Synthetic analogues of the marine bisindole deoxytopsentin: potent selective inhibitors of MRSA pyruvate kinase.
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.
†Department of Chemistry, Rhodes University, Grahamstown, South Africa.
Clinton G L
CG
Veale
Roya
R
Zoraghi
†Department of Chemistry, Rhodes University, Grahamstown, South Africa.
Ryan M
RM
Young
James P
JP
Morrison
Manoja
M
Pretheeban
†Department of Chemistry, Rhodes University, Grahamstown, South Africa.
Kevin A
KA
Lobb
Neil E
NE
Reiner
Raymond J
RJ
Andersen
⊥Department of Chemistry, University of the Western Cape, Bellville, South Africa.
Michael T
MT
Davies-Coleman
D000595:Amino Acid Sequence; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008386:Marine Biology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D015394:Molecular Structure; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D026121:Indole Alkaloids; C000598719:bromodeoxytopsentin; D011770:Pyruvate Kinase