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Synthesis of Adamantane Aminoethers with Antitubercular Potential

[ Vol. 13 , Issue. 7 ]

Author(s):

Angeliki-Sofia Foscolos, Ioannis Papanastasiou*, Andrew Tsotinis, Nicolas Kolocouris, George B. Foscolos, Anthony Vocat and Stewart T. Cole   Pages 670 - 681 ( 12 )

Abstract:


Background: Intrigued by the fact that aminoadamantane derivatives, bearing the active 1,2-ethylenediamine moiety, are promising antitubercular agents, we report herein the synthesis and the antitubercular evaluation of N,N'-substituded-4,4'-[adamantane-2,2-diyl]bis(phe-noxyalkylamines) 1a-g, N,N'-substituded-4,4'-[adamantane-1,3-diyl]bis(phenoxyalkylamines) 2a-f, N,N'- substituded-[4-(1-adamantyl)phenoxy]alkylamines 3a-d and N,N'-substituded-[4-(2-adamantyl)- phenoxy]alkylamines 4a,b.

Method: A substituted diarylmethane moiety was introduced on the adamantane skeleton of the new derivatives. The synthesis of the above compounds involved the nucleophilic attack of the corresponding phenoxide, to the appropriate aminoalkylchloride hydrochloride under heating.

Results: The double substituted adamantane derivatives with an aminoether side chain exhibit significant activity against Mycobacterium tuberculosis.

Conclusion: The length and the nature of the amino end of the side chain influence the antitubercular activity. The double phenolic substitution of the adamantane scaffold and the aminoether side chain with a three-methylene spacer between the phenoxy group and the nitrogen atom present the better results. (analogues 1f,g and 2e,f). These findings merit further investigation aiming at the design of more potent adamantane antituberculars, bearing a number of different substituents on the diarylmethane pharmacophore, which will also be translocated to other posititions on the adamantane ring.

Keywords:

(Adamantane-2, 2-diyl) substitution, (adamantane-1, 3-diyl) substitution, aminoethers, antitubercular activity, Tuberculosis (TB), antitubercular chemotherapy.

Affiliation:

School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 84 Athens, Department of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupoli- Zografou, 157 84 Athens, School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 84 Athens, School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 84 Athens, School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 84 Athens, Global Health Institute, Ecole Polytechnique Federale de Lausanne, Station 19, 1015 Lausanne, Global Health Institute, Ecole Polytechnique Federale de Lausanne, Station 19, 1015 Lausanne

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