Discovery of a 1,2-bis(3-indolyl)ethane that selectively inhibits the pyruvate kinase of methicillin-resistant Staphylococcus aureus over human isoforms

Zoraghi, Roya; Campbell, Sara C.; Kim, Catrina; Dullaghan, Edie; Blair, Lachlan M.; Gillard, Rachel M.; Reiner, Neil E.; Sperry, Jonathan

doi:10.1016/j.bmcl.2014.09.010

Cited by 15 publications

(6 citation statements)

References 10 publications

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“…Several marine and synthetic bisindoles have been shown to inhibit enzymatic activity of pyruvate kinase (PK) of MRSA in vitro . − PK catalyzes the final reaction step in glycolysis generating pyruvate by transfer of a phosphoryl group from phosphoenolpyruvate to ADP. PK has been reported to be essential for S.…”

Section: Resultsmentioning

confidence: 99%

Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

et al. 2020

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Natural bisindole alkaloids such as Hyrtinadine A and Alocasin A, which are known to exhibit diverse bioactivities, provide promising chemical scaffolds for drug development. By optimizing the Masuda borylation–Suzuki coupling sequence, a library of various natural product-derived and non-natural (di)azine-bridged bisindoles was created. While unsubstituted bisindoles were devoid of antibacterial activity, 5,5′-chloro derivatives were highly active against methicillin-resistant Staphylococcus aureus (MRSA) and further Gram-positive pathogens at minimal inhibitory concentrations ranging from 0.20 to 0.78 μM. These compounds showed strong bactericidal killing effects but only moderate cytotoxicity against human cell lines. Furthermore, the two front-runner compounds 4j and 4n exhibited potent in vivo efficacy against MRSA in a mouse wound infection model. Although structurally related bisindoles were reported to specifically target pyruvate kinase in MRSA, antibacterial activity of 4j and 4n is independent of pyruvate kinase. Rather, these compounds lead to bacterial membrane permeabilization and cellular efflux of low-molecular-weight molecules.

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Section: Resultsmentioning

confidence: 99%

Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

et al. 2020

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“…Furthermore, acknowledging the significance of a bisindole motif to increased inhibition of MRSA PK, Sperry and co-workers have recently described the selective MRSA PK inhibition of a cohort of eleven, variously-substituted, synthetic 1,2-bis(3-indolyly)ethane compounds, e.g., 37 [ 37 ] ( Figure 9 ). Compound 37 , accessed via palladium catalyzed heteroannulation of the aldehyde ( 38 ) and 1-iodo-2-amino-4-nitrobenzene ( 39 ) [ 38 ], was the most potent of the series (IC 50 0.9 μM) and exhibited a 20–106-fold selectivity for MRSA PK over four human PK isoforms.…”

Section: Bisindole Alkaloid Inhibitors Of Methicillin-resistant mentioning

confidence: 99%

“…Compound 37 , accessed via palladium catalyzed heteroannulation of the aldehyde ( 38 ) and 1-iodo-2-amino-4-nitrobenzene ( 39 ) [ 38 ], was the most potent of the series (IC 50 0.9 μM) and exhibited a 20–106-fold selectivity for MRSA PK over four human PK isoforms. Replacing the C6 nitro substituent with chloro, nitrile, methoxy and methyl functionalities had a deleterious effect on MRSA PK inhibition, with the nitrile and methoxy analogs inactive and the chloro and methyl analogs two orders of magnitude less active (IC 50 272 and 294 μM, respectively) [ 37 ].…”

Section: Bisindole Alkaloid Inhibitors Of Methicillin-resistant mentioning

confidence: 99%

Recent Advances in Drug Discovery from South African Marine Invertebrates

Davies‐Coleman

Veale

2015

Marine Drugs

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Recent developments in marine drug discovery from three South African marine invertebrates, the tube worm Cephalodiscus gilchristi, the ascidian Lissoclinum sp. and the sponge Topsentia pachastrelloides, are presented. Recent reports of the bioactivity and synthesis of the anti-cancer secondary metabolites cephalostatin and mandelalides (from C. gilchristi and Lissoclinum sp., respectively) and various analogues are presented. The threat of drug-resistant pathogens, e.g., methicillin-resistant Staphylococcus aureus (MRSA), is assuming greater global significance, and medicinal chemistry strategies to exploit the potent MRSA PK inhibition, first revealed by two marine secondary metabolites, cis-3,4-dihydrohamacanthin B and bromodeoxytopsentin from T. pachastrelloides, are compared.

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“…Related bis-indole alkaloids in the hamacanthin, and topsentin series along with synthetic analogs have been reported to have antibacterial activity against in vitro MRSA (MICs range from 15.4 to 25.6 μM with a selectivity of >4). These same compounds have been reported to show low nanomolar activity against the bacterial pyruvate kinase [ 16 , 17 , 18 ]. Dragmacidin G is approximately 15-fold more potent than these other compounds against MRSA.…”

Section: Discussionmentioning

confidence: 99%

Dragmacidin G, a Bioactive Bis-Indole Alkaloid from a Deep-Water Sponge of the Genus Spongosorites

et al. 2017

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A deep-water sponge of the genus Spongosorites has yielded a bis-indole alkaloid which we have named dragmacidin G. Dragmacidin G was first reported by us in the patent literature and has recently been reported by Hitora et al. from a sponge of the genus Lipastrotheya. Dragmacidin G is the first in this series of compounds to have a pyrazine ring linking the two indole rings. It also has a rare N-(2-mercaptoethyl)-guanidine side chain. Dragmacidin G shows a broad spectrum of biological activity including inhibition of methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis, Plasmodium falciparum, and a panel of pancreatic cancer cell lines.

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Discovery of a 1,2-bis(3-indolyl)ethane that selectively inhibits the pyruvate kinase of methicillin-resistant Staphylococcus aureus over human isoforms

Cited by 15 publications

References 10 publications

Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus

Recent Advances in Drug Discovery from South African Marine Invertebrates

Dragmacidin G, a Bioactive Bis-Indole Alkaloid from a Deep-Water Sponge of the Genus Spongosorites

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