Synthetic analogues of the marine bisindole deoxytopsentin: potent selective inhibitors of MRSA pyruvate kinase
- Veale, Clinton G L, Zoraghi, Roya, Young, Ryan M, Morrison, James P, Pretheeban, Manoj, Lobb, Kevin A, Reiner, Neil E, Andersen, Raymond J, Davies-Coleman, Michael T
- Authors: Veale, Clinton G L , Zoraghi, Roya , Young, Ryan M , Morrison, James P , Pretheeban, Manoj , Lobb, Kevin A , Reiner, Neil E , Andersen, Raymond J , Davies-Coleman, Michael T
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448045 , vital:74693 , xlink:href="https://doi.org/10.1021/np500755v"
- Description: As part of an ongoing study to elucidate the SAR of bisindole alkaloid inhibitors against the evolutionary conserved MRSA pyruvate kinase (PK), we present here the synthesis and biological activity of six dihalogenated analogues of the naturally occurring sponge metabolite deoxytopsentin, including the naturally occurring dibromodeoxytopsentin. The most active compounds displayed potent low nanomolar inhibitory activity against MRSA PK with concomitant significant selectivity for MRSA PK over human PK orthologues. Computational studies suggest that these potent MRSA PK inhibitors occupy a region of the small interface of the enzyme tetramer where amino acid sequence divergence from common human PK orthologues may contribute to the observed selectivity.
- Full Text:
- Date Issued: 2015
- Authors: Veale, Clinton G L , Zoraghi, Roya , Young, Ryan M , Morrison, James P , Pretheeban, Manoj , Lobb, Kevin A , Reiner, Neil E , Andersen, Raymond J , Davies-Coleman, Michael T
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448045 , vital:74693 , xlink:href="https://doi.org/10.1021/np500755v"
- Description: As part of an ongoing study to elucidate the SAR of bisindole alkaloid inhibitors against the evolutionary conserved MRSA pyruvate kinase (PK), we present here the synthesis and biological activity of six dihalogenated analogues of the naturally occurring sponge metabolite deoxytopsentin, including the naturally occurring dibromodeoxytopsentin. The most active compounds displayed potent low nanomolar inhibitory activity against MRSA PK with concomitant significant selectivity for MRSA PK over human PK orthologues. Computational studies suggest that these potent MRSA PK inhibitors occupy a region of the small interface of the enzyme tetramer where amino acid sequence divergence from common human PK orthologues may contribute to the observed selectivity.
- Full Text:
- Date Issued: 2015
Synthesis and MRSA PK inhibitory activity of thiazole containing deoxytopsentin analogues
- Veale, Clinton G L, Lobb, Kevin A, Zoraghi, Roya, Morrison, James P, Reiner, Neil E, Andersen, Raymond J, Davies-Coleman, Michael T
- Authors: Veale, Clinton G L , Lobb, Kevin A , Zoraghi, Roya , Morrison, James P , Reiner, Neil E , Andersen, Raymond J , Davies-Coleman, Michael T
- Date: 2014
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448028 , vital:74692 , xlink:href="https://doi.org/10.1016/j.tet.2014.09.007"
- Description: The public health care crisis caused by the emergence of drug resistant bacterial strains, e.g., methicillin resistant Staphylococcus aureus (MRSA) has underlined the urgent need to accelerate the discovery of new chemical entities active against antibiotic resistant bacteria. We report here the synthesis of a series thiazole containing deoxytopsentin analogues, which show moderate activity against a target MRSA pyruvate kinase enzyme: an evolutionary conserved hub protein critical for bacterial survival. A Hantzsch thiazole coupling between a-oxo-1H-indole-3-thioacetamides and 2-bromo-1-(1H-indol-3-yl)-ethanones provided facile access to the thiazole containing deoxytopsentin compounds.
- Full Text:
- Date Issued: 2014
- Authors: Veale, Clinton G L , Lobb, Kevin A , Zoraghi, Roya , Morrison, James P , Reiner, Neil E , Andersen, Raymond J , Davies-Coleman, Michael T
- Date: 2014
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448028 , vital:74692 , xlink:href="https://doi.org/10.1016/j.tet.2014.09.007"
- Description: The public health care crisis caused by the emergence of drug resistant bacterial strains, e.g., methicillin resistant Staphylococcus aureus (MRSA) has underlined the urgent need to accelerate the discovery of new chemical entities active against antibiotic resistant bacteria. We report here the synthesis of a series thiazole containing deoxytopsentin analogues, which show moderate activity against a target MRSA pyruvate kinase enzyme: an evolutionary conserved hub protein critical for bacterial survival. A Hantzsch thiazole coupling between a-oxo-1H-indole-3-thioacetamides and 2-bromo-1-(1H-indol-3-yl)-ethanones provided facile access to the thiazole containing deoxytopsentin compounds.
- Full Text:
- Date Issued: 2014
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