(E)-5-(Methoxyimino)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one

Ihnatenko, Irina; Jones, Peter G.; Kunick, Conrad

doi:10.3390/m1293

Cited by 1 publication

(3 citation statements)

References 16 publications

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“…The synthesis of the oxime ether derivatives constituting series V started with oxime ether 20 [ 58 ], which was N-alkylated to yield the tert -butyl ester 21 . Deprotection of 21 furnished the carboxylic acid 22 , which was further converted to amides 5b – d ( Fig 16 ).…”

Section: Resultsmentioning

confidence: 99%

“…The synthesis of the following compounds was prepared according to published procedures: 8-chloro-3,4-dihydro-1 H -benzo[ b ]azepin-2,5-dione ( 6 ) [ 50 , 80 ], 4-iodophenylhydrazine [ 81 ], 1,3,4,5-tetrahydro-2 H -benzo[ b ]azepin-2-one ( 11 ) [ 51 ], 3,3-dimethyl-1,3,4,5-tetrahydro-2 H -benzo[ b ]azepin-2-one ( 14 ) [ 53 , 82 ], 5,7-dihydro-6 H -dibenzo[ b , d ]azepin-6-one ( 17 ) [ 55 , 56 ] and ( E )-5-methoxyimino-1,3,4,5-tetrahydro-2 H -benzo[ b ]azepin-2-one ( 20 ) [ 58 ].…”

Section: Methodsmentioning

confidence: 99%

“…The evaluation of the results was carried out by comparing the resulting scores of the obtained docking poses, with the help of the ligand interactions function of MOE and by visualisation in UCSF ChimeraX [78,79]. (17) [55,56] and (E)-5-methoxyimino-1,3,4,5-tetrahydro-2H-benzo [b]azepin-2-one (20) [58].…”

Section: Molecular Docking Simulationsmentioning

confidence: 99%

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The indole motif is essential for the antitrypanosomal activity of N5-substituted paullones

Ihnatenko,

Müller,

Orban

et al. 2023

PLoS ONE

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Severe infections with potentially fatal outcomes are caused by parasites from the genera Trypanosoma and Leishmania (class Kinetoplastea). The diseases affect people of remote areas in the tropics and subtropics with limited access to adequate health care. Besides insufficient diagnostics, treatment options are limited, with tenuous developments in recent years. Therefore, new antitrypanosomal antiinfectives are required to fight these maladies. In the presented approach, new compounds were developed and tested on the target trypanothione synthetase (TryS). This enzyme is crucial to the kinetoplastids’ unique trypanothione-based thiol redox metabolism and thus for pathogen survival. Preceding studies have shown that N5-substituted paullones display antitrypanosomal activity as well as TryS inhibition. Herein, this compound class was further examined regarding the structure-activity relationships (SAR). Diverse benzazepinone derivatives were designed and tested in cell-based assays on bloodstream Trypanosoma brucei brucei (T. b. brucei) and intracellular amastigotes of Leishmania infantum (L. infantum) as well as in enzyme-based assays on L. infantum TryS (LiTryS) and T. b. brucei TryS (TbTryS). While an exchange of just the substituent in the 9-position of paullones led to potent inhibitors on LiTryS and T. b. brucei parasites, new compounds lacking the indole moiety showed a total loss of activity in both assays. Conclusively, the indole as part of the paullone structure is pivotal for keeping the TryS inhibitory and antitrypanosomal activity of this substance class.

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Section: Resultsmentioning

confidence: 99%