2. Academic Validation
  3. Synthetic analogues of the marine bisindole deoxytopsentin: potent selective inhibitors of MRSA pyruvate kinase

Synthetic analogues of the marine bisindole deoxytopsentin: potent selective inhibitors of MRSA pyruvate kinase

  • J Nat Prod. 2015 Mar 27;78(3):355-62. doi: 10.1021/np500755v.
Clinton G L Veale 1,  Roya Zoraghi,  Ryan M Young 1,  James P Morrison,  Manoja Pretheeban,  Kevin A Lobb 1,  Neil E Reiner,  Raymond J Andersen,  Michael T Davies-Coleman 2
Affiliations

Affiliations

  • 1 †Department of Chemistry, Rhodes University, Grahamstown, South Africa.
  • 2 ⊥Department of Chemistry, University of the Western Cape, Bellville, South Africa.
PMID: 25372480 DOI: 10.1021/np500755v
Abstract

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.

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