Abstrakt
Pyrazinamide (PZA) is a cornerstone drug of current TB therapy and emerged as an important building block for regimens with promise to shorten TB treatment. PZA is a prodrug which must be activated by the M. tuberculosis enzyme pyrazinamidase within the bacterium in order to exert its antitubercular activity.
The project was focused on discovery of PZA analogues with PZA-like efficiency characteristics along with improved potency and increased safety. The main task was search for new antimycobacterial pyrazines - structure analogues of PZA.
In summary, 115 compounds were synthesized and screened for their antimycobacterial activity in the project. Chemical synthesis was followed by structure confirmation, experimental lipophilicity determination (log k) and theoretical lipophilicity calculation (log P).
Biological evaluation comprised of antimycobacterial activity screening as the main task. This biological part of the project was successfully implemented in co-operation between TAACF, Southern Research Institute, Birmingham, USA, and the Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Czech Republic, in years 1996-2009.
The most active compounds are presented (see Tables 1-4) and discussed. Several very potent compounds (1-4, 92, 93) were discovered.
The compounds relieved into level 2 testing underwent MIC and CC50 determination followed by Selectivity Index calculation (SI, ratio of measured CC50 to MIC). To be relieved to level 3 (in vivo screening) the compound had to exhibit SI>10.
Only one of the presented structures, N-[3-(trifluoromethyl)phenyl]pyrazine-2-carboxamide (1) was relieved to level 3. The in vivo screening of compound 1 was not finished yet.
The results of this project could be a very good starting point for the advanced drug design and development of new antituberculous agents based on pyrazine.