Potential antituberculosis agents

Tuberculosis (TB) is a widespread infectious disease and presents the second greatest killer worldwide due to a single infectious agent. About one third of world population has latent form of TB, which can be activated mainly during immunosuppression (e.g. HIV infection). In 2014, 9.6 mil new cases of TB were found and 1.5 mil people died from TB. Although tuberculosis is curable and preventable disease, the poor quality medicine, incorrect treatment as well as low availability of the medication cause serious problems in the therapy and lead to the formation of resistant strains. Multidrug-resistant TB (MDR-TB) is caused by strains resistant to isoniazid and rifampicin, the most powerful antituberculosis drugs, with or without resistance to other first-line drugs. Extensively drug-resistant tuberculosis (XDR-TB) arose from MDR strains and exhibits an added resistance to fluoroquinolones and second-line injectable aminoglycosides (kanamycin, amikacin and capreomycin). In 2014, 3.3% of new TB cases and 20% of previously treated cases of TB were MDR-TB. Almost 9.7% of them were represented by XDR-TB. Only 50% of patients with MDR-TB were successfully treated, while therapy of patients with the new cases of susceptible TB had 90% cure rate. Moreover, combination of TB with HIV leads to fast progress of both diseases and often is fatal.

Source: World Health Organization – Tuberculosis; http://www.who.int/topics/tuberculosis/en/

Therefore, the search for new antituberculosis drugs, active also against these resistant strains, is highly important. Our group deals with the synthesis of new antituberculotics, with structures different from known anti-TB drugs and with expected novel mechanisms of action.

As a part of this research effort, the chemistry of various nitrogen heterocycles is investigated.


April 2017

In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily accessible compounds possessed high in vitro antimycobacterial activities against Mycobacterium tuberculosis, including clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with submicromolar minimum inhibitory concentrations (MICs). The most promising compounds showed low in vitro cytotoxicity and negligible antibacterial and antifungal activities, highlighting their highly selective antimycobacterial effects. 2-Substituted 5-(3,5-dinitrophenyl)-2H-tetrazole regioisomers, which are the dominant products of 5-(3,5-dinitrophenyl)-1H-tetrazole alkylation, showed better properties with respect to antimycobacterial activity and cytotoxicity than their 1-substituted counterparts. The 2-substituent of 5-(3,5-dinitrophenyl)-2H-tetrazole can be easily modified and can thus be used for the structure optimization of these promising antitubercular agents. The introduction of a tetrazole-5-thioalkyl moiety at position 2 of the tetrazole further increased the antimycobacterial activity. These compounds showed outstanding in vitro activity against M. tuberculosis (MIC values as low as 0.03 uM) and high activity against non-tuberculous mycobacterial strains.

January 2017


Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 µM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.

March 2016






Herein, we report the discovery and structure–activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as a new class of antituberculosis agents. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (0.011–0.026 μg/mL). The investigated compounds had a highly selective antimycobacterial effect because they showed no activity against the other bacteria or fungi tested in this study. Furthermore, the investigated compounds exhibited low in vitro toxicities in four proliferating mammalian cell lines and in isolated primary human hepatocytes. Several in vitro genotoxicity assays indicated that the selected compounds have no mutagenic activity. The oxadiazole and thiadiazole derivatives with the most favorable activity/toxicity profiles also showed potency comparable to that of rifampicin against the nonreplicating streptomycin-starved M. tuberculosis 18b-Lux strain, and therefore, these derivatives, are of particular interest.


© 2017 Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic

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