2-Aminoimidazoles from Leucetta Sponges: Synthesis and Biology of an Important Pharmacophore

Abstract

This review will focus on the ability of the 2-aminoimidazole to occupy a unique subset of chemical space which makes it an ideal pharmacophore for the development of small molecule collections for discovery based research. These observations rely both on the use of 2-aminoimidazoles as building blocks in medicinal chemistry as well as the recent discovery of alkaloids from sponges of the genus Leucetta which exhibit a diverse range of biological activities around a relatively limited structural core. The preparation of these compounds will also be highlighted.

C-N bond forming reactions in the synthesis of substituted 2-aminoimidazole derivatives

“…Several synthetic methods have been reported in the literature to obtain 2-aminoimidazoles that involve the construction of the heterocycle, 1 including the addition of substituted guanidines 12,13 or 2-aminopyrimidines (protected guanidines) 14 to α-haloketones, the basemediated semi cleavage of hemiaminals obtained by reaction of N-Boc protected guanidines and N-carbomethoxy-1,2-dihydropyridines, 15 or the condensation of cyanamide and α-aminoketones 16 or α-aminoesters. 6 In a similar way, the corresponding 2-aminoimidazolines have been synthesized by condensation of N-arylcarbonimidodithioates and ethylenediamine, 17,18 and by intramolecular cyclization of functionalized arylthioureas, obtained by reaction of isothiocyanatobenzene and ethylenediamine.…”

“…For example, Leucetta and Clathrina-derived alkaloids, which have been isolated from marine sponges during the last three decades, were reported to exhibit antibacterial, anti-inflammatory, anticancer, and antiviral activity. [1][2][3] Different types of substituted 2-aminoimidazoles, including the pyrrole-2-aminomidazoles of the oroidin family and their synthetic analogs 4,5 possess anti-biofilm activities, 6,7 while 2-arylamino or iminoimidazolidines (e.g. clonidine), known hypertensive agents, 8 have also been evaluated as α 2 -adrenoceptor antagonists for the treatment of depression ( Figure 1).…”

Studies towards the Leucetta‐Derived Alkaloids Spirocalcaridine A and B – Possible Biosynthetic Implications

“…[1] Many of these imidazole-containing metabolites are biologically active, exhibiting amongst others anti-cancer and antibiotic activity, but their biological roles in Nature have yet to be rigorously defined. [1b] Structurally, these 2-aminoimidazoles fit into five broad subclasses depending on their substitution patterns and oxidation levels.…”

Concise and Diversity‐Oriented Route toward Polysubstituted 2‐Aminoimidazole Alkaloids and Their Analogues

“…[1] In particular, polysubstituted 2-aminoimidazoles have recently been reported as potent modulators of the formation and dispersion of bacterial biofilms, [2] human b-secretase (BACE1) inhibitors, [3] and tubulin-binding agents. [4] Although a variety of synthetic methods [1,5,6] for the preparation of highly functionalized 2-aminoimidazole core structures have been developed owing to the rising demand in natural product synthesis and medicinal chemistry, most of them involve long experimental procedures with many protection/deprotection steps and the use of unstable precursors, such as a-aminoketones,…”