"Hit-to-lead" optimization and biological characterization of novel anti-mycobacterials.

This DOCPRO1-project is intended to supplement the three year fellowship of Maciej Rogacki, a Marie Curie PhD fellow in the ITN-EID project "OpenMedChem". "OpenMedChem" is an open innovation collaboration between the laboratory of Medicinal Chemistry at UA and the R&D-site of Glaxo-Smith-Kline in Tres Cantos (Spain). OpenMedChem focuses on discovery of novel anti-tuberculosis (TB) drug candidates. Despite the existence of treatments for TB, the threat it represents is still a painful reality for the nearly nine million people infected, and the one and a half million that die, each year. The disease also represents an escalating threat for global health, with the increasing prevalence of Multi Drug Resistant (MDR) TB strains that are resistant to at least the two main first-line TB drugs - isoniazid and rifampicin - and Extremely Drug Resistant (XDR) TB strains that are also resistant to three or more of the six classes of second-line drugs.In an unprecedented move in line with the Open Innovation paradigm, GSK has shared with the University of Antwerp, its anti-mycobacterial High-Throughput-Screening data of over 2 million druglike compounds. Initial research in this project consisted of a bioinformatics compound clustering into families with promising antitubercular properties. The most interesting families were subsequently investigated further in depth. Maciej Rogacki first investigated chemical space around a class of (pyridin-2-yl)azahetarylamines. Scaffold hopping and decoration resulted in novel compounds with nanomolar antimycobacterial potency (MIC). Nonetheless, toxicity issues were decisive to leave this class of molecules. As an alternative, Maciej is currently working on a class of hydantoin antitubercular compounds that have been identified by GSK as inhibitors of decaprenyl-phosphoryl-d-ribose oxidase (DprE1), a validated mycobacterial drug target. Research during the running time of the DOCPRO1-project would aim at continuing the in-depth structural exploration of this class of hydantoins. New Scaffold Hopping strategies will also be investigated to evaluate how the central hydantoin building block in these compounds can be replaced.

Keywords:TUBERCULOSIS, MEDICINAL CHEMISTRY, ANTIBIOTICS

Disciplines:Organic chemistry, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences