Pyrazine Derivatives as Potential Antituberculosis Drugs II.

Charles Univeristy in Prague, Faculty of Pharmacy in Hradec Králové Department Department of Pharmaceutical Chemistry and Drug Control Author: Marek Tauchman Supervisor: Prof. PharmDr. Martin Doležal, Ph.D. Title of Diploma Thesis: Pyrazine Derivatives as Potential Antituberculosis Drugs II. Tuberculosis still presents serious worldwide problem of today. The situation is complicated especially by increasing proportion of strains resistant to common antituberculotics. Therefore the need of a new compound active against mycobacterial causer of the disease is very actual. Synthesis of compounds derived from pyrazinamide, very effecitve anti-mycobacterial substance, is one of the perspective way of new drugs development. Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy in Hradec Králové, beside others, deals with this problem in a long term. There were synthesized hundreds of compounds containing pyrazine core and they were tested to antimycobacterial activity. The target of this thesis is join this effort and contribute to increase the number of compound that has been studied for antituberculosis activity. At the beginning of thesis, there is a summary of facts about tuberculosis, such as incidence, patogenesis and cure. Next, there are informations about newly developed..

Synthesis of Novel Pyrazinamide Derivatives Based on 3-Chloropyrazine-2-carboxamide and Their Antimicrobial Evaluation

Aminodehalogenation of 3-chloropyrazine-2-carboxamide with variously substituted benzylamines yielded a series of fifteen 3-benzylaminopyrazine-2-carboxamides. Four compounds possessed in vitro whole cell activity against Mycobacterium tuberculosis H37Rv that was at least equivalent to that of the standard pyrazinamide. MIC values ranged from 6 to 42 μM. The best MIC (6 μM) was displayed by 3-[(4-methylbenzyl)amino]pyrazine-2-carboxamide (8) that also showed low cytotoxicity in the HepG2 cell line (IC50 ≥ 250 μM). Only moderate activity against Enterococcus faecalis and Staphylococcus aureus was observed. No activity was detected against any of tested fungal strains. Molecular docking with mycobacterial enoyl-ACP reductase (InhA) was performed to investigate the possible target of the prepared compounds. Active compounds shared common binding interactions of known InhAinhibitors. Antimycobacterial activity of the title compounds was compared to the previously published benzylamino-substituted pyrazines with differing substitution on the pyrazine core (carbonitrile moiety). The title series possessed comparable activity and lower cytotoxicity than molecules containing a carbonitrile group on the pyrazine ring

Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and α‑Methylidene-β-Lactams

Ru-catalyzed cross-metathesis (CM) reaction between β-arylated α-methylidene-β-lactams and terminal olefins was developed. The CM reaction is effectively catalyzed with Hoveyda–Grubbs second-generation catalyst affording corresponding α-alkylidene-β-aryl-β-lactams in good isolated yields (41–83%) with exclusive <i>Z</i>-selectivity. The developed protocol was successfully applied for stereoselective preparation of Ezetimibe, the commercial cholesterol absorption inhibitor