Abstract
In the present paper, we report on the synthesis, and in vitro antiviral and cytostatic activities of a series of novel imidazole[4,5-e][1,3]diazepine-4,8-dione (compounds 9–11) and acyclic carbamoyl imino-ureido imidazole (compounds 12 and 13) derivatives. These new type of chemical entities showed no significant activity on the broad spectrum of DNA and RNA viruses. Results of antiproliferative assays performed on a panel of selected human tumor cell lines revealed that only compounds 1 and 5 showed moderate and selective cytostatic effect against HeLa cells (IC50 = 24 and 32 µM) with no concomitant cytotoxic effects on human normal fibroblasts (BJ). Importantly, an imidazole derivative containing a pyrrolidine moiety linked via an ethylenic spacer (3) showed a selective cytostatic effect toward cervical carcinoma (HeLa) cells (IC50 = 9.5 µM) with no apparent cytotoxicity on human normal fibroblasts (BJ). This compound can be therefore considered as a potential anti-tumor lead compound for further synthetic structure optimization.
Highlights
It has been found that infection with respiratory syncytial virus (RSV), which manifests primarily as bronchiolitis or viral pneumonia, is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children [1]
The main reason obviously lies in the fact that 6-amino-diazepine-4,8-dione molecules (9–11) are predominantly in solution in their imino tautomeric form as confirmed by NMR spectroscopy, which is inactive in the final step of the synthesis to create the ureido derivative of imidazo[4,5-e][1,3]diazepine-4,8-dione
Compounds 1–12 were evaluated for their antiproliferative effect against several malignant tumor cell lines: cervical carcinoma (HeLa), colorectal adenocarcinoma, metastatic (SW 620), breast epithelial adenocarcinoma, metastatic (MCF-7) and human hepatocarcinoma (HepG2) cells and compared with their effects on the growth of normal human skin fibroblasts (BJ) (Table 1)
Summary
It has been found that infection with respiratory syncytial virus (RSV), which manifests primarily as bronchiolitis or viral pneumonia, is the leading cause of lower respiratory tract infections (LRTIs) in infants and young children [1]. Ribavirin still is the only antiviral agent approved for the treatment of RSV infection, but due to efficacy and toxicity issues, it has only limited utility [2]. There is a clear need for new anti-RSV therapeutics, with improved efficacy and safety for broader applications [3]. Powell and his colleagues have recently identified a new class of RSV inhibitors, namely. Imidazole is an entity incorporated into many important biological molecules with a wide range of pharmacological activity. In the field of drug discovery the imidazole scaffold is widely used in the drug design strategy and imidazoles are generally well known as anticancer agents as well [6]
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