Synthesis, biological activity, and in silico studies of thieno[2,3-d]pyrimidine and thieno[2,3-d]triazine derivatives

Background The chemistry of condensed heterocyclic compounds has emerged in numerous reports for their diverse biological properties and drug discovery. Pyrimidine and triazine scaffolds have been utilized as therapeutic agents in many medicinal applications. Many research groups have designed and synthesized pyrimidine moieties as they are incorporated in nucleic acid bases. Objective In this report, we have designed and synthesized a variety of 2-mercaptothieno pyrimidine and thienotriazine derivatives and 2-mercaptothienopyrimidines conjugated with sugar moiety. The newly synthesized compounds were tested for their biological activity against breast (MCF-7), liver (HepG-2), and prostate (PC-3) cancer cell lines as well as a normal cell line (human normal melanocyte, HFB4) and were also analyzed for in silico studies to determine their potential. Materials and methods A variety of 2-mercaptothienopyrimidine and thienotriazine derivatives were prepared via cyclization of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (1) and 2-amino-N-phenyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (9). Two derivatives of 2-mercaptothienopyrimidines conjugated with sugar moiety were also prepared. The products were screened for their biological activity against breast (MCF-7), liver (HepG-2), and prostate (PC-3) cancer cell lines as well as the normal cell line (human normal melanocyte, HFB4) in comparison with the known anticancer drug 5-fluorouracil using the MTT assay. Results and conclusion The results indicated that most of the tested compounds exhibited no activity against the growth of HFB4. Compounds 5, 8, 10, 12, and 14 revealed effective antiproliferative activity against MCF-7 cell lines with IC50 of 4.6, 6.2, 5.4, 7, and 3.25 µg/ml, respectively, compared with 5-fluorouracil (IC50 of 3.97 µg/ml). In the same sense, the evaluation of cytotoxic effect of the tested compounds against human liver HepG-2 cancer cell lines revealed that compounds 5, 8, 10, 12, and 14 showed cytotoxic activity close to that of the standard drug (IC50 values of 5.77±0.99, 7.23±0.98, 4.42±1.32, 7.9±0.90, and 5.1±11.28 µg/ml, respectively, vs. 4.27±0.58 µg/ml for 5-fluorouracil). Free binding energy was estimated by docking and MM-GBSA calculation. Molecular dynamics simulation followed by MM-GBSA calculation was correlated to the cytotoxic effect. Compound 14 illustrated the highest MM-GBSA value (−20.38) and the best cytotoxic effect.