Synthesis of Ethyl N-Functionalized β-Amino Benzimidazole Acrylate Derivatives and their Cytotoxic Biological Evaluation

Sixteen (16) new ethyl β-amino benzimidazole acrylate derivatives have been synthesized by using a multi-step strategy such as reductive amination [1], deprotection in acidic media and transamination. The new compounds bear two points of diversity. Indeed, they have been designed from ethyl 3-dimethylamino-2-(1H-benzimidazol-2-yl)acrylate and mono substituted N-Boc diamines. The new benzimidazole derivatives presented a (2E)-s-cis/trans conformation [2,3] associated to a strong polarization of the C-2/C-3 double bond by a push-pull effect.

The sixteen (16) new synthesized compounds were evaluated in biology for their in vitro cytotoxic activity against six representative human tumoral cell lines. Eight (8) of them have a potential activity against some tumoral cell lines which are Huh7-D12, MDA-MB231, NCI-H727, HCT116 and Caco2 (IC₅₀ < 5 μM). Three (3) of the eight (8) bioactive compounds have interesting micromolar inhibition activity on Huh7-D12 (IC₅₀ = 4-5 μM) and Caco2 (IC₅₀ = 3 μM). Therefore, the good results for these three (3) active benzidamidazole derivatives show them as potential cytotoxic agents. Moreover, their structural modification could lead to the generation of promising anticancer agents.

All the compounds were synthesized in moderate to good yields and were also characterized by ¹H and ¹³C NMR.

References

[1]. Bazureau J-P, Draye M (eds) (2011) Ultrasound and microwave: recent advances in organic chemistry. Research Signpost, Kerala. ISBN 978-81-7895-532-2

[2]. Brugidou R, Bazureau JP, Hamelin J, Dahmani Z, Rahmouni M (1999) Stereoselective synthesis of (2E) 3-amino-2-(1H-benzimidazol-2-yl)acrylate and symmetric bis-acrylates by transamination reactions. Het Chem 10: 446-454.

[3]. Rahmouni M, Derdour A, Bazureau JP, Hamelin J (1994) A new route to pyrimido[1,6-a]benzimidazoles: Reactivity of activated 2-benzimidazoles with N-acyl imidates as β-dielectrophiles under microwave irradiation. Tet. Letters 35: 4563-4564.