The in-vitro anticancer activities of these compounds were evaluated against four human tumor cell lines. Among all the synthesized derivatives, compound 4i, which has substituent 3-hydroxy-4-methoxyphenyl is found to have the highest GI50 value of 32.7 μM, 55.3 μM, 34.3 μM, 28.9 μM for MCF-7, K562, HeLa and PC-3 cancer cell lines respectively. A docking study of the newly synthesized compounds were performed, and the results showed good binding mode in the active site of thymidylate synthase enzyme. ADME properties of synthesized compounds were also studied and showed good drug like properties.
Highlights
Cancer is a disease in which cells grow and proliferate in an uncontrolled manner
The purity of the synthesized compounds was monitored by ascending thin layer chromatography (TLC) on silica gel-G (Merck, Darmstadt, Germany) coated aluminum plates, visualized by iodine vapor and melting points were determined in open capillary tubes
The present work reports green synthetic route leading to the formation of antitumor active 5-amino-2-(4-chlorophenyl)-7-substituted phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α) pyrimidine-6-carbonitrile and gives an impression about a clue for the mode of action by performing molecular docking study
Summary
Cancer is a disease in which cells grow and proliferate in an uncontrolled manner. Cancer disease evokes a high level of mortality regardless of recent advances in the development of clinically authorized anticancer agents [1]. Many scientists are intensively engaged in the development of new anticancer active agents that reveal a selective cytotoxicity for cancer cells over normal cells which is undoubtedly needed to treat the severe cancer disease more efficiently and is less toxic, since many of the marketed anticancer drugs are toxic in nature [2,3,4]. Folate metabolism is considered as an important target for the development of new anticancer agents due to its role in the biosynthesis of nucleic acid precursors [5,6]. The inhibition of folate dependent enzymes such as thymidylate synthase (TS), which catalyzes the reductive methylation of deoxyuridylate (dUMP) to thymidylate (dTMP) has been recognized as an interesting target for drug discovery [7,8]
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