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, Manoja; Lobb, Kevin A.; Reiner, Neil E.; Andersen, Raymond J.; Davies‐Coleman, Michael T.

doi:10.1021/np500755v

Cited by 37 publications

(37 citation statements)

References 43 publications

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“…The synthesis and characterisation of several 3‐acetylindoles and corresponding α‐bromoketones has previously been reported by us . Below are compounds used in this study, which are yet to be reported by us.…”

Section: Methodsmentioning

confidence: 99%

“…95 %b yLC-UV/Vis-MS. (23) The synthesis and characterisation of several 3-acetylindoles and corresponding a-bromoketones has previously been reported by us. [41,42] Below are compounds used in this study,w hich are yet to be reported by us. General synthetic procedure for compounds 3-22:Ar elevant phenol or thiophenol (2 equiv) was added to as tirring suspension of ac orresponding 2-bromo-1-(1H-indol-3-yl)ethanone (1 equiv) and K 2 CO 3 (2 equiv) in acetone.…”

Section: Chemistrymentioning

confidence: 99%

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Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

et al. 2018

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Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3-yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non-haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long-term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.

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Section: Methodsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

et al. 2018

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“…It is noteworthy that structural modifications of these natural products had led to synthetic analogs with DNAquadruplex recognition, 4 antibacterial, 5,6 antilesihmanial, 7 antitumoral, [8][9][10][11] and angiogenesis inhibition 12 activity. Most of these compounds are linked through the indole C3 position, with only a few exceptions such as Gelliusines F which is a C2-C3 linked bis-indole.…”

Section: Introductionmentioning

confidence: 99%

Preparation of symmetrical C2-C2-linked bis- and tris-6-bromoindoles by Sonogashira couplings and 5-endo-dig cyclization induced by nBu4NF

Balderrama-Martínez-Sotomayor¹,

Flores-Jarillo²,

Álvarez‐Hernández³

2015

Arkivoc

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Preparation of symmetrical C2-C2 linked bis-6-bromoindoles and one tris-6-bromoindole containing ether spacers is described. Double regioselective Sonogashira coupling at the C-I bond of benzyl (5-bromo-2-iodophenyl)carbamate with dialkynes allowed preparation of the corresponding bis-benzyl(2-alkynyl-5-bromo)carbamates. Tetrabutylammonium fluoride (TBAF) promoted 5-endo-dig cyclization was successful with substrates derived from alkyldialkynes but failed with substrates derived from aryldialkynes as base catalysis was not sufficient to promote nucleophilic attack on these electron rich alkynes.

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“…4 Bartik and co-workers isolated three new bisindole alkaloids namely topsentin ( 1a ), bromotopsentin ( 1b ) and deoxytopsentin ( 1c ) from the Mediterranean sponge Topsentia genitrix , near Banyuls in France. 5 Topsentin ( 1a ) exhibited anticancer activity (IC 50 ~ 4–40 µM) towards cultured human and murine tumor cells whereas bromotopsentin ( 1b, IC 50 = 12 µg/mL) and deoxytopsentin ( 1c, IC 50 = 6.3 µg/mL) were found to be cytotoxic against human broncopulmonary (NSCLC-N6) cancer cells. Deoxytopsentin 1c also showed potent antibacterial activity against various bacteria (MIC = 3.12–12.5 µg/mL).…”

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confidence: 99%

Sequential one-pot synthesis of bis(indolyl)glyoxylamides: Evaluation of antibacterial and anticancer activities

Tantak

Gupta

Nikhil

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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A series of bis(indolyl)glyoxylamides 10a–n has been designed and synthesized. In situ generated indole-3-glyoxalylchloride from the reaction of readily available indole 9 with oxalyl chloride was treated with tryptamine to produce bis(indolyl)glyoxylamides 10a–n in 82–93% yields. All the synthesized bis(indolyl)glyoxylamides were well characterized and tested for their antibacterial activity against Gram-positive and Gram-negative bacterial strains. Compounds 10d, 10g and 10i were found to display potent antibacterial activity against Gram-negative strain. Further, the cytotoxicity of bis(indolyl)glyoxylamides 10a–n were evaluated against a panel of human cancer cell lines. Of the screened analogues, compound 10f (IC50 = 22.34 µM; HeLa, 24.05 µM; PC-3, 21.13 µM; MDA-MB-231 and 29.94 µM; BxPC-3) was identified as the most potent analogue of the series. Exposure of PC-3 cells to either 10a or 10f resulted in increased levels of cleaved PARP1, indicating that bis(indolyl)glyoxylamides induce apoptosis in PC-3 cells. Most importantly, compounds 10d, 10g and 10i were completely ineffective in mammalian cells, suggesting that they target bacterial-specific targets and thus will not display any toxicity in host cells.

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Synthetic Analogues of the Marine Bisindole Deoxytopsentin: Potent Selective Inhibitors of MRSA Pyruvate Kinase

Cited by 37 publications

References 43 publications

Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

Expanding the SAR of Nontoxic Antiplasmodial Indolyl‐3‐ethanone Ethers and Thioethers

Preparation of symmetrical C2-C2-linked bis- and tris-6-bromoindoles by Sonogashira couplings and 5-endo-dig cyclization induced by nBu4NF

Sequential one-pot synthesis of bis(indolyl)glyoxylamides: Evaluation of antibacterial and anticancer activities

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