Development of new potential drugs with antimicrobial activity and cholinesterase inhibitors

Responsible persons: prof. Jarmila Vinšová, Dr. Martin Krátký

This part of our group deals with the design and synthesis of agents that interact with Mycobacterium tuberculosis, non-tuberculosis mycobacteria, MDR-TB strains and other pathogens. Development is directed to the search of new agents that interact predominantly by a new/different mechanism of action. We are seeking for a new inhibitors of specific mycobacterial enzymes (drug targeting), modelling of new active forms of molecules and prodrug forms (esters, carbamates, sulfonates, carbonates, phosphates and others).

In collaboration with Prof. S. Bősze and her research group of peptide chemistry, (Hungarian Academy of Sciences – Eötvös Loránd University, Budapest), we will devote the most effective derivatives connecting to a specific carrier and selective targeting to macrophages. With the group of Prof. S. Polanc (University of Ljubljana, Slovenia) we are cooperating in the preparation of mutual prodrugs and isosters of active molecules.

In the field of microbiological evaluation we continue to work with the workplace in the Czech Republic, especially Department of Bacteriology and Mycology, Laboratory for mycobacterial diagnostics and TB, Institute of Public Health in Ostrava, with Dr. J. Stolaříková and Department of Clinical Microbiology, Faculty of Medicine and University Hospital, Charles University, Hradec Králové, headed by Assoc. Prof. V. Buchta. At the Faculty of Pharmacy, Charles University has run collaboration with the Department of Biochemical Sciences, namely with Dr. E. Novotná and the head of the department, Prof. V. Wsól. They launched isolation and testing of some selected mycobacterial enzymes (e.g. ICL). A group of Assoc. Prof. F. Trejtnar from the Department of Pharmacology and Toxicology performs in vitro evaluation and characterization of toxicities. In further evaluation of antibacterial activity and antifungal activity of our prepared compounds we cooperate with Assoc. Prof.  V. Buchta, Dr. M. Vejsová and I. Dufková from the Department of Biological and Medical Sciences.

Additionally, in the targeting of mycobacterial enzymes, we cooperate in the field of MetAP enzyme testing with Prof. Jun O. Liu (Department of Pharmacology and Molecular Sciences, John Hopkins School of Medicine, Baltimore, MD, USA) and other kinds of bacterial enzymes with Prof. D. Sriram (Birla Institute of Technology & Science-Pilani, Hyderabad, India).

The goal of our research is summarized in the scheme:

We are developing potential antibacterial and antifungal drugs and prodrugs that can deliver the agents to the site of the therapeutic action, increase the drug bio-availability and selectivity of the therapeutic action, and overcome various problems associated with the oral administration and cell membrane permeability.

The synthesized compounds are based on the following general structures:

Salicylanilides