Divergent Synthesis of Unsymmetrical Annulated Biheterocyclic Compound Libraries: Benzimidazole Linked Indolo-benzodiazepines/quinoxaline

Abstract

Diversity-oriented synthesis of novel benzimidazole linked indolo-benzodiazepine/quinoxaline ring systems using poly(ethylene glycol) as soluble polymer support is described. Commercially available 4-fluoro-3-nitrobenzoic acid and indoline were utilized for the construction of these annulated biheterocyclic compound libraries having multiple privileged structures with three-point structural diversity. A reagent based diversification approach coupled with the Pictet-Spengler-type condensation was used to construct the tetracyclic indolo-benzodiazepines/quinoxalines on substituted benzimidazoles.

Perturbing pro-survival proteins using quinoxaline derivatives: A structure–activity relationship study

“…23, 7b The quinoxaline analogs 1a – 1o screened here for anti-Mcl-1 activity were previously reported by us to have antiproliferative activity. 7b The emergence of Mcl-1 as a potential target led us to screen quinoxaline analogs for Mcl-1 specific inhibitors. We used a cell line (Dox-Bad3SA) that expressed Bad3SA (a BH3 only protein that binds Bcl-xL) under doxycycline control.…”

“…Reduction of the resulting nitro compounds 4a–e to the amine 5a–e followed by condensation with substituted isocyanates yielded the quinoxaline urea analogs 1p–v (Scheme 1). 7b …”

“…1a This led to the synthesis of focused libraries of quinoxaline analogs to further explore the chemical space and structure activity relationship studies. 7 …”

Microwave-Assisted Multicomponent Synthesis of Dihydroquinoxalinones on Soluble Polymer Support

“…27 The PEG-supported amino ester 1 was condensed with aldehydes 2, Fmoc protected α-amino acids 4 and isocyanides 5 in methanol at either room temperature (10 h) or reflux (5 h) to obtain key intermediate 7 in moderate yields (40−55%). To check the feasibility of Ugi MCRs on PEG support under microwave conditions, a coupling reaction was performed in the microwave cavity for 25 min at 110°C to afford the diamide 7{4,1,1} in 63% yield.…”

Present status of quinoxaline motifs: Excellent pathfinders in therapeutic medicine

“…The final cleavage of the soluble polymer support was achieved using 1% KCN in methanol at room temperature to obtain polymer free benzimidazolylquinoxalinones 32 (Scheme 9) [55]. <<<<Scheme 9>>>> (d) Chen and coworkers reported solution-phase synthetic protocol as a convenient route for the preparation of a small library of unsymmetrically annulated benzimidazole-linked indolo quinoxalines 33 [56] (Scheme 10). A reagent-based diversification approach coupled with the Pictet-Spengler type condensation used, was also reported to afford of 4,5-dihydroimidazo-and imidazo [1,5-a]quinoxalines in another study [57].…”