Search for Inhibitors of Bacterial and Human Protein Kinases among Derivatives of Diazepines[1,4] Annelated with Maleimide and Indole Cycles

Abstract

Aminomethylation of 9b,10-dihydro-1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino-[1,7-a]indole-1,3(2H)-diones or 1H-indolo[1,7:4,5,6]pyrrolo[3,4:2,3][1,4]diazepino[1,7-a]indole-1,3(2H)-diones resulted in dialkylaminomethyl derivatives. Alkylation of the nitrogen atom of maleimide moiety of polyannelated diazepines with 1,3-dibromopropane and subsequent reaction with thiourea or its N-alkyl derivatives gave isothiourea-carrying compounds. The compounds containing isothiourea moiety were active against individual human serine/threonine and tyrosine kinases at low micromolar concentrations. Dialkylaminomethyl derivatives of diazepines sensitized Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting serine/threonine kinase(s) mediated aphVIII phosphorylation.

Regioselective acylation of congeners of 3-amino-1H-pyrazolo[3,4-b]quinolines, their activity on bacterial serine/threonine protein kinases and in vitro antibacterial (including antimycobacterial) activity

“…At subtoxic concentrations no inhibition of bacterial growth was observed. The detailed methods are given in previous publication 2,5 . …”

“…The detailed methods are given in previous publication [9][10][11][12] . The antimycobacterial activity was evaluated by the agar diffusion test with Mycobacterium smegmatis as described previously 2,5 .…”

“…Since it is evident that BSTK play an indispensable role in some prokaryotic organisms, these protein kinases are considered as attractive antibacterial drug targets 1,4 . It was also shown that protein kinase inhibitors of eukaryotic serine/threonine protein kinase(s) (ESTK) could be active against some BSTK 1,4,5 . Several years ago, we have synthesized a combinatorial library of compounds to find inhibitors of ESTK 5 .…”

“…It was also shown that protein kinase inhibitors of eukaryotic serine/threonine protein kinase(s) (ESTK) could be active against some BSTK 1,4,5 . Several years ago, we have synthesized a combinatorial library of compounds to find inhibitors of ESTK 5 . Surprisingly, we found that some of bis-3,4-bis(indol-1-yl)maleimide analogues of known inhibitor Bis I ( Figure 1 and Table 1) are active in tests on Streptomyces lividans with overexpressed aminoglycoside phosphotransferase type VIII (aphVIII) to kanamycin by inhibiting BSTK mediated aphVIII phosphorylation 4,5 .…”

Environmentally Friendly Synthesis of Indoline Derivatives using Flow‐Chemistry Techniques

“…[1][2][3] Several 7-arylazepinoindolines were shown to have selective 5-HT 2C receptor activities, [4,5] and polycyclic indoline derivatives were tested as sensitizers of bacteria against -lactam antibacterial agents; [6] other derivatives were described as promising human protein kinase inhibitors. [7] Recently, some novel indoline derivatives were also described as apoptosis protein inhibitors [8] and monoacylglycerol acyltransferase-2 inhibitors. [9] Accordingly, numerous synthetic methods leading to these structures can be found in the literature, and the frequently applied methods have been summarized in recent reviews.…”