Bioorganic & Medicinal Chemistry Letters 17 (2007) 2811–2816
Phosphonoxins: Rational design and discovery
of a potent nucleotide anti-Giardia agent
Dae-Hwan Suk,a Dominik Rejman,a,b Christine C. Dykstra,c Radek Pohl,b
Krzysztof W. Pankiewicza and Steven E. Pattersona,*
aCenter for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA
bIOCB, Academy of Sciences of the Czech Republic Flemingovo nam 2, 166, 10 Prague 6, Czech Republic
cDepartment of Pathobiology, Auburn University, Auburn, AL 36832, USA
Received 17 January 2007; revised 19 February 2007; accepted 22 February 2007
Available online 25 February 2007
Abstract—Phosphonoxins, a new class of synthetic, rationally designed anti-microbial agents, are described. From this class a sub-
micromolar inhibitor of Giardia trophozoite growth has been identified.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Protozoa are one of the more common causes of infec-
tions and illness in humans and animals worldwide.1,2
For example, an estimated 1 billion humans are infected
with Toxoplasma gondii.3 Specifically, infections caused
by the flagellated protozoan Giardia are widespread.
Yearly, there is an estimated 100 million cases of giardi-
asis worldwide and Giardia is the most commonly diag-
nosed waterborne cause of diarrhea in the United
States.4 Giardia is also commonly found in livestock
and many mammals may serve as important reservoirs
capable of transmitting disease to humans.5–9 To date
widely effective treatment, broad-spectrum anti-micro-
bial agents for prophylaxis, or effective vaccines for these
pathogens are not available.10,11 In addition, clinical
resistance has been reported for current anti-protozoals,
including cases where both metronidazole and albend-
azole failed in treatment of giardiasis.9–12 Diseases
caused by protozoans are therefore a worldwide risk to
the health of humans and animals.
the environment where they can infect another host.
Giardia cysts are highly infective and exceptionally well
adapted for survival in, and dissemination by, water.
They are difficult to detect and are resistant to com-
mon treatments such as chlorine and ozone. These
adaptations further complicate treatment of Giardia
infections.1,2,4
While differing protozoal species have quite different life
cycles the environmentally resistant and infective cyst is
common to many protozoans.13,14 Because encystation
appears to occur in response to unfavorable growth con-
ditions, it is highly likely that prevention of cyst forma-
tion would be fatal.15 However, unlike bacterial cell wall
synthesis protozoal cyst wall synthesis has not been well
exploited as a drug target.16
While protozoal cyst walls are not as fully character-
ized as cell walls in other organisms, it is known that
some, e.g., Giardia, Entamoeba, and Toxoplasma, con-
tain chitin or a chitin-like polysaccharide.3,15–19 Recent
description of enzyme activity termed cyst wall syn-
thase (CWS) in Giardia17 inspired our discovery of a
micromolar inhibitor of Giardia trophozoite growth.20
We report here design, synthesis, and activity of a po-
tent and non-toxic second generation anti-giardial
agent that was designed as an inhibitor of CWS. Be-
cause these agents bear passing resemblance to polyox-
ins21 we have termed these new synthetic agents
phosphonoxins.
Giardia species have two major stages in their life cy-
cles. The trophozoite stage is the vegetative form that
replicates in the small intestine of its host causing diar-
rhea and symptoms of malabsorption. Upon exposure
to biliary fluid some trophozoites differentiate to the
encysted form. The cysts are passed in feces, and enter
Keywords: Giardia; Encystation; Cyst wall synthase; Nucleotide.
*
Corresponding author. Tel.: +1 612 625 7962; e-mail:
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.02.063