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. 2019 Jun 5;17(22):5615-5632.
doi: 10.1039/c9ob01076a.

Functionalised bicyclic tetramates derived from cysteine as antibacterial agents

Tharindi D Panduwawala  1 , Sarosh Iqbal, Amber L Thompson, Miroslav Genov, Alexander Pretsch, Dagmar Pretsch, Shuang Liu, Richard H Ebright, Alison Howells, Anthony Maxwell, Mark G Moloney
Affiliations

Functionalised bicyclic tetramates derived from cysteine as antibacterial agents

Tharindi D Panduwawala et al. Org Biomol Chem. .

Abstract

Routes to bicyclic tetramates derived from cysteine permitting ready incorporation of functionality at two different points around the periphery of a heterocyclic skeleton are reported. This has enabled the identification of systems active against Gram-positive bacteria, some of which show gyrase and RNA polymerase inhibitory activity. In particular, tetramates substituted with glycosyl side chains, chosen to impart polarity and aqueous solubility, show high antibacterial activity coupled with modest gyrase/polymerase activity in two cases. An analysis of physicochemical properties indicates that the antibacterially active tetramates generally occupy physicochemical space with MW of 300-600, clog D7.4 of -2.5 to 4 and rel. PSA of 11-22%. This work demonstrates that biologically active 3D libraries are readily available by manipulation of a tetramate skeleton.

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Conflict of interest statement

Conflicts of interest

There are no conflicts of interest to declare.

Figures

Figure 1.
Figure 1.
HMBC correlation data of selected carboxamide tetramates.
Figure 2.
Figure 2.
NOE analysis of selected carboxamide tetramates.
Figure 3:
Figure 3:
The structure of 9f from single crystal X-ray diffraction studies. Displacement ellipsoids drawn at 50% probability.
Figure 4.
Figure 4.
NOESY correlation data for 9k suggesting tautomer A as the major tautomer. The distance between H-5 and enol O-H for each tautomer was calculated for the MM2-energy minimized molecular model using Chem3D v.15.
Figure 5.
Figure 5.
1H NMR spectra of tetramate 9d (a) post-column purification, before acid-wash and (b) post-column purification, after acid-wash.
Figure 6.
Figure 6.
(a) IC50 values of tetramates against M. tuberculosis gyrase and S. aureus topoisomerase IV. Compounds 9a and 9m were weak inhibitors of M. tuberculosis gyrase and 9d’ was a weak inhibitor of S. aureus topoisomerase IV. (b) IC50 values of tetramates against S. aureus RNAP and E. coli RNAP.
Figure 7.
Figure 7.
Bioactivity of carboxamide tetramates with/without HSA.
Figure 8.
Figure 8.
Correlation of physicochemical properties (MW, clogD7.4, and rel. PSA) with antibacterial activity.
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See this image and copyright information in PMC

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