Miscellaneous

Design and synthesis of novel heteroarylpyridinones as potential antibacterial agents

(Pr. Nadia Walchshofer, Dr. Sylvie Radix, Dr. Luc Rocheblave)

The emerging problem of antibiotic resistance is a serious threat which is becoming increasingly important (1). In the meantime, the situation is aggravated by a substantial decline in the research and development of new antibacterial agents (2), principally for economic reasons. However, these health concerns have aroused much interest regarding the identification of new therapeutic targets to treat infectious diseases.
Our research project is in keeping with the aim of designing and synthesizing more powerful antibacterial agents I (quinolone analogs) with a central core consisting of a heteroarylpyridinone nucleus which can be substituted in different positions (R, R1, R2) to allow the introduction of side chains.

Structure I


In this research, we have recently developed the synthesis of imidazo[4,5-b]pyridin-7-one derivatives (3,4) which are already known to possess versatile biological activity (5) (antiviral, cytostatic, antimicrobial, fungicidal, cardiovascular, antisecretory and other functions).

imidazopyridinone


Then, in vitro evaluation of the antibacterial activity of the derivatives I against Gram positive and Gram negative bacteria will be performed.

(1) L. Diaz Högberg, A. Heddini, O. Cars Trends Pharmacol. Sci. 2010, 31, 509-515.
(2) S.J. Projan Curr. Opin. Microbiol. 2003, 6, 427-430.
(3) W. Zeinyeh, H. Xia, P. Lawton, S. Radix, C. Marminon, P. Nebois, N. Walchshofer Eur. J. Med. Chem. 2010, 45, 2480-2488.
(4) W. Zeinyeh, J. Pilmé, S. Radix, N. Walchshofer Tetrahedron Lett. 2009, 50, 1828-1833.
(5) Y. M. Yutilov Heterocycl. Chem. 2005, 89, 159-270 and references therein.

Cinnamides derivatives as Efflux Pump Inhibitors to overcome bacterial Multi-Drug Resistance

(Pr. Nadia Walchshofer, Dr. Sylvie Radix, Dr. Luc Rocheblave)

The emerging problem of antibiotic resistance is a serious threat which is becoming increasingly important (1). In the meantime, the situation is aggravated by a substantial decline in the research and development of new antibacterial agent (2), principally for economic reasons.

A novel and promising strategy to overcome bacterial multi-drug resistance (MDR) is to improve the clinical performance of various antibiotics by employing efflux pump inhibitors (EPIs) (3). The use of EPIs as adjuvants in antibacterial therapy could restore antibiotic activity of classical drugs in resistant strains (4). On the one hand, extract from leaves and stems of Mirabilis jalapa led to the isolation of an active phenolic compound 1 as EPI against Staphylococcus aureus MDR (5). On the other hand, citral derived amides 2 are also potent bacterial NorA efflux pump inhibitors (6). So, we decided to develop cinnamides derivatives as potential EPIs since acrylamide group, present in natural and synthetic compounds (1 and 2), seems to be a very interesting moiety.

Cinnamides

(1) L Diaz Högberg, A Heddini, O Cars. “The global need for effective antibiotics: challenges and recent advances”. Trends Pharmacol. Sci. 2010, 31, 509-515.
(2) SJ Projan « Why is big Pharma getting out of antibacterial discovery” Curr. Opin. Microbiol. 2003, 6, 427-430.
(3) F Van Bambeke, JM Pages, VJ Lee “Inhibitors of bacterial efflux pumps as adjuvants in antibacterial therapy and diagnostic tools for detection of resistance by efflux”. Frontiersin anti-infect Drug Discov, 2010, 1, 1-37.
(4) O lomovskaya, KA Bostian, “Practical applications and feasibility of efflux pump inhibitors in the clinic – A vision for applied use” Biochem. Pharmacol. 2006, 71, 910-918.
(5) S Michalet et al, “N-Caffeoylphenalkylamide derivatives as bacterial efflux pump inhibitors”. Bioorg. Med. Chem. Lett. 2007, 17, 1755.1758.
(6) N Thota et al. “Citral derived amides as potent bacterial NorA efflux pump inhibitors ». Bioorg. Med. Chem. 2008, 16, 6535-6543.
 

Analysis of potential impurities and metabolites of Active Pharmaceutical Ingredients (API)

Acquisition - with support of the Faculty of Pharmacy, Lyon - of a uHPLC-MS allowed to develop projects in close collaboration with LAGEP team (Dir. H. Fessi, UMR CNRS 5007, UCB Lyon 1 and CNRS).

One of the first developed projects is the structural determination of tetrabenazine potential impurities, an API used in treatment of dyskinesias and Huntington's disease.
 
Publications:
Agusti G, Bourgeois S, N Cartiser, Fessi H, Le Borgne M, Lomberget T. A safe and practical method for the preparation of 7α-thioether and thioester derivatives of spironolactone. Steroids. January 2013, 78 (1) :102-7.

Bourezg Z Cartiser N, Ettouati L, Guillon J, Lacoudre A, Pinaud N, Le Borgne M, Fessi H Structural elucidation of two photolytic degradation products of tetrabenazine. J Pharm Biomed Anal. 2014 January 3, 91C :138-43.