Cyclophostin and Cyclipostins Phosphonate Analogs as Potent Inhibitors of Microbial Lipases:
New Potential Antituberculous Compounds?
J.-F. Cavalier a, V. Point a, R. K. Malla b, V. Delorme a,c, F. Carrière a, P. Brodin c, 
S. Canaan a and C. D. Spilling b
a CNRS – Aix-Marseille Université – EIPL – UMR 7282, Marseille, France
b Department of Chemistry and Biochemistry, University of Missouri-St. Louis, USA
c CIIL, INSERM U1019 – CNRS UMR 8204, Lille, France

It is now acknowledged that microbial lipolytic enzymes are involved in bacterial growth, cell wall biosynthesis, carbon sources management and virulence during infections by M. tuberculosis, the causative agent of Tuberculosis. Although lipolytic enzymes are also present in host cells, preliminary results have clearly shown that mycobacterial enzymes may be considered as possible therapeutic targets. Consequently, specific inhibitors of such enzymes might turn out to be valuable anti-tuberculosis agents. 
In this exiting and very competitive context, new series of customizable diastereomeric trans-(α) and cis-(β) enolphosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition towards several lipases from M. tuberculosis were examined. Best inhibitors displayed a cis conformation and exhibited higher inhibitory activities than the lipase inhibitor Orlistat towards same enzymes. Our results have revealed that chemical group at the γ carbon of the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in specificity toward a target lipase over another. More interestingly, this family of lipase inhibitors was found to display promising anti-mycobacterial activities on M. tuberculosis with similar or even higher activities (IC50) towards intramacrophagic bacilli than first line antibiotics Rifampin, Ethionamide or Isoniazid. Furthermore, our compounds did not exhibit cytotoxicity effects on macrophages. 
The powerful and selective inhibition of mycobacterial lipases suggests that these enolphosphonates should provide useful leads for the development of novel, more selective and powerful antimicrobial agents.

[1]	V. Point et al., J. Med. Chem. 2012, 55, 10204-10219.
[2]	V. Point et al., J. Med. Chem. 2013, 56, 4393-4401.