Synthesis, Pharmacological Evaluation, and Docking Studies of Ethyl Coumarilate Derivatives as Potential Anti-bladder Cancer in a Mouse Model

Abstract

In our study, we performed the green synthesis of twenty-one new organic compounds derived from ethyl coumarilate and treated with ammonia derivatives, such as hydrazine, phenylhydrazine, semicarbazide, and thiosemicarbazide. These reactions yielded a five-member ring incorporating benzofuran, and similar reactions with urea, thiourea, and guanidine produced a six-member ring incorporating benzofuran. All compounds were synthesized in our previous work1 and evaluated for their effects on bladder cancer in experimental mice using docking analysis. Among these twenty-one compounds, we selected five based on docking program analysis. These five compounds showed the highest negative ΔG value, indicating strong interaction and effective inhibition of three important enzymes, TNF-alpha, COX-2, and IL-6, responsible for inflammation in the body. The results demonstrated that the prepared organic compounds exhibited robust binding and inhibition towards these enzymes. Subsequently, a study was conducted on 85 male mice, divided equally into seven groups, with each group consisting of five mice. The control group received a normal diet and distilled water, while groups 2 to 7 were administered doses of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) at a dose of 0.05% in drinking water for four months. Groups 3 to 7 received intraperitoneal injections of compounds A, B, C, D, and E at three different doses (0.5-1-1.5 mg/kg) for 21 days. Unfortunately, all the mice in group 7 died when this compound was used, possibly due to its high dose. Biochemical results revealed that compound B exhibited intriguing anticancer activity, reducing TNF-alpha levels and inhibiting COX-2 and IL-6 enzymes, reversing bladder cancer injury. Moreover, histopathological examination indicated significant improvement, with the complete disappearance of cancer in the bladder caused by compound B.