Violeta Mangalagiu
Alexandru Ioan Cuza University
Title: Azaheterocycles with antimycobacterial activity
Biography
Biography: Violeta Mangalagiu
Abstract
Despite the progress achieved by modern medicinal science in tuberculosis (TB) therapy, TB remains seriously life-threatening disease among humans, annually being registered about 9 (nine) million new cases and about 1.5 million people are dying from TB. Severely infectious caused by Mycobacterium tuberculosis (Mtb), have substantially increased over the last few years mostly due to development of drug resistance TB, Multi-Drug Resistant (MDR) TB, Extensively Drug Resistant (XDR) TB and association with human immunodeficiency virus (HIV). Therefore, the search for new antituberculous drugs active against Mtb remains one of the priority tasks of medicinal chemistry. Nitrogen heterocyclic compounds, especially five and six member rings derivatives, represent the most effective and administered class of drugs in TB therapy.
As part of our ongoing research aiming the design and synthesis of novel anti-TB derivatives with azaheterocycles skeleton, we report here the design, synthesis, structure and in vitro antimycobacterial activity of new six membered ring with azaheterocyclic skeleton. The synthesis of compounds was straight and efficient, and the antimycobacterial activity against Mtb was evaluated, some of the compounds showing a very good to excellent anti-TB activity. SAR correlations have been done. The most active compounds passed the second stage of anti-TB testing, the assay demonstrating that our compounds are potent against both replicating and non-replicating Mtb, have a bactericidal mechanism of action, are active against drug-resistant Mtb strains, present a moderate to good activity against nontuberculous mycobacteria, a good intracellular activity, and a moderate to low cytotoxicity. For the most promising compounds with anti-TB profile, a complete absorption, distribution, metabolism, excretion and toxicity (ADMET) study has been performed (including Plasma Protein Binding, Caco-2 Permeability, Cytochrome P450 Inhibition and in vitro Microsomal Stability studies), the results beeing very promising.