Galina Karabanovich

1-Substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their isosteric analogs: A new class of selective antitubercular agents active against drug-susceptible and multidrug-resistant mycobacteria

In this work, a new class of highly potent antituberculosis agents, 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles and their oxa and selanyl analogs, is described. The minimal inhibitory concentration (MIC) values reached 1 μM (0.36-0.44 μg/mL) against Mycobacterium tuberculosis CNCTC My 331/88 and 0.25-1 μM against six multidrug-resistant clinically isolated strains of M. tuberculosis. The antimycobacterial effects of these compounds were highly specific because they were ineffective against all eight bacterial strains and eight fungal strains studied. Furthermore, these compounds exhibited low in vitro toxicity in four mammalian cell lines (IC50 > 30 μM). We also examined the structure-activity relationships of the compounds, particularly the effects on antimycobacterial activity of the number and position of the nitro groups, the linker between tetrazole and benzyl moieties, and the tetrazole itself. Relatively high variability of substituent R(1) on the tetrazole in the absence of negative effects on antimycobacterial activity allows further structural optimization with respect to toxicity and the ADME properties of the 1-substituted-5-[(3,5-dinitrobenzyl)sulfanyl]-1H-tetrazoles lead compounds.

Development of 3,5-Dinitrobenzylsulfanyl-1,3,4-oxadiazoles and Thiadiazoles as Selective Antitubercular Agents Active Against Replicating and Nonreplicating Mycobacterium tuberculosis

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.

Tetrazole regioisomers in the development of nitro group-containing antitubercular agents

Tetrazole derivatives containing nitro substituents have been identified as promising antitubercular agents. In this study, the antitubercular potency, selectivity and toxicity of tetrazole 1,5- and 2,5-regioisomers were examined. We prepared a series of 1- and 2-alkyl-5-benzylsulfanyl-2H-tetrazoles and their selenium analogs with various nitro group substitutions. These 1,5- and 2,5-regioisomers were isolated and unambiguously identified using 1H and/or 13C NMR. Among the prepared compounds, 1- and 2-alkyl-5-[(3,5-dinitrobenzyl)sulfanyl]-2H-tetrazole derivatives and their selenium bioisosteres showed the highest antimycobacterial activity, with minimal inhibitory concentration (MIC) values of approximately 1 μM (0.37–0.46 μg mL−1) against Mycobacterium tuberculosis CNCTC My 331/88. The 2-alkyl regioisomers exhibited consistently higher antimycobacterial activity and lower in vitro toxicity against a mammalian cell line compared to the 1-alkyl isomers. The antimycobacterial activity of the 2-alkyl regioisomers was less influenced by the type of alkyl substituent in contrast to 1-alkyl isomers. Furthermore, the 3,5-dinitrobenzyl moiety per se is not the carrier of mutagenicity. These findings encourage further optimization of the 2-alkyl chain to improve the pharmacokinetic properties and toxicity of 2-alkyl-5-[(3,5-dinitrobenzyl)sulfanyl]-2H-tetrazole lead compounds.

Tetrazoles: LV. Perparation of 2-anilino-5-aryl(hetaryl)-1,3,4-oxadiazoles from 5-substituted tetrazoles under microwave activation

In reaction of 5-aryl(hetaryl)tetrazoles with phenyl isocyanate under the conditions of microwave activation the corresponding 2-anilino-5-aryl(hetaryl)-1,3,4-oxadiazoles formed in high yields. The application of the microwave activation fourfold reduced the reaction time.

Microwave-assisted synthesis of 2-aryl(hetaryl)-5-phenylamino-1,3,4-thiadiazoles from 5-substituted tetrazoles

In the recent years 2-aryl-5-arylamino-1,3,4-thiadiazoles have attracted considerable attention due to their intrinsic high biological activity [1]. Compounds of the 2-aryl-5-arylamino-1,3,4-thiadiazole series were found to exhibit antimicrobial [2], antituberculous [3], and antiphlogistic properties [4], as well as to inhibit development of some cancer diseases [5]. However, the lack of convenient methods for the preparation of 2,5-disubstituted 1,3,4-thiadiazoles strongly restricts their potential application in medical practice. Known and widely used methods of synthesis of 2,5-disubstituted 1,3,4-thiadiazoles often include a number of steps and are insufficiently effective [1, 6]. On the other hand, as early as 1961 Huisgen et al. [7] reported a simple one-step procedure for the synthesis of 2-phenyl-5-phenylamino-1,3,4-thiadiazole from 5-phenyl-1H-tetrazole and phenyl isothiocyanate.

Investigation of novel dexrazoxane analogue JR-311 shows significant cardioprotective effects through topoisomerase IIbeta but not its iron chelating metabolite

Novel dexrazoxane derivative JR-311 was prepared to investigate structure-activity relationships and mechanism(s) of protection against anthracycline cardiotoxicity. Its cardioprotective, antiproliferative, iron (Fe) chelation and inhibitory and/or depletory activities on topoisomerase IIbeta (TOP2B) were examined and compared with dexrazoxane. While in standard assay, JR-311 failed in both cardioprotection and depletion of TOP2B, its repeated administration to cell culture media led to depletion of TOP2B and significant protection of isolated rat neonatal ventricular cardiomyocytes from daunorubicin-induced damage. This effect was explained by a focused analytical investigation that revealed rapid JR-311 decomposition, resulting in negligible intracellular concentrations of the parent compound but high exposure of cells to the decomposition products, including Fe-chelating JR-H2. Although chemical instability is an obstacle for the development of JR-311, this study identified a novel dexrazoxane analogue with preserved pharmacodynamic properties, contributed to the investigation of structure-activity relationships and suggested that the cardioprotection of bis-dioxopiperazines is likely attributed to TOP2B activity of the parent compound rather than Fe chelation of their hydrolytic metabolites/degradation products. Moreover, this study highlights the importance of early stability testing during future development of novel dexrazoxane analogues.

Development of water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents

In this work, four series of tertiary amine-containing derivatives of 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. We found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. The N-benzylpiperazine derivatives, which had the highest lipophilicity among all of the series, showed the highest in vitro antimycobacterial activities against Mycobacterium tuberculosis CNCTC My 331/88 (H37Rv), comparable to those of the first-line drugs isoniazid and rifampicin. The presence of two tertiary amines in these N-benzylpiperazine derivatives enabled us to prepare water-soluble dihydrochloride salts, overcoming the serious drawback of previously described 3,5-dinitrophenyl tetrazole and oxadiazole lead compounds. The water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents described in this work are good candidates for further in vitro and in vivo pharmacokinetic and pharmacodynamic studies.

Pharmacokinetics of the cardioprotective drug dexrazoxane and its active metabolite ADR-925 with focus on cardiomyocytes and the heart

Dexrazoxane (DEX), the only cardioprotectant approved against anthracycline cardiotoxicity, has been traditionally deemed to be a prodrug of the iron-chelating metabolite ADR-925. However, pharmacokinetic profile of both agents, particularly with respect to the cells and tissues essential for its action (cardiomyocytes/myocardium), remains poorly understood. The aim of this study is to characterize the conversion and disposition of DEX to ADR-925 in vitro (primary cardiomyocytes) and in vivo (rabbits) under conditions where DEX is clearly cardioprotective against anthracycline cardiotoxicity. Our results show that DEX is hydrolyzed to ADR-925 in cell media independently of the presence of cardiomyocytes or their lysate. Furthermore, ADR-925 directly penetrates into the cells with contribution of active transport, and detectable concentrations occur earlier than after DEX incubation. In rabbits, ADR-925 was detected rapidly in plasma after DEX administration to form sustained concentrations thereafter. ADR-925 was not markedly retained in the myocardium, and its relative exposure was 5.7-fold lower than for DEX. Unlike liver tissue, myocardium homogenates did not accelerate the conversion of DEX to ADR-925 in vitro, suggesting that myocardial concentrations in vivo may originate from its distribution from the central compartment. The pharmacokinetic parameters for both DEX and ADR-925 were determined by both noncompartmental analyses and population pharmacokinetics (including joint parent-metabolite model). Importantly, all determined parameters were closer to human than to rodent data. The present results open venues for the direct assessment of the cardioprotective effects of ADR-925 in vitro and in vivo to establish whether DEX is a drug or prodrug.