Simple dihydrosphyngosine analogues with potent activity against MDR-Mycobacterium tuberculosis

doi:10.1016/j.bmcl.2009.07.147

Bioorganic & Medicinal Chemistry Letters

Volume 19, Issue 19, 1 October 2009, Pages 5764-5768

https://doi.org/10.1016/j.bmcl.2009.07.147 Get rights and content

Abstract

Fifteen dihydrosphingosine analogues have been synthesized and tested in vitro against Mycobacterium tuberculosis (MTB). Two ether (3 and 4b) and one diamine (8b) derivatives have displayed high mycobactericidal potency, with similar MIC values of 1.25 μg/mL, against the virulent strain H37Rv, as well as against a clinical isolate resistant to the five first-line anti-TB drugs. The three compounds, tested on other eleven cultured MTB strains with different multi-drug-resistance (MDR) patterns, retained their MIC values for most strains, or even lowered it, as in the case of compound 4b, which, assayed on strain No. 332, also resistant to all first-line anti-TB drugs, attained the MIC value of 0.78 μg/mL.

Graphical abstract

A number of dihydrosphingosine analogues were tested in vitro against several strains of Mycobacterium tuberculosis (MTB). Three (3, 4b and 8b) out of the fifteen evaluated compounds, displayed MIC values of 1.25 μg/mL on virulent H37Rv and several MDR strains and, more interestingly, on one clinical isolate resistant to all the first-line anti-TB drugs.

Section snippets

Acknowledgements

Collaborative work performed under the auspices of Programa Iberoamericano de Ciencia y Tecnología para el Desarrollo (CYTED), Project X.11: PIBATUB. Financial support came from Spanish Minister of Science (Grant: AGL-2005-02168 GAN). SSF and GMMS wish to thank the Instituto Mexicano del Seguro Social for financial support, which allowed the development of antituberculosis bioassays. We would like to thank Mr. G. H. Jenkins for his help with the English version of the ms.

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Simple dihydrosphyngosine analogues with potent activity against MDR-Mycobacterium tuberculosis

Abstract

Graphical abstract

Section snippets

Acknowledgements

Trends Mol. Med.

Lancet

Chem. Biol.

Biochem. Biophys. Acta

J. Infect. Dis.

Bioorg. Med. Chem. Lett.

Vaccine

Vaccine

Vet. Parasitol.

Arch. Med. Res.