Recently, we have synthesized  a group of FMDP amides displaying good inhibitory properties against  glucosamine-6-phosphate synthase,  an important enzyme in the biosynthetic pathway of cell - wall  macromolecules.These amides also exerted reasonable good antifungal activity.  To extend our studies we have decided to obtain a new group of FMDP  derivatives containing   amides of glycolic and lactic acids.

In our communication  we present  the  synthesis of FMDP conjugates with amides of glycolic and lactic acid (Figure 1) and their antifungal activity.

R₁=H, CH₃; R₂ = NH₂,NHCH₃, N(CH₃)₂

 Figure 1: Structure of new derivatives of FMDP. 

FMDP is one of the specific inhibitors of enzyme glucosamine-6-phospate (GlcN-6-P)  syntase, a potential molecular target for antimicrobial therapy.¹ This enzyme is involved in the biosynthesis of amino sugars building  cell wall in microbial cells and its inhibition leads to cell lysis. FMDP is the most potent inhibitor of enzyme, however, this molecule displayed  a weak activity in antimicrobial tests.² The polar structure of inhibitor makes free diffusion  through the cell membrane difficult.

An example of the use of amide of a-hydroxy acids (AHAs)  as drug carriers is using the nanoparticles made ​​of copolymers of lactic and glycolic acid.³ Furthermore, amides of glycolic and lactic acids associated with biologically active compounds take on a properties of the prodrug.⁴

The novel FMDP derivatives with glycolamides and lactamides increased the lipophilicity this molecule and may be a chance to find new effective antimicrobial chemoterapeutic agent.

References:

[1] Milewski S., Biochim. Biophys. Acta, 2002, 1597, 173-192.

[2]  Andruszkiewicz R, et al., J. Enzyme Inhib. Med. Chem., 2005; 20, 115-21

[3] Cheng J.,  et al., Biomaterials, 2007, 28, 869–76.

[4] Kumar L., Int. J. Pharm., 1995, 118, 31–39.

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