Hit-to lead and lead optimization approaches in Mycobacterium tuberculosis drug-discovery.

This DOCPRO1-project is intended to supplement the three year fellowship of Olga Balabon, a Marie Curie PhD fellow in the ITN-EID network "OpenMedChem". OpenMedChem project is open innovation collaboration between the laboratory of Medicinal Chemistry at UA and a major industrial Research&Development unit of GlaxoSmithKline (GSK I+D, Tres Cantos, Spain). OpenMedChem focuses on discovery of novel anti-tuberculosis drug candidates. Despite the existence of treatments for tuberculosis (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, which are resistant to at least the two main first-line TB drugs - isoniazid and rifampicin - and extensively-drug resistant (XDR) TB 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 shared with the University of Antwerp its anti-mycobacterial High-Throughput-Screening (HTS) campaign results of over 2 million druglike compounds tested against M.tb. Initial research in this project consisted of a bioinformatics compound clustering into families with promising antitubercular properties. The most promising families were selected for further investigation within the project. Fellow Olga Balabon started with investigating chemical space around a class dihydrotriazines, containing a typical dihydrofolate reductase pharmacophore. Scaffold hopping and decoration delivered a substantial set of novel compounds. Nonetheless, cytotoxicity issues and limitations were decisive to abandon this class of molecules. Instead, Olga is currently working on a class of hydantoin antitubercular compounds that have been identified by GSK as inhibitors of the mycobacterial target decaprenyl-phosphoryl-d-ribose oxidase (DprE1). DprE1 is a recently validated promising mycobacterial drug target. The research during the running time of the DOCPRO1-project aims at in-depth SAR investigation of the substitution pattern on the hydantoin-based DprE1 inhibitors. In addition, a series of hydantoin analogues containing a central pyrrolidine ring, will be explored. Finally, hybrid compounds will be synthesized that consist of complementary fragments of the hydantoin-based DprE1 inhibitors and a previously reported very potent inhibitor (TCA1).

Keywords:MYCOBACTERIOLOGY, CELL WALL ENZYMES, MEDICINAL CHEMISTRY, ENZYME INHIBITORS

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