New Approaches for the Synthesis N-alkylated Benzo[b]thiophene Derivatives together with their Antiproliferative and Molecular Docking Studies

Abstract

Background: 2-Amino thiophene derivatives are important compounds not only for their uses in many heterocyclic reactions but also due to their wide range of pharmaceutical and biological activities. background: Sulfur containing heterocyclic compounds are important compounds that were recently used in many heterocyclic reactions. 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile belongs to these compounds which was used in plenty of reactions to produce biologically active compounds. Objective: The aim of this work was to explore a number of new heterocyclic derivatives, studying their inhibitions toward cancer cell lines and studying their structure activity relation ship. objective: This work aimed to produce novel heterocyclic compounds such as thiophene, pyran and pyridine derivatives. The newly synthesized heterocyclic compounds were evaluated against cancer cell lines aiming to get new anticancer agents. Method: Alkylation of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was achieved through its reaction with chloroacetone and 2-bromo-1-(4-aryl)ethanone derivatives to give compounds 3 and 11a-c. The produced compoumds were subjected to further heterocylization reactions and cytotoxic evaluation against the three cancer cell lines MCF-7, NCI-H460 and SF-268, together with the normal cell line WI 38. Further evaluations were obtained through studying their inhibitions against cancer cell lines classified according to the disease. Anticancer screening against hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines for all compounds together with the molecular docking of 12c, 12d, 12d and 12f were studied. method: The reaction of 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile with chloroacetone and 2-bromo-1-(4-aryl)ethanone derivatives afforded the N-alyylated products 3 and 11a-c, respectively. The latter products underwent different reactions to yield new bioactive products. The anti-proliferative activity of the newly synthesized compounds toward three cancer cell lines was studied. In addition, inhibitions of the most active compounds toward cancer cell lines classified according to the disease were also studied. Moreover, the newly synthesized compounds were screened for their anticancer potentials against hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines. Results: Anti-proliferative evaluations and inhibitions for all of the synthesized compounds showed that many compounds exhibited high inhibitions. Conclusion: Toward the three cancer cell lines, compounds 3, 5a, 7a, 9a, 9b, 11b, 12b, 12d, 12e, 12f, 14c, 14e, 14f, 15e, 15f, 16e, 16f, 17c, 18b, 22a and 22c were the most cytotoxic compounds. The high activities of some compounds were attributed to the presence of the electronegative CN and or Cl groups within the molecule. Most of the tested compounds exhibited inhibitions higher than the reference doxorubicin toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines. The score of binding energy of compounds 12c, 12d, 12d and 12f was close to the reference Foretinib which appeared through the molecular docking results of such compounds. conclusion: Compounds 3, 5a, 7a, 9a, 9b, 11b, 12b, 12d, 12e, 12f, 14c, 14e, 14f, 15e, 15f, 16e, 16f, 17c, 18b, 22a and 22c were the most cytotoxic compounds toward the six cancer cell lines. Inhibitions toward cancer cell lines classified according to the disease showed that, in most cases, the presence of the electronegative CN and or Cl groups within the molecule were responsible for the high activities. Inhibitions toward hepatocellular carcinoma HepG2 and cervical carcinoma HeLa cell lines showed that most of the tested compounds exhibited inhibitions higher than the reference doxorubicin. Molecular docking of compounds 12c, 12d, 12d and 12f showed that these compounds exhibited score of binding energy close to the reference Foretinib. other: The work was done using chemically available reagents