One-pot microwave assisted synthesis of new 2-alkoxycarbonylmethylene-4-oxo-1,5-benzo-, naphtho-, and pyridodiazepines and assessment of their cytogenetic activity

• Published in: European journal of medicinal chemistry 2013-09, Vol.67, p.302-309
• Main Authors: Eleftheriadis, Nicolaos, Neochoritis, Constantinos G., Tsoleridis, Constantinos A., Stephanidou-Stephanatou, Julia, Iakovidou-Kritsi, Zafiroula
• Format: Article
• Language: English
• Subjects: 1,5-Benzodiazepines; Azepines - chemical synthesis; Azepines - chemistry; Azepines - pharmacology; Cells, Cultured; Cytogenetic activity; Dose-Response Relationship, Drug; Humans; Lymphocytes - cytology; Lymphocytes - drug effects; Microwave irradiation; Microwaves; Molecular Structure; Proliferation Rate Index; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Sister Chromatid Exchange - drug effects; Sister Chromatid Exchange - genetics; Sister Chromatid Exchanges; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.06.028

1,5-Benzo-, naphtho-, and pyridodiazepines 3 have been synthesized in excellent yields in one-step from the reaction of o-phenylenediamines with acetonedicarboxylates through microwave assisted acid catalysis. In order to ascertain their cytogenetic activity in vitro at doses equivalent to the per os doses of common 1,4-benzodiazepine drugs, Sister Chromatid Exchanges (SCEs) were employed, and for the determination of cytostaticity the Proliferation Rate Index (PRI) on lymphocytes of human whole blood cultures was estimated. It was found that benzodiazepines 3a, 3c, and 3e exhibit significant cytoprotection, but mild cytostatic effect (a statistically significant reduction of SCEs and a confined decrease of PRI values at similar concentrations). The most active compound was found to be 3e. [Display omitted] •Synthesis of new 2-aryloxymethylene-4-oxo-1,5-benzodiazepines.•Microwave assisted reaction of o-phenylenediamines with acetonedicarboxylates.•Structural assignments have been unambiguously achieved.•Study of cytogenetic activity in vitro.•Sister Chromatid Exchanges (SCEs) and Proliferation Rate Index were employed.