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Relevant articles and documents
Ellipticines and 9-acridinylamines as inhibitors of d-alanine:d-alanine ligase
Vehar, Bla? Hrast, Martina Kova?, Andreja Konc, Janez Mariner, Katherine Chopra, Ian O'Neill, Alex Jane?i?, Du?anka Gobec, Stanislav
d-Alanine:d-alanine ligase (Ddl), an intracellular bacterial enzyme essential for cell wall biosynthesis, is an attractive target for development of novel antimicrobial drugs. This study focused on an extensive evaluation of two families of Ddl inhibitors encountered in our previous research. New members of both families were obtained through similarity search and synthesis. Ellipticines and 9-acridinylamines were both found to possess inhibitory activity against Ddl from Escherichia coli and antimicrobial activity against E. coli and Staphylococcus aureus. Ellipticines with a quaternary methylpyridinium moiety were the most potent among all studied compounds, with MIC values as low as 2 mg/L in strains with intact efflux mechanisms. Antimicrobial activity of the studied compounds was connected to membrane damage, making their development as antibacterial drug candidates unlikely unless analogues devoid of this nonspecific effect can be discovered.
Synthesis and evaluation of 9-hydroxy-5-methyl-(and 5,6-dimethyl)-6H- pyrido[4,3-b]carbazole-1-N-[(dialkylamino)alkyl]carboxamides, a new promising series of antitumor olivacine derivatives
Jasztold-Howorko Landras Pierre Atassi Guilbaud Kraus- Berthier Leonce Rolland Prost Bisagni
Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9- methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate was obtained through a three-step sequence. This compound and its 6-methyl derivative react with (dialkylamino)alkylamines to provide various 9-methoxy-5-methyl-6H- pyrido[4,3-b]carbazole-1-(N-substituted carboxamides) whose boron tribromide demethylation afforded corresponding 9-hydroxy-1-(N-substituted carbamoyl)- olivacines. The same pathway but starting from 2-(2-aminoethyl)-6-methoxy- 1,4-dimethylcarbazole led to ethyl 9-methoxy-5,11-dimethyl-6H-pyrido[4,3- b]carbazole-1-carboxylate which did not normally react with amines. It provided either the recovered starting material at 120 °C or 9- methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 °C. Biological testing of the newly obtained 1- carbamoylolivacine derivatives showed that 9-hydroxylated compounds displayed high cytotoxicity for cultured L1210 and colon 38 cells (IC50 range 5-10 nM) and good antitumor activity in vivo in the P388 leukemia and colon 38 models when administered by the iv route. The most active compound in these series is 9-hydroxy-5,6-dimethyl-1-[N-[2-(dimethylamino)ethyl]carbamoyl]-6H- pyrido[4,3-b]carbazole which was selected for further evaluation on murine solid tumors and for toxicological studies.
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