Topic

This research topic concerns in silico approach design and the synthesis of non-natural heterocyclic systems for their potential activity on biological targets identified by the team or partners.

Research focus and main results

 
  • Potential inhibitors of the enzymatic pathways involved in the FAS II system - Development of anti-TB drugs. (contact: Mr Baltas, Ch. Lherbet)

From the X-Ray structure of InhA co-crystallized with triclosan and GEQ, two active compounds, we have designed and studied two major families of derivatives:
a) triazole nucleus analogues of triclosan
         
About 60 "simple" and α-carbonyl triazoles were synthesized by Huisgen 1,3-dipolar cycloaddition assisted by copper. During the synthesis of α-ketotriazoles, we have demonstrated the formation of the corresponding α, β-diketotriazole. α-ketotriazoles and α, β-diketetriazoles have no inhibitory activity on InhA (overexpressed protein, produced and purified in the laboratory). However, "simple" triazoles exhibit InhA inhibition up to 75% at 50 μM.
 
b) fluorene derivatives with succinimide, pyrrolidinone or pyrrolidine units, analogs of GEQ.
  • Design and synthesis of GIP receptor ligands (GIPR) as therapeutic and diagnostic tools. (contact: Michel Baltas, Joelle Azema-Despeyroux)

The primary role of GIP (Glucose-dependent Insulinotropic Peptide) is to regulate, by activation of its G protein-coupled receptor, carbohydrate and lipid homeostasis. GIP stimulates lipogenesis, improves the absorption of fatty acids and can therefore potentially increase adiposity. As GIPR is overexpressed by some cancer cells, it represents a potential therapeutic and diagnostic target. To date, there are no synthetic GIPR ligands that can be used in vivo to block, stimulate or detect it. Various synthetic GIP receptor ligands were designed and synthesized by combining "rational drug design" and "fragment-based drug design" around the molecular scaffold "6-fluoro-4-oxo-1,4-dihydro-quinolone ". Indeed, the quinolone part represents one of the most common structures in the search for medicinal molecules with many applications as antibacterial agents, antituberculous agents, antiproliferative agents, anticancer agents, antagonists or agonists of transmembrane receptors.
Some of these quinolone derivatives are also active against the Herpes virus by reducing 10-fold  the infection rate by the virus.
 

Main publications

Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth.
Aurélien Chollet, G. Mori, Ch. Menendez, F. Rodriguez, I. Fabing,  M.R. Pasca,  J. Madacki,  J. Kordul, P. Constant, A. Quémard, V. Bernardes-Génisson, Ch. Lherbet, M. Baltas. Eur. J. Med. Chem, 2015, 101, 218-235.
Distinct CCK-2 Receptor Conformations Associated with β-Arrestin-2 Recruitment or Phospholipase-C Activation Revealed by a Biased Antagonist.
R. Magnan, Ch. Escrieut, V. Gigoux, K. De, Pascal Clerc, Fan Niu, Joelle Azema, Bernard Masri, Arnau Cordomi, Michel Baltas, Irina G. Tikhonova, and Daniel Fourmy. J. Am. Chem. Soc., 2013, 135, 2560–2573.