Bioorganic & Medicinal Chemistry Letters
Triazoxins: Novel nucleosides with anti-Giardia activity
Praveen K. Pogula , Atasi De Chatterjee , Miguel Chi , Harrison W. VanKoten , Siddhartha Dasb,⁎,
a
b
b
a
a,⁎
Steven E. Patterson
a
Center for Drug Design, College of Pharmacy, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, United States
b
Department of Biological Sciences, University of Texas at El Paso, El Paso, TX 79968-0519, United States
A R T I C L E I N F O
A B S T R A C T
Keywords:
Giardia
Novel nucleoside analogues named “triazoxins” were synthesized. Of these, two analogues were found to be
highly effective against Giardia lamblia, an intestinal parasite and a major cause of waterborne infection,
worldwide. While compound 7 reduced the growth of trophozoites in culture (IC50, ~5 μM), compound 21
Trophozoite
Cyst
blocked the in vitro cyst production (IC50 ~5 μM). Compound 21 was also effective against trophozoites (IC50
,
,
Phosphonoxin
Triazoxin
Anti-giardiasis
~
36 μM). A third analogue (compound 8) was effective against both trophozoites (IC50, ~36 μM) and cysts (IC50
~
20 μM) although at higher concentration. Thus triazoxin analogues are unique and exhibit morphology (i.e.,
trohozoites or cysts) -specific effects against Giardia.
Giardia lamblia is a dimorphic intestinal protozoan responsible for
designed to be analogues of the putative UDP-GalNAc substrate tran-
sition state. Because these agents are nucleoside-phosphonates that bear
passing similarity to polyoxins we named them phosphonoxins. To date
our most potent anti-giardial phosphonoxin has EC50 of 0.48 μM against
1
waterborne illness or “giardiasis” worldwide. The symptoms of giar-
diasis include diarrhea, irritable bowel syndrome (IBS), indigestion,
weight loss, malabsorption and gastric pain. Giardiasis is endemic in
developing nations and children below five years old are especially
vulnerable to the infection. Children with giardiasis frequently suffer
6
–9
trophozoite growth (cf. metronidazole EC50 = 5.2 μM).
Here we synthesized a novel series of phosphonoxin-like agents with
anti-giardial activity, where the phosphonate moiety was replaced with
a triazole moiety. Because these novel compounds contain a triazole
moiety, we have named the resulting agents triazoxins. Our inspiration
for this series of novel agents was influenced in part by our previous
work with polyoxin analogues along with that of Finney and colleagues
who have reported a series of uridine dimers with modest activity
2
,3
from malnutrition, stunted growth and a failure to thrive.
Giardia
exists in two morphologic forms that are: a vibrant and replicative
trophozoite, and a relatively dormant but infective cyst. Exposure of
water-resistant cysts to gastric acid during passage through the human
stomach triggers excystation (i.e., transformation of cysts to tropho-
zoites) and the emerging trophozoites colonize the intestinal tract.
Factors such as bile, dietary lipids and slightly higher pH (~pH 7.8) in
the duodenum and jejunum portion of the small intestine trigger en-
cystation (e.g., morphological differentiation from trophozoites to
cysts). The newly formed cysts are excreted in feces and infect a new
1
0,11
against chitin synthase.
The target molecules were synthesized from key intermediate 3
1
2
(Scheme 1) prepared from uridine via a standard method to give 2.
The resulting acetonide was treated with tosyl chloride in pyridine and
reaction of the resulting 5′-tosylate with lithium azide gave modified
4
host (reviewed by Das et al. 2002). Although metronidazole (a ni-
1
3
troimidazole class drug) is generally prescribed to treat giardiasis in
humans, reports of treatment failures and the occurrence of me-
tronidazole-resistant giardiasis are alarmingly common. Reports of
treatment failures have approached 40% and multi-drug resistant
uridine 3. The triazole 4 was synthesized using the copper-catalyzed
14
azide-alkyne “click” cycloaddition of azide 3 with propargyl alcohol.
Swern oxidation of hydroxymethyl triazole 4 gave the corresponding
aldehyde 5 that was converted to its corresponding alkyne via the
2
3
15
giardiasis has been described.
Ohira-Bestmann modified Seyferth-Gilbert homologation. Sonoga-
Giardia must encyst to complete its life cycle making the cyst en-
shira coupling of the resulting alkyne with 5-iodorouracil followed by
removal of the acetonide protecting group gave the target molecule 8.
Catalytic hydrogenation of 7 followed by removal of the acetonide gave
the modified uridine 9.
5
velope an extremely attractive drug target. Because the chitin-like β-1-
3
-linked poly(N-acetylgalactosamine) [poly(GalNAc)] is a major com-
ponent of the cyst wall we have previously synthesized a novel class of
compounds that are potent inhibitors of Giardia trophozoite growth
The dimeric uridines 12 and 13 (Scheme 2) were prepared by
⁎
Received 5 February 2020; Received in revised form 5 April 2020; Accepted 6 April 2020
Available online 07 April 2020
0960-894X/ © 2020 Elsevier Ltd. All rights reserved.