Progress in antischistosomal N,N′-diaryl urea SAR

Article abstract of DOI:10.1016/j.bmcl.2017.12.064

N,N′-Diaryl ureas have recently emerged as a new antischistosomal chemotype. We now describe physicochemical profiling, in vitro ADME, plasma exposure, and ex vivo and in vivo activities against Schistosoma mansoni for twenty new N,N′-diaryl ureas designed primarily to increase aqueous solubility, but also to maximize structural diversity. Replacement of one of the 4-fluoro-3-trifluoromethylphenyl substructures of lead N,N′-diaryl urea 1 with azaheterocycles and benzoic acids, benzamides, or benzonitriles decreased lipophilicity, and in most cases, increased aqueous solubility. There was no clear relationship between lipophilicity and metabolic stability, although all compounds with 3-trifluoromethyl-4-pyridyl substructures were metabolically stable. N,N′-diaryl ureas containing 4-fluoro-3-trifluoromethylphenyl, 3-trifluoromethyl-4-pyridyl, 2,2-difluorobenzodioxole, or 4-benzonitrile substructures had high activity against ex vivo S. mansoni and relatively low cytotoxicity. N,N-diaryl ureas with 3-trifluoromethyl-4-pyridyl and 2,2-difluorobenzodioxole substructures had the highest exposures whereas those with 4-fluoro-3-trifluoromethylphenyl substructures had the best in vivo antischistosomal activities. There was no direct correlation between compound exposure and in vivo activity.

Full text of DOI:10.1016/j.bmcl.2017.12.064

Accepted Manuscript
Progress in Antischistosomal N,N'-Diarylurea SAR
Jianbo Wu, Chunkai Wang, Derek Leas, Mireille Vargas, Karen L. White, David
M. Shackleford, Gong Chen, Austin G. Sanford, Ryan M. Hemsley, Paul H.
Davis, Yuxiang Dong, Susan A. Charman, Jennifer Keiser, Jonathan L.
Vennerstrom
PII:
S0960-894X(17)31238-6
https://doi.org/10.1016/j.bmcl.2017.12.064
BMCL 25520
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 November 2017
27 December 2017
28 December 2017
Please cite this article as: Wu, J., Wang, C., Leas, D., Vargas, M., White, K.L., Shackleford, D.M., Chen, G., Sanford,
A.G., Hemsley, R.M., Davis, P.H., Dong, Y., Charman, S.A., Keiser, J., Vennerstrom, J.L., Progress in
Antischistosomal N,N'-Diarylurea SAR, Bioorganic & Medicinal Chemistry Letters (2017), doi: https://doi.org/
10.1016/j.bmcl.2017.12.064
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Graphical Abstract
F
Cl
Cl
Cl
F
F
N
O
O
O
F3C
N
H
N
H
CF3
N
H
N
H
Cl F3C
N
H
N
H
CF3
18
MMV665852
1
LogP 3.8, sol. 3.1-6.3 µg/mL
S. mansoni IC50 0.66 µM
S. mansoni WBR 50%
AUC0-last 1,486 µM.h
LogP 5.2, sol. <1.6 µg/mL
S. mansoni IC50 0.80 µM
S. mansoni WBR 0%
LogP 4.5, sol. <1.6 µg/mL
S. mansoni IC50 0.19 µM
S. mansoni WBR 40%
AUC0-last 394 µM.h
1

Progress in Antischistosomal N,N'-Diarylurea SAR
Jianbo Wua, Chunkai Wanga, Derek Leasa, Mireille Vargasb,c, Karen L. Whited, David M.
Shacklefordd, Gong Chend, Austin G. Sanforde, Ryan M. Hemsleye, Paul H. Davise, Yuxiang
Donga, Susan A. Charmand, Jennifer Keiserb,c, Jonathan L. Vennerstroma*
aCollege of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical
Center, Omaha, NE, United States
bDepartment of Medical Parasitology and Infection Biology, Swiss Tropical Institute,
Socinstrasse 57, CH-4002 Basel, Switzerland
cUniversity of Basel, CH-4003 Basel, Switzerland
dCentre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash
University, 381 Royal Parade, Parkville, Victoria 3052, Australia
eDepartment of Biology, University of Nebraska at Omaha, Omaha, NE, United States
tel: 402.559.5362
fax: 402.559.9543
email: jvenners@unmc.edu
Abstract
2

N,N'-diarylureas have recently emerged as a new antischistosomal chemotype. We now describe
physicochemical profiling, in vitro ADME, plasma exposure, and ex vivo and in vivo activities
against Schistosoma mansoni for twenty new N,N'-diarylureas designed primarily to increase
aqueous solubility, but also to maximize structural diversity. Replacement of one of the 4-fluoro-
3-trifluoromethylphenyl substructures of lead N,N'-diarylurea 1 with azaheterocycles and
benzoic acids, benzamides, or benzonitriles decreased lipophilicity, and in most cases, increased
aqueous solubility. There was no clear relationship between lipophilicity and metabolic stability,
although all compounds with 3-trifluoromethyl-4-pyridyl substructures were metabolically
stable. N,N'-diaryl ureas containing 4-fluoro-3-trifluoromethylphenyl, 3-trifluoromethyl-4-
pyridyl, 2,2-difluorobenzodioxole, or 4-benzonitrile substructures had high activity against ex
vivo S. mansoni and relatively low cytotoxicity. N,N-diaryl ureas with 3-trifluoromethyl-4-
pyridyl and 2,2-difluorobenzodioxole substructures had the highest exposures whereas those
with 4-fluoro-3-trifluoromethylphenyl substructures had the best in vivo antischistosomal
activities. There was no direct correlation between compound exposure and in vivo activity.
Keywords: N,N'-diarylurea, antischistosomal, SAR
3

Schistosomiasis is a widespread tropical parasitic disease1; Schistosoma mansoni, S.
haematobium and S. japonicum are the predominant pathogenic species.2-4 Praziquantel is the
only drug used for treatment of schistosomiasis. Even so, praziquantel drug resistance is not yet
widespread.4-7 We thus have a window of opportunity to identify a new antischistosomal drug.
In this regard, several antischistosomal lead compounds have recently been identified by
phenotypic screening of drug and chemical compound libraries.8-11 One of these was the
symmetrical N,N'-diaryl urea MMV665582,9 a structural analog of triclocarban,12,13 an
antibacterial agent used in detergents, cosmetics, and other products (Figure 1).
Cl
Cl
Cl
X
O
N
H
N
H
MMV665852, X = Cl
Triclocarban, X = H
Figure 1.
With an IC50 of 0.8 µM, MMV665852 is only 4-fold less potent than praziquantel against ex vivo
S. mansoni and has a 64-fold in vitro selectivity index. A single 400 mg/kg oral dose of
MMV665852 administered to S. mansoni-infected mice reduced worm burden by 53%. In an
initial pharmacokinetic investigation of MMV665852, this symmetrical N,N’-diarylurea was
characterized by a half-life of 4.7 h and Cmax of 4.4 µM at a 46.3 mg/kg oral dose.9 Thus, this
very simple compound offers intriguing possibilities for further optimization, although this is
tempered by its high Log P of 5.2, and the low aqueous solubility14 and potential
pharmacological promiscuity12,13,15,16 of this compound class. Following the discovery of
MMV665852, two subsequent studies17,18 established an initial SAR for this compound series: 1)
substitution at positions 3 and 4 of the phenyl rings with H, F, Cl, CN, and CF3 groups was
optimal; 2) substitution at positions 3 and 4 of the phenyl rings with OCH3, NH2 and other
4

electron-donating groups diminished activity; 3) replacement of one of the phenyl rings with
alkyl substituents diminished or abolished activity; 4) cyclization of the urea to imidazoline-2-
ones abolished activity; and 5) replacement of the urea with carbamates, thioureas, sulfonamides,
or oxalamides diminished or abolished activity. Concurrent with this work, we found that the
symmetrical N,N’-diarylurea 1,19 a side-reaction product formed in the synthesis of aryl
hydantoins,20 had promising antischistosomal activity, better than that of MMV665582. We now
describe physicochemical profiling, in vitro ADME, plasma exposure, and ex vivo and in vivo
activities against S. mansoni for a number of analogs of 1 (2-20, Table 1) designed primarily to
increase aqueous solubility, but also to maximize structural diversity.
Target N,N'-diarylureas 2 and 6-20 were prepared (Supporting Information) by reactions of
phenyl isocyanates (Table 1 Ar = a, d, l, n) with the requisite anilines under three slightly
different reaction conditions (Scheme 1). Phenyl isocyanates were prepared in situ by treatment
of the precursor anilines with triphosgene. Target N,N'-diarylureas 3,21 4,22 and 5 were prepared
by treatment of the corresponding anilines with 1,1'-carbonyldiimidazole (CDI) (Scheme 1).
O
a, b, or c
Y
X
Y
X
+
NCO H2N
N
H
N
H
2, 6-20, 11-79%
O
d or e
Y
Y
Y
N
H
N
H
H2N
3-5, 17-84%
Scheme 1. Reagents and conditions: (a) N,N-diisopropylethylamine, CH2Cl2, rt, 12 h (2, 17, 18);
(b) THF, 25-80 °C; 12 h (6-9, 19, 20); (c) CH3CN, 80 °C, 12 h (10-16); (d) CDI, THF, rt, 48 h (3,
4); (e) CDI, 1,2-dimethoxyethane, reflux, 16 h (5).
We first consider the physicochemical and in vitro ADME properties of these analogs of 1
(Table 1). The calculated polar surface area (PSA) values of between 41 and 93 Å2 indicate that
5

the polarity of these compounds is unlikely to be a rate-limiting factor for membrane
permeability and oral bioavailability.23 Symmetrical N,N-diaryl urea 1 had a high LogD7.4 of 4.5,
similar to that of 5.2 for MMV665852,9 and its kinetic solubility was very poor (<1.6 µg/mL).
The symmetrical azaheterocycle N,N-diaryl ureas 2, 3, and 4 were considerably more polar and
more soluble at both pH 2 and 6.5 compared to 1. In contrast, the symmetrical 2,2-
difluorobenzodioxole N,N-diaryl urea 5 had a similar LogD7.4 to that of 1 and was not more
soluble.
Table 1. Physicochemical and in vitro ADME properties for N,N'-diarylureas 1-20.
a
Compd
Ar
LogD7.4
PSA
(Å2)b
Sol2.0/Sol6.5
(µg/mL)c
h/m CLint
(µL/min/mg
protein)d
10/7
a,a
l,l
4.5
3.0
1.3
41.1
66.9
66.9
<1.6/<1.6
12.5-25/12.5-25
>100/12.5-25
1
2
3
<7/<7
h,h
<7/188
k,k
n,n
a,h
a,i
0.8
4.4
3.2
3.0
3.7
92.7
78.1
54.0
54.0
54.0
6.3-12.5/6.3-12.5
<1.6/<1.6
18/157
<7/12
4
5
6
7
8
6.3-12.5/6.3-12.5
50-100/12.5-25
1.6-3.1/<1.6
12/37
13/154
188/705
a,j
6

a,k
a,m
a,b
a,f
3.0
3.2
1.5
1.6
2.7
3.3
3.8
3.6
4.5
3.8
3.0
3.7
66.9
67.2
81.3
81.3
84.2
84.2
64.9
58.2
59.6
54.0
77.8
72.5
1.6-3.1/<1.6
12.5-25/6.3-12.5
<1.6/12.5-25
1.6-3.1/12.5-25
6.3-12.5/6.3-12.5
1.6-3.1/1.6-3.1
<1.6/<1.6
210/160
73/108
<7/<7
<7/<7
28/22
81/69
<7/12
16/14
<7/<7
<7/<7
<7/<7
<7/16
9
10
11
12
13
14
15
16
17
18
19
20
a,c
a,g
a,d
a,e
a,n
a,l
<1.6/<1.6
<1.6/<1.6
3.1-6.3/3.1-6.3
1.6-3.1/1.6-3.1
3.1-6.3/3.1-6.3
d,l
l,n
aLogD values were estimated by correlation of their chromatographic retention properties using a
modified gradient HPLC method adapted from Lombardo et al.27
bcalculated using ChemAxon JChem for Excel
cCompounds in DMSO were spiked into either pH 6.5 phosphate buffer or 0.01 M HCl (approx. pH 2.0)
and analyzed by nephelometry28 to determine a concentration range.
din vitro intrinsic clearance measured in human and mouse liver microsomes
Substitution of one of the 4-fluoro-3-trifluromethylphenyl substructures of 1 with
azaheterocycles 6-10 decreased lipophilicity, and with the exception of 8 and 9, increased
solubility significantly. Replacing one of the 4-fluoro-3-trifluromethylphenyl substructures of 1
with benzoic acids (11, 12), benzamides (13, 14), a benzonitrile (15) or an acetophenone (16)
decreased lipophilicity, and with the exception of 14, 15, and 16, all were more soluble than 1.
Compounds where one of the 4-fluoro substituents were replaced with pyridine nitrogen atoms
(18 vs. 1, 20 vs. 17, 19 vs. 15) were less lipophilic and marginally more soluble.
7

Twelve of twenty N,N-diaryl ureas (Table 1) had low intrinsic clearance values in human and
mouse liver microsomes and three of these (1, 5, 17) were the most lipophilic of the series,
possibly reflecting high protein binding in the microsomal test system. The eight N,N-diaryl
ureas with intermediate to high intrinsic clearance contained either pyridine nitrogen atoms (4, 6-
10) or primary carboxamide functional groups (13, 14). Notably, N,N-diaryl ureas with 3-
trifluoromethyl-4-pyridyl substructures (2, 18-20) were metabolically stable.
As a gatekeeping assessment of antischistosomal activity, the N,N'-diaryl ureas were tested
against newly transformed schistosomula (NTS)24 (Table 2). At 10 µM, 9 out of 20 of the
compounds killed the NTS. A subsequent concentration titration revealed NTS IC50 values
ranging from 0.15 to 5.6 µM. Further assessment indicated that these compounds killed adult S.
mansoni at a similar IC50 range of 0.18 to 3.3 µM. The aryl substructures (Table 1) in the active
N,N'-diaryl ureas were 4-fluoro-3-trifluoromethylphenyl = 3-trifluoromethyl-4-pyridyl > 2,2-
difluorobenzodioxole > 4-benzonitrile. Notably, none of the new N,N'-diaryl ureas were more
potent than 1 ex vivo.
Table 2. Ex vivo antischistosomal activity and cytotoxicity for selected N,N'-diarylureas.
Cytotoxicity IC50 (µM)
S. mansoni IC50 (µM)
8

Compd
NTS
0.15
2.4
adult
0.19
0.88
0.49
>10
0.94
0.49
0.66
3.3
HFF
57
U-20S
>100
>100
>100
ND
HEK293
>100
>100
>100
ND
HC-04
>100
>100
>100
ND
1
2
>100
79
0.26
5.6
5
ND
60
6
1.6
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
15
17
18
19
20
0.21
0.74
1.9
67
71
>100
80
1.3
0.75
To assess host cell cytotoxicity, the active N,N'-diaryl ureas were tested for growth inhibition of
four human cell lines: human foreskin fibroblast (HFF), kidney (HEK293), hepatocyte (HC04),
and B lymphocyte (RAJI) (Table 2). The HFF cell line was inhibited by 6 out of 8 of the
compounds with IC50 values ranging from 57 to 80 µM; the remaining cell lines were unaffected
at compound concentrations up to 100 µM. Thus, these compounds appeared to have high
antischistosomal selectivity, although the six compounds that inhibited the HFF cell line were
also among the most potent against ex vivo S. mansoni with IC50 values < 1 µM.
Single 100 mg/kg oral doses of the most active N,N'-diaryl ureas were administered to non-
infected mice to assess exposure (Table 3). For logistical reasons, we made the assumption that
exposure profiles generated in non-infected mice give a reasonable estimation of exposure in S.
mansoni-infected mice. Plasma concentrations of 1 increased until 2 h post-dose after which
they remained above 1 µM up to at least 48 h (Figure 2A). Similarly, plasma concentrations of 2
9

and 18 increased until about 4 h post-dose and then remained high for the duration of the 48 h
post-dose sampling period. Based on the AUC values up to the last measured concentration, the
overall systemic exposures of 2 and 18 were approximately 2-4-fold higher than that of 1.
Absorption of 15 and 19 resulted in similar Tmax and Cmax values compared to 1, 2, and 18 (Table
1), however concentrations declined with a much shorter half-life than seen for either 1, 2, or 18
and were well below 1 µM by ~18 h post-dose. Based on in vitro studies with liver microsomes,
both 15 and 19 were not highly susceptible to cytochrome P450-mediated metabolism, so
alternative in vivo degradation/clearance pathways are likely for these benzonitriles.
Unfortunately, the basis for these differences in half-life cannot be determined based only on the
oral exposure data and additional studies with intravenous dosing would be needed to
differentiate between absorption, distribution, and clearance-related differences.
Table 3. Exposure parameters and in vivo antischistosomal activity of selected N,N'-diarylureas
following administration of a single 100 mg/kg oral dose.
S. mansoni
Compd
Cmax (µM)
Tmax (h)
Half-Life (h) AUC0-last (µM.h)
WBR (%)
31
40
4
11
10
394
953
40
20
1
2
4.0
10

5
25
31
27
56
20
55
c.n.d.
4
13
2.7
679
216
0
15
17
18
19
20
37
0
c.n.d.
7.5
c.n.d.
18
989
1486
175
50
1.6
2.1
2.0
2.3
c.n.d.
c.n.d.
2273
c.n.d. = could not determine
Following oral administration, 5, 17, and 20 were each very slowly absorbed and exhibited
relatively flat profiles precluding the assessment of Tmax (Figure 2B). The shape of these profiles
likely reflects the high dose and very poor aqueous solubility leading to very prolonged
absorption. For these three 2,2-difluorobenzodioxole-containing N,N-diaryl ureas, plasma
concentrations remained above ~5 µM during the entire 48 h sampling period. Based on AUC0-last
values ranging from 679 to 2273 µM.h, the exposure of 5, 17, and 20 was much higher than that
of 1 (394 µM.h) but comparable to that for 2 and 18 (953 and 1486 µM.h). From these data, we
see a trend that N,N-diaryl ureas containing 3-trifluoromethyl-4-pyridyl and 2,2-
difluorobenzodioxole substructures had the highest plasma exposures of the compounds tested.
11

Figure 2. Plasma concentration versus time profiles following oral administration of 100 mg/kg
to non-infected male Swiss outbred mice. Symbols represent the mean of n=2 mice at each time
point. Panel A shows the profiles for 1, 2, 15, 18, and 19. Panel B shows the profiles for 5, 17,
and 20.
In vivo antischistosomal activity was determined by measuring worm burden reduction (WBR)
values following administration of single 100 mg/kg oral doses to S. mansoni-infected mice
(Table 3). None of the compounds tested showed high in vivo activity, but the three (1, 15, and
18) with moderate WBR values (37-50%) contained a 4-fluoro-3-trifluoromethylphenyl
substructure. We also found that at this same 100 mg/kg dose, MMV665852 had no activity (0%
WBR). There was no direct correlation between plasma exposure and in vivo activity. For
example, even though all compounds had Cmax levels an order-of-magnitude greater than their S.
12

mansoni IC50 values, and with the exception of 15 and 19, maintained high plasma concentrations
for extended periods, their overall in vivo efficacy was weak to moderate with only 1 and 18
having WBR values of 40-50%. When 18 was administered as four consecutive 80 mg/kg oral
doses, the WBR of 53% was no better than that of 50% obtained with a single 100 mg/kg dose.
Given that most of the compounds in this series are quite lipophilic (Log D >3), the
disappointing in vivo efficacy despite high plasma exposure could be a reflection of high plasma
protein binding and low unbound concentrations with insufficient concentrations reaching the
site of action within the worms to achieve the desired killing effect. Additional pharmacokinetic
and pharmacodynamic studies are needed to better understand the relationship between plasma
and/or tissue exposure and in vivo activity for this series of compounds. Even though none of the
N,N-diaryl ureas had high in vivo activity, it is useful to note that at this same 100 mg/kg dose,
praziquantel also has a low WBR value of only 15%;25 however, a higher 400 mg/kg dose of
praziquantel reduces worm burden by 96%.26
In summary, replacement of one of the 4-fluoro-3-trifluoromethylphenyl substructures of 1 with
azaheterocycles and benzoic acids, benzamides, or benzonitriles decreased lipophilicity, and in
most cases, increased aqueous solubility. There was no clear relationship between lipophilicity
and metabolic stability, although all N,N-diaryl ureas with 3-trifluoromethyl-4-pyridyl
substructures were metabolically stable. N,N'-diaryl ureas containing 4-fluoro-3-
trifluoromethylphenyl, 3-trifluoromethyl-4-pyridyl, 2,2-difluorobenzodioxole, or 4-benzonitrile
substructures had high activity against ex vivo S. mansoni and relatively low cytotoxicity. N,N-
diaryl ureas with 3-trifluoromethyl-4-pyridyl and 2,2-difluorobenzodioxole substructures had the
highest exposures whereas those with 4-fluoro-3-trifluoromethylphenyl substructures had the
13

best in vivo antischistosomal activities. Finally, there was no direct correlation between
compound exposure and in vivo activity.
Acknowledgment
We acknowledge the U.S. National Institutes of Health (GM103427-16, AI097802-02 and
AI116723-01) and the European Research Council (ERC-2013-CoG 614739-A HERO) for
financial support.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
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Highlights
► Expansion of antischistosomal N,N'-diaryl urea SAR.
► 3-Trifluoromethyl-4-pyridyl and 2,2-difluorobenzodioxole improve exposure.
► 4-Fluoro-3-trifluoromethylphenyl required for best antischistosomal activity.
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