Planarity of benzoyldithiocarbazate tuberculostatics. II. Diesters of benzoyldithiocarbazic acid

The emergence of drug‐resistant strains of Mycobacterium tuberculosis has intensified efforts to identify new lead tuberculostatics. Our earlier studies concluded that the planarity of a molecule correlates well with its tuberculostatic activity. According to our hypothesis, only derivatives whose molecules are capable of adopting a planar conformation may show tuberculostatic activity. The structures of three new potentially tuberculostatic compounds, namely N′‐[bis(methylsulfanyl)methylidene]‐N‐methyl‐4‐nitrobenzohydrazide (denoted G1), C₁₁H₁₃N₃O₃S₂, N′‐[bis(benzylsulfanyl)methylidene]‐N‐methyl‐4‐nitrobenzohydrazide (denoted G2), C₂₃H₂₁N₃O₃S₂, and N′‐[(benzylsulfanyl)(methylsulfanyl)methylidene]‐4‐nitrobenzohydrazide (denoted G3), C₁₆H₁₅N₃O₃S₂, were determined by X‐ray diffraction. The significant distortion from planarity caused by the methyl substituent at the N atom of the hydrazide group or the NO₂ substituent in the aromatic ring leads to the loss of tuberculostatic activity for G1, G2 and G4 {systematic name: N′‐[bis(methylsulfanyl)methylidene]‐2‐nitrobenzohydrazide}. A similar effect is observed when there are large substituents at the S atoms (G2 and G3).     

New synthesis of N-substituted benz[g]isoquinoline-3,5,10(2H)-triones

Various N-substituted benz[g]isoquinoline-3,5,10(2H)-triones 7 were prepared starting from vitamin K₃ (menadione) 9. The key steps involve substitution of a benzylic bromide by a primary amine and intramolecular condensation across the ester moiety of a (3-bromomethyl-naphth-2-yl)acetate 8 followed by oxidation with cerium(IV) ammonium nitrate (CAN) and spontaneous dehydrogenation, resulting in the title compounds 7. A selection of the synthesised new compounds was tested in vitro against Mycobacterium tuberculosis.     

Detection of Paratuberculosis in Dairy Herds by Analyzing the Scent of Feces,Alveolar Gas,and Stable Air

Paratuberculosis is an important disease of ruminants caused by Mycobacterium avium ssp. paratuberculosis (MAP). Early detection is crucial for successful infection control, but available diagnostic tests are still dissatisfying. Methods allowing a rapid, economic, and reliable identification of animals or herds affected by MAP are urgently required. This explorative study evaluated the potential of volatile organic compounds (VOCs) to discriminate between cattle with and without MAP infections. Headspaces above fecal samples and alveolar fractions of exhaled breath of 77 cows from eight farms with defined MAP status were analyzed in addition to stable air samples. VOCs were identified by GC–MS and quantified against reference substances. To discriminate MAP-positive from MAP-negative samples, VOC feature selection and random forest classification were performed. Classification models, generated for each biological specimen, were evaluated using repeated cross-validation. The robustness of the results was tested by predicting samples of two different sampling days. For MAP classification, the different biological matrices emitted diagnostically relevant VOCs of a unique but partly overlapping pattern (fecal headspace: 19, alveolar gas: 11, stable air: 4–5). Chemically, relevant compounds belonged to hydrocarbons, ketones, alcohols, furans, and aldehydes. Comparing the different biological specimens, VOC analysis in fecal headspace proved to be most reproducible, discriminatory, and highly predictive.     

Syntheses and studies of hydantoin derivatives as potential anti-tuberculosis inhibitors

A short and efficient synthesis of(Z)-2-substituted-5-(4-((2-substitued-5-oxoimidazolidin-4-ylidene)methyl)benzamido)ben-zoic acid derivatives(8a-g) as potential type of FabH inhibitors is described.Their structures were confirmed by MS,NOE and ~1H NMR.     

The Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein, a toll-like receptor 4 agonist, enhances dendritic cell-based cancer vaccine potency

In this study, we showed the direct interaction between Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein (FAP) and toll-like receptor4 (TLR4) via co-localization and binding by using confocal microscopy and co-immunoprecipitation assays. FAP triggered the expression of pro- and antiinflammatory cytokines in a TLR4-dependent manner. In addition, FAP-induced cytokine expression in bone marrow-derived dendritic cells (BMDCs) was modulated in part by glycogen synthase kinase-3 (GSK-3). FAP-induced expression of CD80, CD86, major histocompatibility complex (MHC) class I, and MHC class II in TLR4(+/+) BMDCs was not observed in TLR4(-/-) BMDCs. Furthermore, FAP induced DC-mediated CD8(+) T cell proliferation and cytotoxic T lymphocyte (CTL) activity, and suppressed tumor growth with DC-based tumor vaccination in EG7 thymoma murine model. Taken together, these results indicate that the TLR4 agonist, FAP, a potential immunoadjuvant for DC-based cancer vaccination, improves the DC-based immune response via the TLR4 signaling pathway.     

A New Bacteriophage-Modified Piezoelectric Sensor for Rapid and Specific detection of Mycobacterium

Detection of tuberculosis and related diseases caused by mycobacteria is costly, time-consuming, and labor-intensive. Here a new phage-modified piezoelectric system for rapid and specific detection of mycobacteria was developed. In this system, interdigital gold electrode immobilized with lytic phage was used as a probe in place of a steel electrode in the multi-channel series piezoelectric quartz crystal (MSPQC) system. The probe was directly connected to the piezoelectric detection system. Mycobacterium was specifically captured to the phage-modified electrode and then lysed by immobilized phage, which caused the electrode electrical properties change. This change can be sensitively monitored by the piezoelectric detection system. The detection time of Mycobacterium smegmatis was less than 2 hours and a detection limit of 10³cfu mL^?1 was obtained. Additionally, it was successfully used to detect Mycobacterium tuberculosis. The developed system using phage-modified interdigital electrode showed high specificity and reproducibility for mycobacterium detection. Compared with the MSPQC system, the proposed system was faster and more specific.     

Vanadium complexes with thiosemicarbazones: Synthesis,characterization, crystal structures and anti-Mycobacterium tuberculosis activity

The development of more efficient anti-tuberculosis drugs is of interest. Three oxovanadium(IV) and three cis-dioxovanadium(V) complexes with thiosemicarbazone derivatives bearing moieties with different lipophilicity have been prepared and had their inhibitory activity against Mycobacteriumtuberculosis H₃₇Rv ATCC 27294 evaluated. The analytical methods used by the complexes’ characterization included IR, EPR, ¹H, ¹³C and ⁵¹V NMR spectroscopies, elemental analysis, cyclic voltammetry, magnetic susceptibility measurement and single crystal X-ray diffractometry. [VO(acac)(aptsc)], [VO(acac)(apmtsc)] and [VO(acac)(apptsc)] (acac = acetylacetonate; Haptsc = 2-acetylpyridinethiosemicarbazone; Hapmtsc = 2-acetylpyridine-N(4)-methyl-thiosemicarbazone and Happtsc = 2-acetylpyridine-N(4)-phenyl-thiosemicarbazone) are paramagnetic and their EPR spectra are consistent with the monoanionic N,N,S-tridentate coordination of the thiosemicarbazone ligands, resulting in octahedral structures of rhombic symmetry and with the oxidation state +IV for the vanadium atom. As result of oxidation of the vanadium(IV) complexes above, the diamagnetic cis-dioxovanadium(V) complexes [VO₂(aptsc)], [VO₂(apmtsc)] and [VO₂(apptsc)] are formed. Their ¹H, ¹³C and ⁵¹V NMR spectra were acquired and support a distorted square pyramidal geometry for them, in accord with the solid state X-ray structures determined for [VO₂(aptsc)] and [VO₂(apmtsc)]. In general, the vanadium compounds show comparable or larger anti-M. tuberculosis activities than the free thiosemicarbazone ligands, with MIC values within 62.5–1.56 (μg/mL).     

Quinoxaline Moiety: A Potential Scaffold against Mycobacterium tuberculosis

Background. The past decades have seen numerous efforts to develop new antitubercular agents. Currently, the available regimens are lengthy, only partially effective, and associated with high rates of adverse events. The challenge is therefore to develop new agents with faster and more efficient action. The versatile quinoxaline ring possesses a broad spectrum of pharmacological activities, ensuring considerable attention to it in the field of medicinal chemistry. Objectives. In continuation of our program on the pharmacological activity of quinoxaline derivatives, this review focuses on potential antimycobacterial activity of recent quinoxaline derivatives and discusses their structure—activity relationship for designing new analogs with improved activity. Methods. The review compiles recent studies published between January 2011 and April 2021. Results. The final total of 23 studies were examined. Conclusions. Data from studies of quinoxaline and quinoxaline 1,4-di-N-oxide derivatives highlight that specific derivatives show encouraging perspectives in the treatment of Mycobacterium tuberculosis and the recent growing interest for these scaffolds. These interesting results warrant further investigation, which may allow identification of novel antitubercular candidates based on this scaffold.     

Isatin hybrids and their anti-tuberculosis activity

Tuberculosis (TB) is one of the most common and even fatal infectious diseases known to mankind. Millions of new cases are reported every year over the world, and one-third of the world's population is potentially infected with mycobacteria tuberculosis (MTB). Research to develop novel anti-TB drugs led to the identification of several isatin-based antimycobacterial agents, among which a number of potential candidates displayed excellent antimycobacterial activity and were found to be free of cytotoxicity. This review outlines the advances in the application of isatin hybrids as antimycobacterial agents and the critical aspects of design and structure-activity relationship of these derivatives.     

Lansoprazole‐sulfide,pharmacokinetics of this promising anti‐tuberculous agent

Lansoprazole (LPZ) is a commercially available proton‐pump inhibitor whose primary metabolite, lansoprazole sulfide (LPZS) was recently reported to have in vitro and in vivo activity against Mycobacterium tuberculosis . It was also reported that a 300 mg kg⁻¹ oral administration of LPZS was necessary to reach therapeutic levels in the lung, with the equivalent human dose being unrealistic. A validated liquid chromatography–tandem mass spectrometric method (LC–MS/MS) for the simultaneous quantification LPZ and LPZS in rat plasma and lung homogenates was developed. We administered 15 mg kg⁻¹ oral doses of LPZ to a healthy rat model to determine the pharmacokinetics of its active metabolite, LPZS, in plasma and lung tissue. We found that the LPZS was present in amounts that were below the limit of quantification. This prompted us to administer the same dose of LPZS to the experimental animals intraperitoneally (i.p.). Using this approach, we found high concentrations of LPZS in plasma and lung, 7841.1 and 9761.2 ng mL⁻¹, respectively, which were significantly greater than the minimum inhibitory concentration (MIC) for Mycobacterium tuberculosis. While oral and i.p. administration of LPZ resulted in significant concentrations in the lung, it did not undergo sufficient cellular conversion to its anti‐TB metabolite. However, when LPZS itself was administered i.p., significant amounts penetrated the tissue. These results have implications for future in vivo studies exploring the potential of LPZS as an anti‐TB compound.