Synthesis and biological evaluation of crown ether acyl derivatives.

A set of crown ethyl acyl derivatives based on 18-crown-6 moiety was synthesized and evaluated for biological activity. In vitro antiproliferative profiling demonstrated significant activities against HBL-100, HeLa, SW1573 and WiDr human cell lines. The most active compound exhibited GI50 values in the range of 3.7-5.6µM. Antimicrobial evaluation showed that three polyaromatic compounds were active against Staphylococcus aureus (MIC90 values from 8.3µM to 50µM), whereas a (decyloxy)benzene substitution exhibited moderate activity against Candida albicans (MIC90 values 36µM). According to SAR evaluation, the size of the crown ether and the acyl side chain had a significant effect on the bioactivity. Aromatic moieties close to the acyl group led to improved bioactivity as exemplified by some of the tested compounds. These results provide further evidence on the potential of crown ethyl structure as a scaffold for developing new biological probes and lead candidates for drug development.

Large-scale bioprospecting of cyanobacteria, micro- and macroalgae from the Aegean Sea.

Marine organisms constitute approximately one-half of the total global biodiversity, being rich reservoirs of structurally diverse biofunctional components. The potential of cyanobacteria, micro- and macroalgae as sources of antimicrobial, antitumoral, anti-inflammatory, and anticoagulant compounds has been reported extensively. Nonetheless, biological activities of marine fauna and flora of the Aegean Sea have remained poorly studied when in comparison to other areas of the Mediterranean Sea. In this study, we screened the antimicrobial, antifouling, anti-inflammatory and anticancer potential of in total 98 specimens collected from the Aegean Sea. Ethanol extract of diatom Amphora cf capitellata showed the most promising antimicrobial results against Candida albicans while the extract of diatom Nitzschia communis showed effective results against Gram-positive bacterium, S. aureus. Extracts from the red alga Laurencia papillosa and from three Cystoseira species exhibited selective antiproliferative activity against cancer cell lines and an extract from the brown alga Dilophus fasciola showed the highest anti-inflammatory activity as measured in primary microglial and astrocyte cell cultures as well as by the reduction of proinflammatory cytokines. In summary, our study demonstrates that the Aegean Sea is a rich source of species that possess interesting potential for developing industrial applications.

Synthesis and Biological Evaluation of 2-Aminobenzothiazole and Benzimidazole Analogs Based on the Clathrodin Structure.

A series of 2-aminobenzothiazole and benzimidazole analogs based on the clathrodin scaffold was synthesized and investigated for their antimicrobial and antiproliferative activities as well as for their effects in hepatitis C virus (HCV) replicon model. Compound 7, derived from 2-aminobenzothiazole, exhibited moderate antimicrobial activity only against the Gram-positive bacterium, Enterococcus faecalis. In the antiviral assay, compounds 4d and 7 were found to suppress the HCV replicon by >70%, but also to exhibit cytotoxicity against the host cells (35 and 44%, respectively). Compounds 4a and 7 demonstrated good activity in the antiproliferative assays on the human melanoma cell line A-375. To assess the selectivity of the effects between cancerous and noncancerous cells, a mouse fibroblast cell line was used. The IC50 values for compound 7 against the melanoma cell line A-375 and the fibroblast cell line BALB/c 3T3 were 16 and 71 µM, respectively, yielding fourfold selectivity toward the cancer cell line. These results suggest that compound 7 should be studied further in order to fully explore its potential for drug development.

N-Phenyl-4,5-dibromopyrrolamides and N-Phenylindolamides as ATP Competitive DNA Gyrase B Inhibitors: Design, Synthesis, and Evaluation.

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 (18a), 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.

Discovery of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazoles as Novel DNA Gyrase Inhibitors Targeting the ATP-Binding Site.

Bacterial DNA gyrase and topoisomerase IV are essential enzymes that control the topological state of DNA during replication and validated antibacterial drug targets. Starting from a library of marine alkaloid oroidin analogues, we identified low micromolar inhibitors of Escherichia coli DNA gyrase based on the 5,6,7,8-tetrahydroquinazoline and 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole scaffolds. Structure-based optimization of the initial hits resulted in low nanomolar E. coli DNA gyrase inhibitors, some of which exhibited micromolar inhibition of E. coli topoisomerase IV and of Staphylococcus aureus homologues. Some of the compounds possessed modest antibacterial activity against Gram positive bacterial strains, while their evaluation against wild-type, impA and ΔtolC E. coli strains suggests that they are efflux pump substrates and/or do not possess the physicochemical properties necessary for cell wall penetration. Our study provides a rationale for optimization of this class of compounds toward balanced dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity.