103514-53-0Relevant articles and documents
Selective AMPK activator leads to unfolded protein response downregulation and induces breast cancer cell death and autophagy
Nascimento Mello, Angélica Lauria,Sagrillo, Fernanda Savacini,de Souza, Alan Gon?alves,Costa, Amanda Rodrigues Pinto,Campos, Vinícius Rangel,Cunha, Anna Claudia,Imbroisi Filho, Ricardo,da Costa Santos Boechat, Fernanda,Sola-Penna, Mauro,de Souza, Maria Cecília Bastos Vieira,Zancan, Patricia
, (2021)
Aims: AMPK plays a critical role regulating cell metabolism, growth and survival. Interfering with this enzyme activity has been extensively studied as putative mechanism for cancer therapy. The present work aims to identify a specific AMPK activator for cancer cells among a series of novel heterocyclic compounds. Materials and methods: A series of novel hybrid heterocyclic compounds, namely naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives, were synthesized via Michael reaction and their structures confirmed by spectral data: infrared; 1H and 13C NMR spectroscopy (COSY, HSQC, HMBC); and high-resolution mass spectrometry (HRMS). The novel compounds were screened and tested for antitumoral activity and have part of their mechanism of action scrutinized. Key findings: Here, we identified a selective AMPK activator among the new hybrid heterocyclic compounds. This new compound presents selective cytotoxicity on breast cancer cells but not on non-cancer counterparts. We identified that by specifically activating AMPK in cancer cells, the drug downregulates unfolded protein response pathway, as well as inhibits mTOR signaling. Significance: These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.
6-Nitro-1-benzylquinolones exhibiting specific antitubercular activity
Beteck, Richard M.,Jordaan, Audrey,Swart, Tarryn,Van Der Kooy, Frank,Warner, Digby F.,Hoppe, Heinrich C.,Legoabe, Lesetja J.
, p. 1387 - 1394 (2020)
In this study, we synthesized novel nitro quinolone-based compounds and tested them in vitro against a panel of Gram-positive and Gram-negative pathogens including Mycobacterium tuberculosis (MTB), Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumonia, Staphylococcus aureus, and Escherichia coli for antibacterial activities and also against HeLa cells for overt cytotoxicity. Compound 8e was identified as a non-toxic, potent hit with selective activity (MIC90???0.24?μm) against MTB. 8e, however, showed no activity against DprE1 mutant, suggesting DprE1 as the likely target for this compound class.
Easily accessed nitroquinolones exhibiting potent and selective anti-tubercular activity
Dube, Phelelisiwe S.,Legoabe, Lesetja J.,Jordaan, Audrey,Jesumoroti, Omobolanle J.,Tshiwawa, Tendamudzimu,Warner, Digby F.,Beteck, Richard M.
, (2021/02/01)
Nitro based DprE1 inhibitors exemplified by benzothiazinones have been reported to elicit potent anti-tubercular activity. Poor PK properties associated with benzothiazinones have inspired the discovery of alternative nitro based DprE1 inhibitors. Quinolone based antibiotics on the other hand have good PK properties. The potent anti-tubercular activity of nitro compounds and the good PK properties of the quinolones have elicited an interest in us to construct a new class of nitro containing compounds around the quinolone scaffold with the aim of identifying novel DprE1 inhibitors with potent anti-tubercular activity. Thus, we report herein the anti-tubercular activity of novel 6-nitroquinolone-3-carboxamide derivatives achieved using less than five cheap synthetic transformations. Among the 23 target compounds evaluated for anti-tubercular activity, 12 were active against Mtb─ exhibiting activity in the range of a molecular weight of 399 Da and ClogP value of 2.7 is the most active (MIC90: 2) and C-3 (R3) of the quinolone ring. The activity data suggest that the nature of R3 has a stronger influence on the SAR compared to R2; with a fluorobenzyl and chlorobenzyl moiety at R2 being the most favoured when R3 is an aliphatic amine. Docking study confirms that compound 25 binds to the same hydrophobic pocket as does TCA1, and other nitro based DprE1 inhibitors, with its nitro group in close proximity with Cys387 residue.
Easy-to-access quinolone derivatives exhibiting antibacterial and anti-parasitic activities
Beteck, Richard M.,Hoppe, Heinrich C.,Jordaan, Audrey,Khanye, Setshaba D.,Laming, Dustin,Seldon, Ronnett,Warner, Digby F.
, (2021/06/11)
The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24-31 μM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4-20 μM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.
