Syntheses of potential drugs and studies of structure-activity relationships

Bioorganic and Medicinal Chemistry Group

The research of the Bioorganic and Medicinal Chemistry Group (group leader: Assoc. Prof. Jaroslav Roh, Ph.D.) mainly deals with the synthesis of compounds based on aromatic/heterocyclic scaffolds with potential antimicrobial activity and with the study of their structure-activity relationships with respect to antimicrobial activity, cytotoxicity, and selectivity. Especially compounds active against drug-resistant and multidrug-resistant strains are investigated. In cooperation with several research groups, we study the mode of action of the prepared compounds. We also focus on the peptide drug-delivery systems for the studied compounds.

The second line of our research is focused on the structure-activity relationships of the 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 deal with the medicinal chemistry of topoisomerase II beta inhibitors as potential cardioprotective agents. In addition, we deal also with centrally acting inhibitors of acetylcholinesterase and butyrylcholinesterase as potential drugs for neurodegenerative diseases.

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) and explained differences in PDT activity between anionic and cationic species (Kollar et al., J. Med. Chem., 2020). Investigation of derivatives for PDT is done in the cooperation with Kuwait University and research group of prof. Šimůnek. The second application covers the 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. Recently, we studied assembly of these probes into unique J-dimers and described its impact in the development of logic gates (Demuth et al., Org. Chem. Front., 2020). 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., ACS Sensors, 2019; Lochman et al., Sens. Actuators, B, 2017). Fluorescence sensors with improved selectivity and sensitivity toward desired analytes (pH, metal cations, CO2) are investigated. Some of these projects are done in cooperation with Graz University of Technology (Austria). In 2021, an international Czech-Russian research project (Czech Science Foundation) aiming to study the impact of axial ligands in porphyrazinoids for PDT and fluorescence sensing has started.

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 and assembly of barrier lipids in healthy and diseased skin, including atopic dermatitis, ichthyoses, and skin tumors (Engberg et al. Angew Chem 2020, Nováčková et al. J Invest Dermatol 2021, Vávrová et al. J. Invest Dermatol. 2014, Zoschke et al. J. Control. Release 2016), and possible therapeutic use of lipids. We also study the mechanisms of lipid modification to enable transdermal and topical drug delivery. Our methods include lipid synthesis and analysis (Opálka et al. Org. Lett. 2015), synthesis of lipid analogs and modulators, investigation of lipid behavior using biophysical techniques, and permeability experiments with skin and skin models.

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