Synthesis and Cytotoxic Evaluation of Novel Benzimidazole Fused Condensed Thienopyrimdines Derivatives

Abstract

Background: Cancer is a major health problem acting as a global killer and one of the leading causes of death. Most cancer chemotherapeutic drugs currently in clinical use are to kill malignant tumour cells by inhibiting some of the mechanisms implied in cellular division. Thienopyrimidines occupy a special position among the fused pyrimidines, along with other pyrimidines containing an annelated five membered hetero aromatic ring; forms a significant class of drugs which exhibit an array of various biological activities. One of the important current anticancer agent gefitinib acts as tyrosine kinase inhibitors is a quinazoline derivative. The thieno[2,3-d]pyrimidine ring system, is considered as a bioisostere of quinazoline moiety and have attracted great attention due to their broad bioactivities, including antitumor. Methods: Novel thienopyrimidine derivatives were synthesized by cyclization of thiophene o-amino esters with lactam salts such as pyrrolidin-2-one, piperidin-2-one and caprolactam by treating using phosphorous oxychloride. The next set of compounds thieno[2,3-d]pyrimidin-4(3H)-one were synthesised by Niementowski condensations between 2-aminothiophene carboxylate and formamide under reflux condition, followed by its chlorination in good yield. Microwave Fusion of 4-chlorothieno[2,3-d] pyrimidines with o-phenylenediamine afforded target compounds. The target compounds were tested on MCF-7 and HEK293 cell line. Results: The synthesized thirty compounds structures were established by IR, 1H NMR and Mass spectroscopy. The synthesized compounds were obtained in the good yield ranging from 45-70%. The synthesized compounds were subjected to cytotoxicity studies. Among the twenty compounds only one compound showed moderate activity. One of the compound 2c bearing acetyl group had IC50 48.93 μM. However decrease in the size of the lactam ring from six to five member ring or increase to seven member ring resulted in the loss of activity. The IC50 value of 5a was found to be 70.86μg/ml. The compound 5i have more cytotoxic action among the series. Conclusion: A series of thirty compounds belonging to novel pyyrolo, pyrido and benzimidazole fused thienopyrimidines were synthesized, characterized and were evaluated for their in vitro cytotoxicity. The compounds bearing bulky group such as terbutyl group and chloro substitution had the best activity. In conclusion, these structures seems to have biological properties and further investigation on this group could provide a lead.

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure–activity relationship, and mechanisms of action (2019–2021)

“…The 1 H ‐benzimidazole‐2‐one‐thieno[2,3‐ d ]pyrimidin‐4(3 H )‐one hybrid 49 (IC 50 : 29.0 and 74.0 nM, MTT assay) exhibited pronounced activity against MCF‐7 and MDA‐MB‐231 breast cancer cell lines, demonstrating its potential as a novel antibreast cancer candidate. [ 105,106 ]…”

“…[104] The mechanistic study revealed that hybrid 48 and MDA-MB-231 breast cancer cell lines, demonstrating its potential as a novel antibreast cancer candidate. [105,106]…”

Recent advances of benzimidazole as anticancer agents

“…In this comprehensive review, we focused on the role of benzimidazole in the treatment of cancer disease. Benzimidazole is a fusion of a six-membered benzene ring and a five-membered imidazole/imidazoline ring, which is an azapyrrole in the nucleus (Kaliraj & Kathiravan, 2020).…”