Synthesis and biological evaluation of a C5-biphenyl thiolactomycin library

Veemal Bhowruth; Alistair Brown; SJ Senior; John Snaith; Gurdyal Besra

doi:10.1016/j.bmcl.2007.07.082

Synthesis and biological evaluation of a C5-biphenyl thiolactomycin library

Veemal Bhowruth, Alistair Brown, SJ Senior, John Snaith, Gurdyal Besra

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18 Citations (Scopus)

Abstract

Fifteen novel C5 analogues of thiolactomycin (13 biphenyl analogues and two biphenyl mimics) have been synthesised and assessed for their in vitro mtFabH and whole cell Mycobacterium bovis BCG activity, respectively. Analysis of the 15 compounds revealed that six possessed enhanced in vitro activity in a direct mtFabH assay. Encouragingly analogues 11, 12 and 13 gave a significant enhancement in in vitro activity against mtFabH. Analogue 13 (5-(4-methoxycarbonyl-biphenyl-4-ylmethyl)-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one) gave an IC(50) value of 3 microM compared to the parent drug thiolactomycin (75 microM) against mtFabH. The biological analysis of this library reaffirms the requirement for a linear pi-rich system containing hydrogen bond accepting substituents attached to the para-position of the C5 biphenyl analogue to generate compounds with enhanced activity.

Original language	English
Pages (from-to)	5643
Number of pages	1
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	17
Issue number	20
DOIs	https://doi.org/10.1016/j.bmcl.2007.07.082
Publication status	Published - 15 Oct 2007

Keywords

mycobacterium bovis BCG
inhibitors
mycobacterium tuberculosis
thiolactomycin
mycolic acids

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2007.07.082

MAGPIE Project: The Structure and Assembly of the Mycobacterial Cell Envelope
Besra, D., Lammas, T. & Minnikin, D.
Medical Research Council
1/02/06 → 31/01/11
Project: Research Councils

Cite this

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title = "Synthesis and biological evaluation of a C5-biphenyl thiolactomycin library",

abstract = "Fifteen novel C5 analogues of thiolactomycin (13 biphenyl analogues and two biphenyl mimics) have been synthesised and assessed for their in vitro mtFabH and whole cell Mycobacterium bovis BCG activity, respectively. Analysis of the 15 compounds revealed that six possessed enhanced in vitro activity in a direct mtFabH assay. Encouragingly analogues 11, 12 and 13 gave a significant enhancement in in vitro activity against mtFabH. Analogue 13 (5-(4-methoxycarbonyl-biphenyl-4-ylmethyl)-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one) gave an IC(50) value of 3 microM compared to the parent drug thiolactomycin (75 microM) against mtFabH. The biological analysis of this library reaffirms the requirement for a linear pi-rich system containing hydrogen bond accepting substituents attached to the para-position of the C5 biphenyl analogue to generate compounds with enhanced activity.",

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AU - Bhowruth, Veemal

AU - Brown, Alistair

AU - Senior, SJ

AU - Snaith, John

AU - Besra, Gurdyal

PY - 2007/10/15

Y1 - 2007/10/15

N2 - Fifteen novel C5 analogues of thiolactomycin (13 biphenyl analogues and two biphenyl mimics) have been synthesised and assessed for their in vitro mtFabH and whole cell Mycobacterium bovis BCG activity, respectively. Analysis of the 15 compounds revealed that six possessed enhanced in vitro activity in a direct mtFabH assay. Encouragingly analogues 11, 12 and 13 gave a significant enhancement in in vitro activity against mtFabH. Analogue 13 (5-(4-methoxycarbonyl-biphenyl-4-ylmethyl)-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one) gave an IC(50) value of 3 microM compared to the parent drug thiolactomycin (75 microM) against mtFabH. The biological analysis of this library reaffirms the requirement for a linear pi-rich system containing hydrogen bond accepting substituents attached to the para-position of the C5 biphenyl analogue to generate compounds with enhanced activity.

AB - Fifteen novel C5 analogues of thiolactomycin (13 biphenyl analogues and two biphenyl mimics) have been synthesised and assessed for their in vitro mtFabH and whole cell Mycobacterium bovis BCG activity, respectively. Analysis of the 15 compounds revealed that six possessed enhanced in vitro activity in a direct mtFabH assay. Encouragingly analogues 11, 12 and 13 gave a significant enhancement in in vitro activity against mtFabH. Analogue 13 (5-(4-methoxycarbonyl-biphenyl-4-ylmethyl)-4-hydroxy-3,5-dimethyl-5H-thiophen-2-one) gave an IC(50) value of 3 microM compared to the parent drug thiolactomycin (75 microM) against mtFabH. The biological analysis of this library reaffirms the requirement for a linear pi-rich system containing hydrogen bond accepting substituents attached to the para-position of the C5 biphenyl analogue to generate compounds with enhanced activity.

KW - mycobacterium bovis BCG

KW - inhibitors

KW - mycobacterium tuberculosis

KW - thiolactomycin

KW - mycolic acids

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DO - 10.1016/j.bmcl.2007.07.082

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JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

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ER -

Synthesis and biological evaluation of a C5-biphenyl thiolactomycin library

Abstract

Keywords

UN SDGs

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Projects

MAGPIE Project: The Structure and Assembly of the Mycobacterial Cell Envelope

Cite this