The giardicidal activity of lobendazole, fabomotizole, tenatoprazole and ipriflavone: A ligand-based virtual screening and in vitro study

Article abstract of DOI:10.1016/j.ejmech.2020.113110

A ligand-based virtual screening study to search for giardicidal compounds on a 6551 ChEMBL drugs database was carried out using molecular similarity. Three fingerprints implemented in MayaChemTools with different design and validated by ROC curves, were used. Twelve compounds were retrieved from this screening, from which, four representative compounds were selected to carry out biological assays. Whereas two compounds were commercially available, the additional two compounds were synthesized during the development of this work. The biological assays revealed that the compounds possess in vitro activity against five strains of Giardia intestinalis, each with different susceptibility/resistance rates to metronidazole, albendazole and nitazoxanide. Particularly, tenatoprazole showed the best effect against the WB and IMSS strains. Furthermore, fabomotizole, tenatoprazole and ipriflavone showed a higher activity against resistant strains than the reference drugs: metronidazole, albendazole and nitazoxanide.

Full text of DOI:10.1016/j.ejmech.2020.113110

Journal of the Formosan Medical Association (2016) 115, 591e592
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PERSPECTIVES
Pentoxifylline: Evidence strong enough
for renoprotection?
Tai-Shuan Lai a, Wen-Chih Chiang b, Yung-Ming Chen b,
*
a Department of Internal Medicine, National Taiwan University Hospital, Bei-Hu Branch, Taipei,
Taiwan, ROC
b Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, ROC
Received 3 December 2015; accepted 23 December 2015
Pentoxifylline is a methylxanthine derivative and nonse-
lective phosphodiesterase inhibitor that has been widely
used for improving peripheral and cerebral vascular
microcirculation. In addition to its hemorheologic activity,
laboratory evidence has shown that pentoxifylline provides
antiproliferative and anti-inflammatory effects that are
organoprotective. Since Professor Tsai proposed in 1995
that pentoxifylline may have a potential to delay the pro-
gression of chronic glomerulopathy associated with
mesangial proliferation, we have become one of the lead-
ing groups investigating the renoprotective effect of pen-
toxifylline in both experimental and clinical fields.1 We
demonstrated beneficial effects of pentoxifylline in atten-
uating proteinuria and glomerulosclerosis in different ani-
mal models of renal diseases, including rasts with anti-Thy1
nephritis, crescentic glomerulonephritis, and remnant kid-
ney.2 Mechanistically, we proved that pentoxifylline sup-
presses the increased expression of tumor necrosis factor a,
intercellular adhesion molecule-1, monocyte chemo-
attractant protein-1, and osteopontin. In addition to anti-
proliferative effect, these anti-inflammatory actions are
associated with reduction of proteinuria and attenuation of
glomerular crescents, sclerosis, and interstitial fibrosis.
Moreover, we recently demonstrated that pentoxifylline
can attenuate the evolution of tumor necrosis factor a and
transforming growth factor b/activin pathways underlying
the pathogenetic mechanisms of proteinuria via down-
regulation of nuclear factor k-light-chain-enhancer of
activated B cells (NF-kB) and Smad signals and restoration
of the podocyte component of the glomerular filtration
barrier.3
In the clinical aspect, although meta-analysis or sys-
tematic reviews suggested that pentoxifylline might
decrease proteinuria in patients with diabetic nephropathy,
the low quality and high heterogeneity of the included
studies made the pooled results unconvincing. Subsequent
studies in diabetic nephropathy with overt proteinuria,
including a recent Korean 174-patient randomized trial,
have shown a significant greater reduction of proteinuria in
the pentoxifylline group than in the control group.4 How-
ever, studies examining the antiproteinuric effect of pen-
toxifylline in type 2 diabetes patients with microalbuminuria
showed conflicting results.
Although proteinuria is a cardinal feature predictive of
renal impairment and advanced renal outcome, the meta-
analysis and subsequent studies did not show any significant
changes in the glomerular filtration rate (GFR) between
pentoxifylline and control groups until the PREDIAN trial, an
open-labeled randomized controlled trial investigating the
renoprotective effects of pentoxifylline in addition to
renineangiotensin system (RAS) blockade, in patients with
diabetic kidney disease.5 After 24 months of follow-up, a
significant mean difference of 4.3 mL/min/1.73 m2 was
shown in the reduction of estimated GFR (eGFR) between
the two groups. The difference in the reduction of eGFR
between the groups reached statistical significance after
Conflicts of interest: The authors have no conflicts of interest
relevant to this article.
* Corresponding author. Department of Internal Medicine, National
Taiwan University Hospital, Yun-Lin Branch, College of Medicine,
National Taiwan University, Taipei, Taiwan, ROC.
E-mail address: chenym@ntuh.gov.tw (Y.-M. Chen).
http://dx.doi.org/10.1016/j.jfma.2015.12.010
0929-6646/Copyright ª 2016, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

592
T.-S. Lai et al.
1 year, suggesting that a long period of pentoxifylline
treatment is necessary to retard the renal function pro-
gression. The study was limited by its single-center enroll-
ment without double-blind, placebo-controlled design.
Nonetheless, it provided promising evidence that pentox-
ifylline is beneficial with RAS blockade in patients with type
2 diabetes mellitus and stage 3 or 4 chronic kidney disease
(CKD).
pentoxifylline treatment on GFR, a recent study did prove
that long period of pentoxifylline use in addition to RAS
blockades might retard renal function progression in pa-
tients with diabetes and advanced CKD. The antiproteinuric
effect of pentoxifylline and its ability to slow renal function
progression remained debated in nondiabetic kidney dis-
ease. Studies examining the effect of pentoxifylline use on
creatinine doubling, incidence of ESRD, and mortality are
still lacking. Large-scale, high-quality, and multicenter
randomized trial investigating hard endpoints of renal
outcome are still warranted, either for diabetic or nondi-
abetic CKD.
Until now, there have been no clinical trials examining
the protective effect of pentoxifylline on renal outcome or
mortality. We recently conducted a single-center retro-
spective study and demonstrated that the use of pentox-
ifylline in patients with stage 3be5 CKD decreased the
hazard of end-stage renal disease (ESRD) (hazard ratio,
0.71; 95% confidence interval, 0.50e1.00; p Z 0.048).6 The
effect was more prominent in the higher proteinuria group.
In the nationwide population-based study using Taiwan
health insurance data, we further explored the effect of
pentoxifylline on the development of ESRD and mortality
among patients with predialysis stage 5 CKD.7 After multi-
variable adjustment, pentoxifylline use had a 36% reduction
of hazard on developing ESRD (hazard ratio, 0.64; 95%
confidence interval, 060e0.68; p < 0.001), regardless of
RAS blockade use. The study also demonstrated a dos-
eeresponse relationship of pentoxifylline on the initiation
of long-term dialysis. The study based on a claim database
and the definition of stage 5 CKD identified by the Inter-
national Classification of Diseases, 9th Revision, CKD code
plus drug codes for erythropoiesis-stimulating agents were
the major limitations.
There are only a few clinical trials focusing on nondia-
betic CKD. In 2008, we conducted a randomized controlled
trial evaluating the additional effect of pentoxifylline
adding on losartan in 85 patients with stage 3e5 CKD, of
whom 71% were nondiabetic. Pentoxifylline for 1 year
added to losartan therapy decreased proteinuria signifi-
cantly, but no notable change was seen in eGFR.8 The study
is limited by its small sample size, single-center enroll-
ment, and short follow-up time.
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In conclusion, evidence that pentoxifylline reduces
proteinuria in diabetic kidney disease is robust in the overt
proteinuria stage but vague in the microalbuminuria stage.
Although most previous studies did not show the effect of