Three New Strategies to the Synthesis Of Structurally Diverse Dipyrrolobenzodiazepines. Bioactivity Evaluation

Abstract Simple and efficient strategies have been developed for the synthesis of three structurally diverse dipyrrolo[1,2‐ a : 2′,1′‐ c ][1,4]benzodiazepine (DPBD) derivatives. Firstly, two‐component reaction between 4‐aroylpyrrolo[1,2‐ a ][1,4]benzodiazepines and electron‐deficient internal alkynes in different conditions was applied to obtain isomeric geminal and vicinal DPBDs ( gem and vic ). Secondly, multicomponent synthesis from 2‐pyrrolylbenzylamine, arylglyoxal monohydrates and same alkynes led to the formation of other vicinal DPBDs ( vic ’ ). These transformations could be conducted under mild and metal‐free conditions to provide a number of dipyrrolo[1,2‐ a : 2′,1′‐ c ][1,4]benzodiazepine derivatives in moderate to good yields. The in vitro biological activity of title compounds have been tested. Further physicochemical and pharmacokinetic computations also demonstrated the drug‐like characteristics of synthesized compounds. The cytotoxic activity IC 50 27.59 (KB cell culture) as well as molecular docking with bromodomain‐containig protein 4 (BRD4) indicated the importance of dipyrrolobenzodiazepine moieties in the development of potential anticancer agents.