Bacterial eukaryotic type serine-threonine protein kinases: from structural biology to targeted anti-infective drug design.

Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive approach to cure infections. In this review we focused on actinobacterial STPKs to demonstrate that these enzymes can be used for crystal structure studies, modeling of 3D structure, construction of test systems and design of novel chemical libraries of low molecule as weight inhibitors. In particular, the prototypic pharmacological antagonists of Mycobacterium tuberculosis STPKs are perspective for development of a novel generation of drugs to combat the socially important disease. These inhibitors may modulate both actinobacterial and host STPKs and trigger programmed death of pathogenic bacteria.

Search for inhibitors of bacterial and human protein kinases among derivatives of diazepines[1,4] annelated with maleimide and indole cycles.

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.

Synthesis of 6H-pyrrolo[3',4':2,3][1,4]diazepino[6,7,1-hi]indole-8,10(7H,9H)-diones using 3-bromo-4-(indol-1-yl)maleimide scaffold.

Series of 3-arylalkyl- or 3-alkylamino-4-(indol-1-yl)maleimides and bis(indol-1-yl)maleimides were synthesised. The cyclization of the 3-substituted 4-(indol-1-yl)maleimides under the action of acids resulted in the formation of diazepine[1,4] derivatives with indoline and maleimide nuclei annelated. These compounds readily produced the corresponding indolomaleimidodiazepines[1,4] after dehydrogenation.