General objective

Our research group deals with the synthesis of mainly nitrogen-containing heterocyclic derivatives with potential antimycobacterial activity. Antimycobacterial activitites of our compounds are evaluated in vitro against collection strains of Mycobacteria sp. and also agains multi-drug resistant strains of Mycobacterium tuberculosis isolated from patients. In order to determine the selectivity, effect of our compounds on human cell lines and their activities against bacterial and fungal strains are also studied.

The compounds with the most promising results are further studied in vivo. Firstly, we determine some basic pharmacokinetic parameters. Then, antituberculosis action of the selected compounds are studied in vivo in tuberculosis mouse model at the Biological Defence Department at Těchonín.

Recent results

In the last decade, series of compounds based on 2-benzylsulfanylbenzimidazoles, 2-benzylsulfanylbenzoxazoles, 2-benzylsulfanylbenzothiazoles as well as 3-benzylsulfanyltriazoles and 2- or 4-benzylsulfanylpyridines were synthesized and studied. Especially benzazole derivatives bearing dinitrobenzylsulfanyl fragment exhibited antimycobacterial activities comparable to isoniazid, first-line antituberculosis drug.

Later on, we reported a huge structure-activity relationship study of dinitrobenzylsulfanyl tetrazoles and their analogs. As a result of this study, 1-substituted-5-(3,5-dinitrobenzylsulfanyl)-1H-tetrazoles and their oxa and selenium analogs have been identified as the new lead compounds. They displayed high and selective antimycobacterial activity, low cellular toxicity and genotoxicity. Furthermore, they are active also against MDR M. tuberculosis strains, with no cross-resistance with currently used antiTB drugs.

Moreover, 2,5-regioisomeric analogs of lead compounds - 2-substituted-5-(3,5-dinitrobenzylsulfanyl)-2H-tetrazoles - have more beneficial properties compared to 1,5-regioisomers.

                       G. Karabanovich et al. EJMC 2014                                                  G. Karabanovich et al. MedChemComm 2015

Recently, we reported a structure-activity relationship study of dinitrobenzylsulfanyl oxadiazoles and thiadiazoles. Compounds described in this work possess outstanding and highly selective in vitro antimycobacterial activity against both replicating and nonreplicating mycobacteria. Several experiments suggested that these compounds possess a novel mechanism of action affecting the synthesis of mycobacterial nucleic acids. Our recent research deals with the structure-activity relationship studies of lead structures analogs.

G. Karabanovich et al. JMC 2016


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