Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis

Nicholas Smith; Diana Quan; Gayathri Nagalingam; James A. Triccas; Louis M. Rendina; Peter J. Rutledge

doi:10.1039/D2MD00150K

Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis†

Nicholas Smith,^a Diana Quan,^bc Gayathri Nagalingam,^bc James A. Triccas,^bc Louis M. Rendina

*^ad and Peter J. Rutledge

*^a

Author affiliations

* Corresponding authors

^a School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
E-mail: peter.rutledge@sydney.edu.au, louis.rendina@sydney.edu.au
Tel: +61 2 9351 5020

^b Sydney Institute of Infectious Diseases and Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia

^c School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia

^d The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, Sydney, NSW 2006, Australia

Abstract

Bis-substituted cyclam derivatives have recently emerged as a promising new class of antibacterial agents, displaying excellent activity against drug-resistant Mycobacterium tuberculosis (Mtb) and in vivo efficacy in a zebrafish assay. Herein we report the synthesis and biological activity of new carborane derivatives within this class of antitubercular compounds. The resulting carborane–cyclam conjugates incorporating either hydrophobic closo-1,2-carborane or anionic, hydrophilic nido-7,8-carborane clusters display promising activity in an antibacterial assay employing the virulent Mtb strain H37Rv. The most active of these carborane derivatives exhibit MIC₅₀ values of <1 μM, making them the most active compounds in this unique class of antibacterial cyclams reported to date.

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DOI: https://doi.org/10.1039/D2MD00150K
Article type: Research Article
Submitted: 20 May 2022
Accepted: 28 Jul 2022
First published: 02 Aug 2022

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RSC Med. Chem., 2022,13, 1234-1238

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Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis

N. Smith, D. Quan, G. Nagalingam, J. A. Triccas, L. M. Rendina and P. J. Rutledge, RSC Med. Chem., 2022, 13, 1234 DOI: 10.1039/D2MD00150K

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RSC Medicinal Chemistry

Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis†

Abstract

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Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis

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