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We have shown that asphaltene self-association induces temperature gradients and convection currents and it is necessary to suppress these effects to obtain accurate data by DOSY NMR techniques. An interesting finding of this investigation is that aggregation process has been found to be affected by the magnetic field. The obtained results have shown for the first time a significant increase in diffusion coefficients of aggregates upon the increase in the magnetic field strength indicating higher molecular mobility of the present species and possible degradation of aggregates. We have shown that changes in diffusion coefficients are not a consequence of relaxation or viscosity effects. It is not yet clear what the reason for such behavior is and whether this effect is intrinsic. Traces of paramagnetic metals present in asphaltene samples may play a role in this process but this hypothesis is yet to be explored. Furthermore, this study has revealed a similar concentration range in which the Middle East crude oil asphaltenes aggregate being in agreement with previous results. Aggregates form different molecular weight species with different composition and number of monomer units. Ongoing experiments will throw more light on the magnetic field dependent asphaltene aggregation. This may have an impact on developing strategies for resolving asphaltene precipitation issues.

LC-SPE/cryo NMR and MS methodologies have been developed and employed for a rapid structure determination of 4″-tetrahydrofurfuryl macrozone reaction mixture components. Macrozones, novel conjugates of azithromycin, and thiosemicarbazones have shown very good in vitro antibacterial activities against susceptible and some resistant bacterial strains and are promising agents for further development. The post-column multiple trapping of the chromatographically separated reaction mixture components on the SPE cartridges increased the sensitivity and together with cryogenically cooled NMR probe made it possible to identify and structurally characterize main 4″-tetrahydrofurfuryl macrozone reaction mixture compounds including those present at very low concentration level. This approach has several advantages over a classical off-line procedure, efficiency and low solvent consumption being the two most important ones. All identified components were process-related. It has been demonstrated that two different kinds of compounds with respect to structure were identified, i.e., macrolide-related and thiosemicarbazone-related ones. This methodology can serve as a platform for reliable and effective macrolides reaction components structure profiling, serving as both isolation and identification tools.

Macrolide antibiotics are macrocyclic compounds that are clinically used and prescribed for the treatment of upper and lower respiratory tract infections. They inhibit the synthesis of bacterial proteins by reversible binding to the 23S rRNA at or near the peptidyl transferase center. However, their excellent antibacterial profile was largely compromised by the emergence of bacterial resistance. Today, fighting resistance to antibiotics is one of the greatest challenges in medicinal chemistry. Considering various physicochemical properties of macrolides, understanding their structure and interactions with macromolecular targets is crucial for the design of new antibiotics efficient against resistant pathogens. The solid-state structures of some macrolide-ribosome complexes have recently been solved, throwing new light on the macrolide binding mechanisms. On the other hand, a combination of NMR spectroscopy and molecular modeling calculations can be applied to study free and bound conformations in solution. In this article, a description of advanced physicochemical methods for elucidating the structure and interactions of macrolide antibiotics in solid state and solution will be provided, and their principal advantages and drawbacks will be discussed.

Increasing bacterial resistance to existing antibiotics presents a serious threat to human health, and new antibacterial agents are desperately needed. Unfortunately, the number of newly marketed antibiotics has decreased dramatically in recent years. Withdrawal of the macrolide antibiotic telithromycin and the inability of solithromycin to gain marketing approval have prompted our efforts to search for new anti-infective macrolide compounds. Here we present the design, synthesis and biological evaluation of a novel hybrid class of azithromycin conjugates, the macrozones. Evaluation of prepared compounds against a panel of pathogenic bacteria revealed that these molecules showed excellent activities against susceptible Streptococcus pneumoniae, Streptococcus pyogenes and Enterococcus faecalis strains comparable with or better than azithromycin. Furthermore, prepared macrozones exhibited excellent activity against efflux resistant S. pneumoniae, which was 32 times better than that of azithromycin, and very good activity against an efflux resistant Staphylococcus aureus strain against which azithromycin is inactive. The results described here can serve as a good basis to guide further activities directed toward the discovery of more potent macrolide anti-infectives.

The structure and interactions of several aminopropyl–azithromycin derivatives (1a–c) have been studied by using NMR spectroscopy and docking calculations. Compounds 1a–c are precursors in the synthesis of macrozones, novel bioactive azithromycin–thiosemicarbazone conjugates active against some resistant bacterial strains. Today, bacterial resistance is considered as one of the major threats to human health. Knowledge on drug binding mode and conformations is one of the key factors in the process of designing molecules to fight resistance. In solution state, compounds 1a and 1c exist in the 3-endo-folded-out conformation, while 1b adopts a classical folded-out conformation. 13C and 15N CPMAS NMR spectra pointed towards similar structures in the solid state. The transferred NOESY NMR spectra confirmed binding to the E. coli ribosome and suggest that dominant conformations in the bound state resemble those in the free one. STD experiments identified reactive groups of 1a–c in close contact with the ribosome resembling binding epitopes observed for the related 15-membered macrolides. Docking studies revealed that the studied compounds bind to the same ribosome binding pocket similarly to erythromycin in the crystal state, and that the binding is achieved through H-bonds and van der Waals interactions. The bound conformation is the same as determined by NMR. STD enhancements observed for methylene protons in the aminopropyl side chain indicate additional interactions which contribute to the overall binding energy.

Background and Purpose: Poor cod, Trisopterus minutus (Linnaeus, 1758) is a gadoid fish, which inhabits the Mediterranean and eastern Atlantic. The aim of present work was to investigate the morphological properties of poor cod in the eastern central Adriatic Sea by analyzing classical morphometric and meristic characteristics, and thereby investigating: a) whether there are morphological differences between males and females; b) the existence of possible homogenous or heterogeneous stock morphology; and c) the changes in morphometric characteristics with increase in body length.Material and methods: Samples of 410 poor cod specimens (209 females, 201 males) were collected by bottom-trawl between 2014 and 2016 from five localities in the eastern central Adriatic Sea. In order to analyze biometry of the species; fifteen morphometric and eight meristic characteristics were measured.Results and Conclusions: Total length of all specimens ranged from 8.8 to 27.1 cm. Morphological differences between males and females was not marked. Biometric analysis of the morphometric and meristic characteristics indicated a homogenous morphology stock of Trisopterus minutus in the Adriatic Sea. Changes in some morphometric characteristics obtained in conjunction with an increase in body length showed that smaller specimens have a longer head, eye diameter, ventral fins and second anal fins than adult specimens. The negative correlation recorded for the maximum and minimum body depth indicated that the body elongated with poor cod growth. Comparison of the meristic characteristics that were published earlier show some differences between the poor cod populations inhabiting the Adriatic, Black Sea and eastern Atlantic.

The age, growth and mortality parameters for poor cod, Trisopterus minutus, from the eastern Adriatic were analyzed. Samples were collected monthly from January to December 2009 on a random basis, with a total of 1200 specimens analyzed (885 females and 315 males). The values of parameter b (the exponent of the arithmetic form of length-weight relationships) of males (2.97), females (3.01) and total sample (2.99) indicated isometric growth. Fish aged 1-6 years were present in the samples, including a high proportion of 2-year-old individuals. The oldest female was estimated to be 6 years old, while the oldest male was 5. The von Bertalanffy growth parameters were L? = 26.81, K = 0.186, and to = 1.41 for males; L? = 29.5, K = 0.197, and to = 1.33 for females; L? = 28.76, K = 0.194, and to = 1.34 for all specimens. This study revealed that poor cod is a relatively slow-growing fish with intensive growth during the first two years of life. Total and natural mortality were Z = 1.01 year-1 and M = 0.50 year-1, respectively. The exploitation rate, E = 0.50, revealed a high fishing pressure on the stock in the studied area.