Mycobacterial enoyl acyl carrier protein reductase (InhA) is a clinically validated target for the treatment of tuberculosis infections, a disease that still causes the death of at least a million people annually. A known class of potent, direct and competitive InhA inhibitors based on a tetracyclic thiadiazole structure has been shown to have in-vivo activity in murine models of tuberculosis infection. Based on this template, we have here explored the medicinal chemistry of truncated analogues that have only three aromatic rings. In particular, compounds 8b, 8d, 8f, 8l and 8n show interesting features, including low nanomolar InhA IC50, sub-micromolar antimycobacterial potency, and improved physicochemical profiles in comparison with the tetracyclic analogues. From this series, 8d is identified as having the best balance of potency and properties, whereby the resolved 8d S-enatiomer shows encouraging in-vivo efficacy.
COBISS.SI-ID: 3794801
Bacterial DNA gyrase is a well-known and validated target in the design of antibacterial drugs. However, inhibitors of its ATP binding subunit, DNA gyrase B (GyrB), have so far not reached clinical use. In the present study, three different series of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides were designed and prepared as potential DNA gyrase B inhibitors. The IC50 values of compounds on DNA gyrase from Escherichia coli were in the low micromolar range, with the best compound, (4-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzoyl)glycine (6a), displaying an IC50 of 450 nM. For this compound a high-resolution crystal structure in complex with E. coli DNA gyrase B was obtained, revealing details of its binding mode within the active site. The binding affinities of three compounds with GyrB were additionally evaluated by surface plasmon resonance and the results were in good agreement with the determined enzymatic activities. For the most promising compounds the inhibitory activities against DNA gyrase from Staphylococcus aureus and topoisomerases IV from E. coli and S. aureus were determined. Antibacterial activities of the most potent compounds of each series were evaluated against two Gram-positive and two Gram-negative bacterial strains. The results obtained in this study provide valuable information on the binding mode and structure-activity relationship of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides as promising classes of ATP competitive GyrB inhibitors.
COBISS.SI-ID: 3888753
Study of interaction of mannose-based ligands with receptor DC-SIGN using high resolution NMR in combination with molecular modelling showed that four α-D-mannoside ligands interact with the binding site predominantly through the mannose moiety. The other two aromatic groups that are bound to α-D-mannose through a glycerol linker demonstrate interaction that can be related to their substitution pattern. Ligand with naphthyl and meta-substituted phenyl ring exhibited the most favourable binding characteristics. In addition to the predicted hydrophobic interactions of aromatic moieties our results propose new contacts of substituted phenyl moiety in the more polar area of the flat binding site of DC-SIGN and thus offer new possibilities in further designing of novel, more potent DC-SIGN antagonists. Our results were presented on the Cover page of the journalhttp://pubs.rsc.org/en/content/ articlelanding/ 2016/ob/c6ob90009g#!divAbstract.
COBISS.SI-ID: 3966577
Evaluating immunomodulatory effects of xenobiotics is an important component of the toxicity studies. Herein we report on the establishment of a novel in vitro test system for the immunotoxicity screening of xenobiotics based on human lymphoblastoid cell lines (LCLs). Four immunotoxic compounds; tributyltin chloride, cyclosporine A, benzo(a)pyrene and verapamil hydrochloride, as well as three immune-inert compounds; urethane, furosemide and mannitol were selected for characterization. The treatment of LCLs with immunosuppressive compounds resulted in reduced viability. The IC50 values determined in human LCLs were in agreement with the data obtained for human peripheral mononuclear cells. Since cytokine production reflects lymphocytes responses to external stimuli, we evaluated the functional responses of LCLs by monitoring their pro-inflammatory and immunoregulatory cytokine production.Our findings prove that LCLs allowed for reliable differentiation between immunomodulatory and immune-inert compounds. Hence, pre-treatment with immunomodulatory compounds led to a decrease in the production of pro-inflammatory TNF[alpha] IL-6 and immunoregulatory IL-2, IL-4, IL-10 and IFN[gamma] cytokines, when compared to untreated ionomycin/PMA stimulated cells. Moreover, testing a panel of ten LCLs derived from unrelated healthy individuals reflects inter-individual variability in response to immunomodulatory xenobiotics. In conclusion, LCLs provide a novel alternative method for the testing of the immunotoxic effects of xenobiotics.
COBISS.SI-ID: 3803505
Bisphenol A (BPA) and its analogs (BPF and BPAF) are a class of industrial chemicals that are proven to elicit endocrine disrupting effects, thus it is important to reduce their concentrations in effluent streamsas much as possible. In this study, a simple and highly active glass fiber-supported TiO2 photocatalyst was synthesized and applied in a UV-irradiated three-phase batch and continuous stirred-tank reactor (CSTR)for removal of toxicity and estrogenicity of water dissolved bisphenols. Bioassays of photocatalyticallytreated aqueous samples showed no estrogenic activity and complete removal of toxicity after 4 h ofillumination, which was in accordance with high mineralization extent of bisphenols and their reactionderivatives. The photocatalytic examination of bisphenolic compounds revealed considerably higher sta-bility of BPAF under UV light irradiation, due to two CF3groups attached to the central C atom. Moreover,these fluorinated groups were responsible for markedly higher toxicity of BPAF to crustaceans Daphniamagna in comparison to non-halogenated BPA and BPF, which manifested daphnids as excellent aquaticspecies for sensing fluorinated (halogenated) bisphenolic compounds. In addition, photocatalytic oxida-tion of bisphenol analogs in CSTR demonstrated feasibility of using the immobilized TiO2photocatalystin continuous-flow light-assisted water purification systems. Detailed characterization of fresh and usedphotocatalysts confirmed substantial changes in active material structure. However, the correspondingimpact on photocatalyst stability was found insignificant.
COBISS.SI-ID: 3969137