1,2-Αnnulated Adamantane Heterocyclic Derivatives as Anti-Influenza Α Virus Agents

Abstract

In this report we review our results on the development of 1,2-annulated adamantane heterocyclic derivatives and we discuss the structure-activity relationships obtained from their biological evaluation against influenza A virus. We have designed and synthesized numerous potent 1,2-annulated adamantane analogues of amantadine and rimantadine against influenza A targeting M2 protein the last 20 years. For their synthesis we utilized the key intermediates 2-(2-oxoadamantan-1-yl)acetic acid and 3-(2-oxoadamantan-1-yl)propanoic acid, which were obtained by a simple, fast and efficient synthetic protocol. The latter involved the treatment of protoadamantanone with different electrophiles and a carbon-skeleton rearrangement. These ketoesters offered a new pathway to the synthesis of 1,2-disubstituted adamantanes, which constitute starting materials for many molecules with pharmacological potential, such as the 1,2-annulated adamantane heterocyclic derivatives. To obtain additional insight for their binding to M2 protein three structurally similar 1,2-annulated adamantane piperidines, differing in nitrogen position, were studied using molecular dynamics (MD) simulations in palmitoyl-oleoyl-phosphatidyl-choline (POPC) hydrated bilayers.

Synthesis of 1,2-Disubstituted Adamantane Derivatives by Construction of the Adamantane Framework

“…The protoadamantane-adamantane rearrangement is one of the key transformations employed in the synthesis of 1,2-disubstituted adamantyl amines. Many authors have conducted extensive work describing a plethora of examples of connectivity between ketone 108 and various nucleophiles (Scheme 47), followed by the rearrangement to adamantane and further syntheses to their target compounds, to analyze their biological activities [76,[96][97][98][99][100][101][102]. For compounds, see 189a,e [76]; 189b,d,g [99]; 189c [98]; 189f [96] (Scheme 47).…”

Lipophilic Guanylhydrazone Analogues as Promising Trypanocidal Agents: An Extended SAR Study

“…Over the years, we have synthesized a variety of structurally diverse adamantane derivatives that target influenza A virus, T. brucei and T. cruzi [96][97][98][99][100][101][102][103]. In continuation of our studies, we were interested in developing further active adamantane-based compounds that could inhibit the proliferation of the above-mentioned trypanosomatids.…”

Adamantane Annulation to Arenes: A Strategy for Property Modulation of Aromatic π-Systems

“…The adamantane-substituted unit is also used in materials science because of its ability to provide outstanding rigidity and stability to polymers and porous materials . Despite the attention and effort devoted to adamantane-substituted molecules, adamantane-annulated molecules in which ring structures are constructed across more than two carbon atoms on adamantane have so far been limited to diamondoids , and cycloalkanes. − Hence, the effects of adamantane annulation on other molecular scaffolds are still unknown. From the perspective of creating functional materials, an adamantane annulation to arenes, specifically a compact modification on the periphery of arenes with an adamantane scaffold, should attract significant attention because it could result in combining the functions of adamantane and arenes.…”