Acta Pharm. 67 (2017) 527-542

full paper

Original research paper

Synthesis and evaluation of antitumor activity of new 4-substituted thieno[3,2-d]pyrimidine and thienotriazolopyrimidine derivatives

HEND N. HAFEZ and ABDEL-RHMAN B. A. EL-GAZZAR

profelgazzar@yahoo.com

¹ Al-Imam Mohammad Ibn Saud Islamic University (IMSIU), Faculty of Science, Department of Chemistry, P. O. Box: 90950 Riyadh 11623, Kingdom of Saudi Arabia

² Photochemistry Department (Heterocyclic & Nucleosides Unit), National Research Centre, Cairo, Egypt

Accepted October 12, 2017

Published online October 30, 2017

3-Methyl-6-phenyl-2-thioxo-2,3-dihydro-thieno[3,2-d]pyrimidin-4(1H)-one (2), on treatment with phosphorous oxychoride, affored 4-chloro-3-methyl-6-phenyl -thieno[3,2-d]pyrimidine-2(3H)-thione (3). A series of novel 6-phenyl-thieno[3,2-d]pyrimidine derivatives 4-9 bearing different functional groups were synthesized via treatment of compound 3 with different reagents. On the other hand, compound 2 was used to synthesize ethyl-[(3-methyl-6-phenyl-2-thioxo-2,3-dihydro-thieno[3,2-d]pyrimidin-4-yl)-oxy]acetate (10), 2-hydrazinyl-3-methyl-6-phenyl-thieno[3,2-d]pyrimidin-4(3H)-one (11), 3-methyl-2-(methyl-sulfanyl)-6-phenyl-thieno[3,2-d]pyrimidin-4(3H)-one (12) and N-(phenyl)/4-chlorophenyl or methoxy-phenyl)-2-[(3-methyl-4-oxo-6-phenyl-3,4-dihydro-thieno[3,2-d]pyrimidin-2-yl)-sulfanyl]-acetamide (13a-c). In addition, compound 12 was used to synthesize thieno[1,2,4]triazolopyrimidine derivatives 14 and 15 and 3-methyl-2-(methyl-sulfonyl)-6-phenyl-thieno[3,2-d]pyrimidin-4(3H)-one (16) through the reaction with the respective reagents. Moreover, the reaction of 16 with 4-phenylenediamine gave 2-[(4-aminophenyl)-amino]-3-methyl-6-phenyl-thieno[3,2-d]pyrimidin-4(3H)-one (17), which reacted with methanesulfonyl chloride to afford N-{4-[(3-methyl-4-oxo-6-phenyl-3H,4H-thieno[3,2-d]pyrimidin-2-yl)-amino]phenyl}-methanesulfonamide (18). The majority of the newly synthesized compounds displayed potent anticancer activity, comparable to that of doxorubicin, on three human cancer cell lines, including the human breast adenocarcinoma cell line (MCF-7), cervical carcinoma cell line (HeLa) and colonic carcinoma cell line (HCT-116). Compounds 18, 13b and 10 were nearly as active as doxorubicin whereas compounds 6, 7b and 15 exhibited marked growth inhibition, but still lower than doxorubicin.

Keywords: thieno[3,2-d]pyrimidines, thienotriazolopyrimidine derivatives, antitumor activity