Croatica Chemica Acta, Vol. 92 No. 2, 2019.
Original scientific paper
https://doi.org/10.5562/cca3540
1,2-Αnnulated Adamantane Heterocyclic Derivatives as Anti-Influenza Α Virus Agents
Vasiliki Pardali
; School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece
Erofili Giannakopoulou
; School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece
Athina Konstantinidi
; School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece
Antonios Kolocouris
; School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece
Grigoris Zoidis
orcid.org/0000-0002-9442-5186
; School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis-Zografou, GR-15771 Athens, Greece
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.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Keywords
1,2-Annulated adamantane derivatives; Anti-influenza A virus agents; H3N2; H1N1; Rimantadine; Amantadine; SAR; M2 protein; POPC hydrated bilayers
Hrčak ID:
227081
URI
Publication date:
29.7.2019.
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