Syntheses of potential drugs and studies of structure-activity relationships

Development of Antibacterial, Antifungal and Antituberculosis Drugs

The research of the “Development of Antibacterial, Antifungal and Antituberculosis Drugs” group (group leader: prof. Alexandr Hrabálek) mainly deals with the synthesis of compounds with potential antimicrobial activities and with the study of their structure-activity relationships with respect to antimicrobial activity, cytotoxicity and selectivity. We also focus on the drug-delivery systems for the studied compounds. In cooperation with several research groups, we study the mode of action of the prepared compounds.

Second line of our research is focused on the structure-activity relationships of cardioprotective drug dexrazoxane, the only approved drug capable of preventing anthracycline-induced cardiotoxicity both in experimental models and clinical practice. As a part of this research, we also study the acylhydrazone-type and thiosemicarbazone-type iron chelators.

Design and Development of New Antimicrobial Agents

Other project Design and Development of New Antimicrobial Agents (group leader prof. Martin Doležal) is based on the synthesis of novel potentially active antituberculous drugs to obtain the structures with the higher biological activity against M. tuberculosis and/or M. avium, M. kansasii, on the searching of optimal structural modifications of pyrazinamide, the model compound. In vitro evaluation of the antituberculous activity is carried out within the Institute of Clinical Microbiology University Hospital, Hradec Kralove or in USA (The Lilly Open Innovation Drug Discovery Program). Project component is molecular modelling (Using Molecular Operating Environment software package) of active compounds for better understanding of their mechanism of action on molecular level and calculations and/or experimental determination of their lipophilicity data. The part of the project is the microbiology evaluation (with using of confocal laser scanning microscope, cultivation of microbes, mapping of the growth of microbes, in vitro biofilm formation, evaluation of metabolic activity of microbes and microbial protein isolation, concentration and purification).

Azaphthalocyanine group

Azaphthalocyanine group” led by Prof. Petr Zimcik, Ph.D. focuses on the synthesis and study of photophysical properties of phthalocyanines and their aza-analogues. These compounds absorb light over 650 nm and they are able to dissipate this energy by several different pathways. The research group investigates these compounds in three different applications. For the first application, new photosensitizers for photodynamic therapy (PDT) of cancer are being developed. The research group described cationic derivatives with extraordinary high PDT activity in vitro (IC50 ~ 5 nM) (Machacek et al, J. Med. Chem., 2016). Now, research group focuses on the preparation of anionic and amphiphilic derivatives, the latter being suitable for simple incorporation into delivery systems. Investigation of derivatives for PDT is done in the cooperation with Kuwait University and research group of prof. Šimůnek. The second application covers synthesis of azaphthalocyanine quenchers of fluorescence used in DNA hybridization probes (Demuth et al, Chem. – Eur. J., 2018). Optimized macrocycles enabling more simple and flexible modification of DNA probes are synthesized and studied in the cooperation with company Generi Biotech. The third application of parent macrocycles employs the ability of these compounds to switch on the fluorescence signal upon binding a selective analyte (Lochman et al., Chem. – Eur. J., 2016). Such fluorescence sensors with improved selectivity toward desired analytes and with improved pKa values of recognition moiety in pH sensitive species are investigated. Some of these projects are done in cooperation with Graz University of Technology (Austria).

Skin barrier research group

Group of prof. Kateřina Vávrová deals with the skin barrier, in particular with its lipid component. We aim at obtaining detailed knowledge about the behavior of barrier lipids in healthy and diseased skin, relationships between the ceramide structure and properties, crosstalk between the skin barrier lipids and proteins (for example, in atopic dermatitis (Vávrová et al. J. . Invest Dermatol. 2014), skin tumors (Zoschke et al. J. Control. Release 2016) and skin ageing) and possible therapeutic use of lipids. We also study the mechanisms of lipid modification to enable transdermal and topical drug delivery. Our methods include synthesis of lipids (Opálka et al. Org. Lett. 2015), their analogs and modulators, investigation of their behavior in membrane models using biophysical techniques, permeability experiments using skin and skin models, and skin lipid analysis.

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