Pharmacophore an International Research Journal
The present study involved the development of novel 2-thiouracil-5-sulfonamide isosteres. Reaction of 5-hydroxyl methyl -2-thiouracil 1 with thionyl chloride yielded the targeted chloromethyl analogue 2 which was the starting compound for the synthesis of targeted compounds. Compound (2) was reacted with a series of aromatic amines to give amino derivatives 3a-e. The acetyl derivative (3d) was reacted with ethyl cyanoacetate, and a series of aromatic aldehydes in presence of excess ammonium acetate yielded pyridones (4a- e). Also, a series of thiosemicarbazones were obtained via reaction of the compound 3d with alkyl thiosemicarbazides 5a-e. Moreover, the compound 3d was monobrominated with bromine in acetic acid to give a bromo derivative 6 which in turn was reacted with thiosemicarbazones of some aldehydes to give the corresponding thiazole derivatives 7a-e. All new compounds and their chemical isosteres 2-thiouracil-5-sulfonamides were tested for possible anti-cancer activity against MCF-7 and HEPG-2 cell lines in comparison to the reference drug 5-Fluorouracil. Compound 5d was the most active against the breast carcinoma cell line (MCF-7) and the liver carcinoma cell line (HEPG-2) giving promising IC50 values of 0.52 μg/mL and 0.63 μg/mL, respectively, compared with 5-Fluorouracil with IC50 values of 0.67 and 5 μg/mL, respectively. Structure-activity relationship (SAR) was also discussed.
