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

El-Hag, Fatma A.A.; Elrashedy, Ahmed A.; Sweed, Ayman M.K.; Ewies, Ewies F.; Abd-El-Maksoud, Mansoura A.; Aly, Magdy S.; Atta, Sanaa M.Sh.

doi:10.4103/epj.epj_54_22

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

Authors

Abstract

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 and 2-amino--phenyl-4,5,6,7-tetrahydrobenzo[]thiophene-3-carboxamide . 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 and revealed effective antiproliferative activity against MCF-7 cell lines with IC of 4.6, 6.2, 5.4, 7, and 3.25 µg/ml, respectively, compared with 5-fluorouracil (IC 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 and showed cytotoxic activity close to that of the standard drug (IC 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.

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