Synthesis, Selected Transformations, and Biological Activity of Alkoxy Analogues of Lepidilines A and C.

Grzegorz Mlostoń,Małgorzata Celeda,Marcin Jasiński,Katarzyna Gach-Janczak,Anna Janecka,Wiktor Poper,Mateusz Kowalczyk

doi:10.3390/ma13184190

Grzegorz Mlostoń, Małgorzata Celeda + Show 5 more

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https://doi.org/10.3390/ma13184190

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Abstract

Condensation of diacetyl monooxime with formaldimines derived from alkoxyamines in glacial acetic acid at room temperature leads to corresponding 2-unsubstituted imidazole N-oxides bearing an alkoxy substituent at the N(1) atom of the imidazole ring. Subsequent O-benzylation afforded, depending on the type of alkylating agent, either symmetric or nonsymmetric alkoxyimidazolium salts considered as structural analogues of naturally occurring imidazole alkaloids, lepidilines A and C. Some of the obtained salts were tested as precursors of nucleophilic heterocyclic carbenes (NHCs), which in situ reacted with elemental sulfur to give the corresponding N-alkoxyimidazole-2-thiones. The cytotoxic activity of selected 4,5-dimethylimidazolium salts bearing either two benzyloxy or benzyloxy and 1-adamantyloxy groups at N(1) and N(3) atoms was evaluated against HL-60 and MCF-7 cell lines using the MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay. Notably, in two cases of alkoxyimidazolium salts, no effect of the counterion exchange (Br− → PF6−) on the biological activity was observed.

Highlights

Imidazolium salts constitute an important class of imidazole derivatives with diverse applications in modern organic synthesis and related disciplines
According to the general protocol, condensation of N-alkyl formaldimines 1 with α-hydroxyiminoketones of type 2 in boiling ethanol leads to 2-unsubstituted imidazole N-oxides 3 (Scheme2020, 1) [22]
The present study showed that 2-unsubstituted imidazole N-oxides can be explored for a smooth and efficient preparation of alkoxy-analogues of naturally occurring imidazolium alkaloids known as lepidilines A and C

Summary

Introduction

Imidazolium salts constitute an important class of imidazole derivatives with diverse applications in modern organic synthesis and related disciplines They are known as the core structure of many ionic liquids [1,2,3], which are widely applied as highly polar reaction media recommended as reusable “green solvents”, explored in academic laboratories and in industrial processes. Another relevant field for applications of imidazolium salts relates to generation of nucleophilic heterocyclic carbenes (NHCs) [4,5,6]. Imidazolium salts have extensively been studied as biologically active compounds which display antitumor, antimicrobial, antifungal, and antioxidant activities, among others [9,10,11].

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