Efficient Methods for the Synthesis of Novel Arylazothiazoles Based on Acetylferrocene or Adamantane

Background: Hydrazonoyl halides are convenient for the synthesis of arylazothiazoles. Materials and Methods: A series of novel arylazothiazoles were efficiently synthesized from the reaction of hydrazonoyl chlorides with 2-(adamantan-2-ylidene)hydrazinecarbothioamide or 2-(ferrocenyl-1-ylidene)hydrazinecarbo-- thioamide in dioxane used as an aprotic solvent because of its lower toxicity and higher boiling point (101 °C) and triethylamine at reflux. The reaction mechanistic pathway proceeded by the nucleophilic substitution reaction by the elimination of hydrogen chloride to give thiohydrazonates as intermediate, which in situ undergo intramolecular cyclization and loss of water molecule to afford the final product of novel arylazothiazoles. This method is simple with good yield and excellent purities. Results and Discussion: The synthetic schemes for the final products are proposed and discussed. The chemical structures of the final products were identified by different techniques, such as elemental analysis, Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS). Conclusion: In this article, we prepared arylazothiazoles from the reaction of 2-(adamantan-2-ylidene)hydrazinecarbothioamide or 2-(ferrocenyl-1-ylidene)hydrazinecarbothioamide with hydrazonoyl halides.

Biological Activity, Apoptotic Induction and Cell Cycle Arrest of New Hydrazonoyl Halides Derivatives

Background:The hydrazonoyl halides are presently an important target in the field of medicinal chemistry. The interest in the chemistry of hydrazonoyl halides is a consequence of the fact that they undergo a wide variety of reactions which provide routes to a myriad of both heterocyclic and acyclic compounds. In addition, they have diverse biological activities such as antiviral, anthelmintic, antiarthropodal, fungicidal, herbicidal, insecticidal, pesticidal, acaricidal and miticidal Activity correlated to the presence of hydrazonoyl halides. Moreover, many applications in both industrial and pharmaceutical fields have been found to be associated with these halides. Depending on the above facts and continuation to our work, we herein report on the evaluation of the anticancer activity of these two halides prepared according to the published work and trying to know their molecular mechanism that they proceed to stop proliferation and metastasis of tumor cells by molecular tools such as real time PCR using different apoptotic genes, and cell cycle assay.Objective:The goal of this present study is to bring attention to the biological activities of hydrazonoyl halides and the molecular pathway they follow to exert their role in apoptotic death of cancer cell.Methods:Synthesis of hydrazonoyl halides 2c and 2f. The cytotoxic effect against different human cancer cell lines PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines as MCF-10 and MCF-12 in a monolayer culture model was evaluated. Their mechanism of action inside cancer cell was evaluated using different molecular tools.Conclusion:Strong and promising chemotherapeutic hydrazonoyl halides (2a-2f) were evaluated for their different biological activities. As antimicrobial agents, results indicated that three compounds 2a, 2e and 2f exhibited high activity against two tested gram positive bacteria Staphylococcus aureus, Bacillus subtilis, and gram negative ones Escherichia coli, and Pseudomonas aeruginosa, the rest of the compounds were found to be moderately active against the tested microorganisms. Regarding their antifungal effect, compound 2c exhibited potent and promising effect against Candida albicans, while 2b was the most potent toward Aspergillus flavus Link. The compound 2f has repellent effect. With respect to the in vitro antitumor screening, this was done on different human cancer cell lines; namely PC3, HepG-2, HCT-116, MCF-7 and also on normal human cell lines; as MCF-10 and MCF-12 (normal breast epithelial cell and non-tumorigenic breast epithelial cell line) in a monolayer culture model where screening has been conducted at 100μg/ml (single dose test). Single dose test (100μg/ml) showed that, in case of PC3, all compounds have cytotoxic activity over 90% inhibition, 4 compounds have cytotoxic activity with 100% inhibition with Human colon cancer cell line, 4 compounds showed over 90% inhibition with MCF7 cell line and 4 compounds showed cytotoxic activity over 90% inhibition with HepG-2. Results of IC50 values for most promising compounds showed compounds with values lower than 20μM for all tested human cancer cell line. The promising hydrazonoyl halide 2c and 2f were selected for molecular study to know how they could act inside cancer cell causing death. Two biochemical tests were performed using the two halides 2c and 2f to predict their mechanism of action against breast carcinoma. Real time PCR analysis indicates that the two compounds induced the apoptosis of MCF7 cells through the up regulation of caspase-3, BAX mediated P53 mechanism but unfortunately, they promote the expression of anti-apoptotic protein BCL2. Also, cell cycle assay was performed using two different cell lines MCF7 and HCT116 and data revealed that the two compounds 2c and 2f induced apoptotic cells death of both lines via cell growth arrest at G2/M phase. In addition, it was noted that 2c induced arrest in the two lines more efficiently than 2f at G2/M phase.