Synthesis, Antiproliferative Activity and Molecular Docking of New Thiazole/Benzothiazole Fused Pyranopyrimidine Derivatives

Abstract

A new class of 4H,5H-benzo[4,5]thiazolo[3,2-a]pyrano[2,3-d]pyrimidin-5-one and 5H,6Hpyrano[ 2,3-d]thiazolo[3,2-a]pyrimidin-5-one derivatives were synthesized via the one-pot threecomponent reaction of 2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one and 7-hydroxy-5Hthiazolo[ 3,2-a]pyrimidin-5-one to various aromatic aldehydes and malononitrile. This domino transformation involves the formation of pyranopyrimidine ring by the formation of three C–C bonds and one C– O bond a single synthetic operation. As the products precipitate out of the reaction, simple filtration is enough to gather the products, and thus, there is no need for work-up or column-chromatography. The synthesized thiazole/benzothiazole fused pyranopyrimidine derivatives were evaluated for their antiproliferative activity against four cancer cell lines namely DU 145 (prostate cancer), Hela (Human cervical cancer), MDA-MB-231 (breast cancer), HT-29 (Human colon cancer) and normal cell line HEK293 (human embryonic kidney cells). The results demonstrated that synthesized compounds were selective in its cytotoxicity to cancer cells compared to normal cells. Among these compounds, 2-amino-9- methoxy-5-oxo-4-(3,4,5-trimethoxyphenyl)-4H,5H-benzo[4,5]thiazolo[3,2-a]pyrano[2,3-d]pyrimidine- 3-carbonitrile 4i exhibited the most potent antiproliferative activity against the tested cell lines. Molecular docking studies revealed that these active heterocyclic molecules bind selectively in the colchicine binding site of tubulin polymer.