Novel monocyclic amide-linked phenol derivatives without mitochondrial toxicity have potent uric acid-lowering activity

Article abstract of DOI:10.1016/j.bmcl.2021.127900

Although benzbromarone (BBR) is a conventional, highly potent uricosuric drug, it is not a standard medicine because it causes rare but fatal fulminant hepatitis. We transformed the bis-aryl ketone structure of BBR to generate novel monocyclic amide-linked phenol derivatives that should possess uric acid excretion activity without adverse properties associated with BBR. The derivatives were synthesized and tested for uric acid uptake inhibition (UUI) in two assays using either urate transporter 1-expressing cells or primary human renal proximal tubule epithelial cells. We also evaluated their inhibitory activity against mitochondrial respiration as a critical mitochondrial toxicity parameter. Some derivatives with UUI activity had no mitochondrial toxicity, including compound 3f, which effectively lowered the plasma uric acid level in Cebus apella. Thus, 3f is a promising candidate for further development as a uricosuric agent.

Full text of DOI:10.1016/j.bmcl.2021.127900

Bioorg. Med. Chem. Lett. 40 (2021) 127900
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel monocyclic amide-linked phenol derivatives without mitochondrial
toxicity have potent uric acid-lowering activity
,
Junichiro Udaa *, Seiichi Kobashia, Naoki Ashizawab, Koji Matsumotob, Takashi Iwanagab
a Medical R&D Division, FUJI YAKUHIN CO., LTD., Laboratory 1, 1-32-3, Nishiomiya, Nishi-ku, Saitama-shi, Saitama 331-0078 Japan
b Medical R&D Division, FUJI YAKUHIN CO., LTD., Laboratory 2, 636-1, Iidashinden, Nishi-ku, Saitama-shi, Saitama 331-0068, Japan
A R T I C L E I N F O
A B S T R A C T
Keywords:
Although benzbromarone (BBR) is a conventional, highly potent uricosuric drug, it is not a standard medicine
because it causes rare but fatal fulminant hepatitis. We transformed the bis-aryl ketone structure of BBR to
generate novel monocyclic amide-linked phenol derivatives that should possess uric acid excretion activity
without adverse properties associated with BBR. The derivatives were synthesized and tested for uric acid uptake
inhibition (UUI) in two assays using either urate transporter 1-expressing cells or primary human renal proximal
tubule epithelial cells. We also evaluated their inhibitory activity against mitochondrial respiration as a critical
mitochondrial toxicity parameter. Some derivatives with UUI activity had no mitochondrial toxicity, including
compound 3f, which effectively lowered the plasma uric acid level in Cebus apella. Thus, 3f is a promising
candidate for further development as a uricosuric agent.
Uricosurics
Mitochondrial toxicity
Benzbromarone
Primary human renal proximal tubule
epithelial cells Dotinurad
Increasing evidence indicates that hyperuricemia causes not only
gout but is also associated with renal disease progression and a higher
risk of cardiovascular events.1,2 Thus, there is a critical unmet medical
need to control hyperuricemia, which is caused by increased production
and/or decreased excretion of uric acid (UA).
Japan.7 Furthermore, the use of lesinurad, which was more recently
approved in the US and EU, is limited to combination therapy with XOI,
based on clinical trial results.8 In addition, both BBR and lesinurad are
metabolized by CYP2C9, but they also inhibit this enzyme.9 Due to the
CYP2C9 polymorphism, patients with poor CYP2C9 activity are also
poor drug metabolizers, and patients with reduced CYP2C9 activity are
intermediate metabolizers. Thus, individual differences and drug in-
teractions affect the efficacy and safety of these medicines.10 Because of
the disadvantages associated with each medicine, there is still no stan-
dard uricosuric agent recommended for clinical use. Despite the prob-
lems associated with BBR, it is a useful hyperuricemia medicine because
of its potent uricosuric activity and high substrate selectivity.
The two main classes of medicines for treating hyperuricemia are
xanthine oxidase inhibitors (XOIs), which inhibit UA production from
xanthine, and the uricosuric agents. Allopurinol is a traditional, repre-
sentative XOI, whereas febuxostat and topiroxostat are newer medicines
of the same class.3 Allopurinol is metabolized to oxypurinol, which is
mainly excreted via the kidney and is known to cause rare side effects,
including skin disorders. This medicine often becomes a problem for
patients with impaired renal function.4 However, febuxostat and top-
iroxostat have a hepatic excretion route, which differentiates them from
allopurinol.
The exact cause of BBR-induced hepatotoxicity is still unclear,
despite the many studies that have been performed to clarify the
involved mechanisms, including metabolic processes, metabolites, and
mitochondrial toxicity.11–15 Mitochondrial toxicity-induced hepatic
injury is considered a likely mechanism because similar underlying
processes have been associated with other drugs.13–19
The uricosuric agents used for hyperuricemia treatment include
probenecid, benzbromarone (BBR), and lesinurad.5 However, probene-
cid has low transporter selectivity, and its use is problematic due to
critical drug-drug interactions.6 BBR is known to cause rarely fatal
fulminant hepatitis. It has been withdrawn from the market in the EU,
and a warning document has been issued by regulatory authorities in
We recently reported an approach aimed at finding a new medicine
with potent uricosuric activity while reducing mitochondrial toxicity.20
In this earlier research, we identified some excellent bicyclic derivatives,
Abbreviations: ABCG2, ATP-binding cassette sub-family G member 2; BBR, benzbromarone; GLUT9, glucose transporter 9; MIA, mitochondrial inhibitory activity;
MRP4, multidrug resistance protein 4; OAT1, organic anion transporter 1; PK, pharmacokinetics; RPTECs, renal proximal tubule epithelial cells; UA, uric acid;
URAT1, urate transporter 1; UUI, uric acid uptake inhibition; XOI, xanthine oxidase inhibitor.
* Corresponding author.
E-mail addresses: j-uda@fujiyakuhin.co.jp, jun.ir.ud@gmail.com (J. Uda).
https://doi.org/10.1016/j.bmcl.2021.127900
Received 7 December 2020; Received in revised form 15 February 2021; Accepted 17 February 2021
Available online 6 March 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

J. Uda et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127900
including indoline and 1,2-dihydro-3H-benzothiazole derivatives. As a
result, we developed dotinurad as a new uricosuric medicine, which was
recently approved in Japan (Fig. 1). In the article, we reported that a bis-
aryl ketone structure, such as BBR, could cause mitochondrial toxicity.
We hypothesized that this moiety might affect the mitochondrial elec-
tron transfer system because the structure could stabilize the radical that
is associated with adverse effects.21 Interestingly, other compounds with
a bis-aryl ketone moiety, such as amiodarone,13–16 tolcapone,18 and
fenofibrate,19 are known to induce mitochondrial toxicity. Therefore,
we converted the bis-aryl ketone structures into amide-linked bicyclic
derivatives to prevent unwanted toxicity (Fig. 2). The new compounds
had properties that differed from those of the bis-aryl ketone com-
pounds.20 Specifically, they had potent pharmacological effects and low
mitochondrial inhibitory activity (MIA). Additionally, the higher hy-
drophobicity of the compounds in the novel series could exacerbate the
MIA.
The development of new monocyclic core ring derivatives with uri-
cosuric activity could be a promising approach to obtain alternative
analogs of bicyclic compounds, such as dotinurad (Fig. 2). We postulated
that these derivatives should have a similar pharmacological activity
with a lower hydrophobicity, which could potentially diminish the MIA.
In the present study, we designed and synthesized monocyclic ring de-
rivatives as novel uricosuric agents to investigate their structur-
e–activity relationships, including the association between
hydrophobicity and MIA.
Fig. 2. Strategy for designing novel uricosuric compounds. A = carbon or ni-
trogen; R1, R2 = halogen, alkyl, CF3, CN.
Table 1
Structure-MIA relationships associated with the core ring of cyclopentenyl
derivatives.
Compound
LogPa
MIAb, IC50
(μM)
1a
1b
3.39
3.93
4.95
10
6.6
3.1
As previously reported,20 uricosuric compounds mimic the planar
shape of uric acid. In the present study, we developed a strategy for
synthesizing 5-membered monocyclic amide-linked phenol derivatives
that mimic the planar structure of uric acid but do not contain the bis-
aryl ketone core (Fig. 2). To test the hypothesis about the relationship
between structure and MIA, we initially synthesized ‘phenyl vinyl ke-
tone’ derivatives 1 and evaluated their inhibitory activity against
mitochondrial respiration as a representative parameter for MIA
(Table 1).
BBR
a
LogP was calculated using ChemDraw v19, b MIA: mitochondrial respiratory
control ratio (RCR), IC50 (μM).
Table 2
Structure-MIA relationships associated with the core ring of compounds 2, 3,
and 4.
Compound
LogPa
MIAb IC50
(μM) or %
These compounds were prepared by Fries rearrangement which is a
typical method for phenol acylation. Thus, Fries rearrangement of 2,6-
dichloro- or 2,6-dibromo-phenyl cyclopent-1-ene-1-carboxylate with
acid catalyst (trifluoromethanesulfonic acid) afforded the desired
products 1a and 1b (described in supplementary information). We
found that 1a and 1b possessed high MIA despite having considerably
lower LogP values than BBR (LogP: 4.95). Thus, the aryl vinyl ketone
core in 1a and 1b appeared to maintain the properties of the bis-aryl
ketone core. Specifically, it is possible that the unsaturated bonds in
aryl vinyl ketones were still able to conjugate intramolecularly and
stabilize the radical as in bis-aryl ketones.
2a
3a
3b
4a
2.92
2.22
2.95
3.08
6.7
> 100 (17%)
> 100 (22%)
> 100 (22%)
a
LogP was calculated using ChemDrawv19, b MIA: mitochondrial respiratory
control ratio (RCR), IC50 (μM) or inhibition (%) at 100 μM.
previously reported for the bicyclic derivatives containing indoline and
indole.20 Therefore, these findings are in line with our hypothesis,
indicating that the derivatives of compounds 3 and 4 represented a new
class of potent uricosuric agents.
Next, we synthesized and tested ‘phenyl pyrrolyl ketone’ 2 (benzoyl
aromatic amine), ‘benzoyl 3-pyrroline’ 3 and ‘benzoyl pyrrolidine’ 4
(benzoyl aliphatic amine) containing the amide structure as an alter-
native to the bis-aryl ketone (Table 2). Pyrrole derivative 2a had high
MIA despite having a lower LogP than BBR. In contrast, the 3-pyrroline
amide-derivatives 3a and 3b, along with pyrrolidine derivative 4a, had
considerably lower MIA than 2a, although the LogP of 3b and 4a was
similar to that of 2a. Thus, 2a displayed undesirable bis-aryl ketone-like
properties, probably due to the aromatic pyrrole ring, whereas 3a,3b
and 4a exhibited favorable characteristics. The same trend was
Two assays were performed to investigate uric acid uptake inhibition
(UUI) by the monocyclic derivatives. Urate transporter 1 (URAT1)-
expressing cells are used as the test system in the URAT1 assay, and
primary human renal proximal tubule epithelial cells (RPTECs) are used
in the RPTEC assay. RPTECs are critical for urate excretion and reab-
sorption in humans. Specifically, they can express various transporters,
including URAT1, organic anion transporter 1 (OAT1), OAT3, multidrug
resistance protein 4 (MRP4), ATP-binding cassette sub-family G member
2 (ABCG2), and glucose transporter 9 (GLUT9), which are all involved in
urate transport.22–24
A correlation between the RPTEC and URAT1 assay has been
observed for several compounds, including BBR, a well-studied
hURAT1-specific inhibitor,25 and dotinurad, as previously described.20
Based on this correlation, we hypothesized that urate uptake into
RPTECs was mainly due to URAT1, but results from the RPTEC assay
could be affected by other endogenous transporters. Thus, the RPTEC
assay more closely resembled an in vivo system.
Compounds 2a (core ring; pyrrole), 3a (core ring; 3-pyrroline) and
4a (core ring; pyrrolidine), along with BBR, were tested in the UUI
Fig. 1. Uricosuric agents.
2

J. Uda et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127900
assays (Table 3). These test compounds inhibited URAT1-mediated
transport of uric acid but had almost no inhibitory effect on uric acid
uptake by RPTECs. Thus, our results did not show a correlation between
the URAT1 and RPTEC assays, and these new compounds were not
potent enough to inhibit uptake in the RPTEC assay.
3-Pyrroline derivative 3a and pyrrolidine 4a had moderate URAT1
inhibitory activity, but almost no MIA. Therefore, the aliphatic mono-
cyclic amide-linked structure removed the MIA toxicity of the bis-aryl
ketone structure while maintaining UUI activity. We hypothesized that
the UUI activity in the URAT1 and the RPTEC assay could be enhanced
by structural optimization. We synthesized additional 3-pyrroline and
pyrrolidine derivatives by replacing substituents on the phenyl ring in
compounds 3 and 4.
Scheme 1. Synthetic pathway for 5-membered ring derivatives 2, 3 and 4.
Reagents and conditions: 5-membered ring = 3-pyrroline, pyrrolidine ; (a) X =
OH; EDC, HOBt in DMF and CH2Cl2, or X = Cl; NEt3, CH2Cl2: 5-membered ring
= pyrrole; (a) X = Cl; NaH, THF: (b) R3 = MOM; HCl, AcOEt, R3 = Me; LiCl,
DMF, 21–96% yield over two steps.
The synthetic pathway for 2a, 3 and 4 is shown in Scheme 1. These
amide-linked phenol derivatives were prepared by acylation of 5-
membered amines and following deprotection. Substituted benzoic
acids as intermediates have been prepared earlier,20 and we have
described some new substituted benzoic acids in the supplementary
information. The acylation of 3-pyrroline and pyrrolidine was accom-
plished with 3,5-disubstituted 4-methoxy or 4-methoxymethoxy -ben-
zoic acid and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide
hydrochloride (EDC), or acid chloride and triethylamine. The N-acyla-
tion of pyrrole was accomplished with acid chloride and sodium hydride
as a base. Subsequent deprotection of the hydroxyl group on the phenyl
ring yielded the desired analogs 2a, 3 and 4.
Table 4
UUI and MIA of compounds 3 and 4.
Com-
R1, R2
UUIa
MIAb IC50
pound
URAT1 %
RPTEC IC50
M)
(μM) or %
inhibition at 3
μ
M
(μ
3c
3d
3e
3f
I, CN
79%
58%
49%
83%
66%
25%
69%
70%
92%
69%
> 1000
> 1000
903
8%
6%
CN, SMe
n-Pr, CF3
CF3, CN
Cl, CN
47%
ꢀ 1%
5%
818
3g
3h
3i
> 1000
> 1000
747
Me, CN
Br, CN
ꢀ 10%
0%
Compounds 3 and 4 were assessed in the in vitro uptake assays
(Table 4). Although almost all derivatives inhibited URAT1-mediated
transport of uric acid, they had almost no inhibitory activity against
uric acid uptake by RPTECs, with a few exceptions. Compound 3k
showed potent URAT1 inhibitory activity and moderate inhibition in the
RPTEC assay while having considerably weak MIA. Moreover, although
3f exhibited lower potency than 3k in the URAT1 and RPTEC assays, it is
a promising lead compound due to the absence of MIA.
3j
n-Pr, CN
tert-Bu, CN
cyclopropyl,
CN
> 1000
311
7%
3k
3l
60% (64
μ
M)
> 1000
ꢀ 7%
4b
CF3, CN
66%
> 1000
18%
a
b
UUI: inhibition of urate uptake via URAT1 or by RPTECs.
MIA: mitochondrial respiratory control ratio (RCR), IC50
M.
(μM) or inhibition
(%) at 100
μ
Next, we focused on the core ring structure. Compounds 6 de-
rivatives with various core ring moieties, including azetidine, 3-methyl-
3-pyrroline, thiazolidine and dioxo-thiazolidine were synthesized ac-
cording to the same pathway as compounds 3 and 4 presented in Scheme
1, using 4- or 5-membered ring amines as the starting material. Dioxo-
thiazolidine derivative 6i was prepared by oxidation of thiazolidine
type intermediate 7 using meta-chloroperoxybenzoic acid (m-CPBA)
and following deprotection of phenol (Scheme 2). The UUI activities of
the derivatives were investigated in the URAT1 and RPTEC assays
(Table 5).
Scheme 2. Synthetic pathway for 6i. Reagents and conditions: (a) m-CPBA,
CH2Cl2, 98.8% yield, (b) LiCl, DMF, 83.5% yield.
We found that almost all compounds had URAT1 inhibitory activ-
ities. However, in the RPTEC assay, some thiazolidine and 3-methyl-3-
pyrroline derivatives, especially 6c, 6d, 6f, and 6g, showed moderate
activity, whereas azetidine derivatives showed no activity. The tert-Bu
derivative 6g had the highest URAT1 inhibitory activity among those
four compounds, but it also had the highest MIA. Thus, we found that the
compounds with higher LogP values tended to have higher UUI and MIA
values, which was the same tendency that we observed among the
bicyclic derivatives, such as the indoline analogs, as previously
described.20 Although compounds 6c, 6d, and 6f showed weaker UUI
activity than BBR or dotinurad, they exhibited almost no MIA. Thus,
these derivatives exhibited a clear divergence between two crucial pa-
rameters for uricosuric agents (UUI and MIA). Therefore, if they have
appropriate pharmacokinetics (PK) profiles, sufficient activity might be
observed in humans.
Next, we investigated the PK profiles of the four most promising
compounds from our inhibition analysis, 3f, 6c, 6d, and 6f. According to
our hypothesis, the presence of active compounds in the urine is
essential for the pharmacological effects because URAT1 is located on
the luminal side of epithelial cells of the renal tubule.20 BBR is consid-
ered to produce its activity, at least in part, by the active metabolite 6-
OH-BBR. This BBR metabolite appears to be involved in the inhibition of
uric acid reabsorption from the luminal side of epithelial cells of the
renal tubule where the urine is present.26–28 Unlike BBR, the compounds
in this study do not require the conversion to active metabolites avoi-
dimg the involvement of metabolizing enzymes, such as CYP2C9.
Therefore, the presence of the parent compounds in the urine (Exc. % of
the dose) was a potential indication of activity in humans.
Table 3
UUI (URAT1 and RPTEC assays) and MIA of 2a, 3a and 4a.
Com-
UUIa
MIAb IC50
%
(μM) or
pound
URAT1 % inhibition at 3
RPTEC IC50
M)
μM
(μ
2a
3a
83%
54%
84%
91%
> 1,000
> 1,000
> 1,000
6.8
6.7
> 100 (17%)
> 100 (22%)
3.1
4a
BBR
a
b
UUI: inhibition of urate uptake via URAT1 or by RPTECs.
MIA: mitochondrial respiratory control ratio (RCR), IC50
M.
The PK profiles of 3f, 6c, 6d, and 6f are shown in Table 6. Compound
3f exhibited the highest excretion in the urine and weak CYP2C9
(μM) or inhibition
(%) at 100
μ
3

J. Uda et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127900
Table 5
UUI and MIA of compound 6 derivatives.
Com-
A
R1, R2
UUIa
MIAb IC50
pound
(
μ
M) or %
URAT1 %
inhibition at 3
RPTEC
IC50 M)
(
μ
μM
6a
6b
Azetidine
Azetidine
CN,
CF3
CN,
tert-
Bu
75%
> 1000
> 1000
17%
41%
71%
6c
6d
6e
6f
3-Methyl-3-
pyrroline
CN,
CF3
CN,
CF3
CN,
Br
88%
84%
72%
67%
92%
137
202
401
124
257
9%
Thiazolidine
29%
23%
25%
Thiazolidine
Thiazolidine
Thiazolidine
CN,
Et
Fig. 3. Changes in plasma urate level compared with the baseline value in
Cebus apella at 0–24 h after oral administration of 300 mg/kg 3f or vehicle.
Values are the means + S.D. of three animals. The baseline average value of the
vehicle control group: 2.82 mg/dL. *P < 0.05, significantly different from
control at each time point according to Dunnett’s test.
6g
CN,
tert-
Bu
77% (27
M)
μ
6h
6i
Thiazolidine
CN,
CN
62%
55%
614
272
23%
1,1-Dioxo-
CN,
CF3
ꢀ 3%
thiazolidine
a
b
UUI: inhibition of urate uptake via URAT1 or by RPTECs; MIA: mito-
chondrial respiratory control ratio (RCR), IC50 (μM) or inhibition (%) at 100 μM.
Table 6
PK profiles of 3f, 6c, 6d, and 6f in rats.
a
Compound
Cmax
(μg/mL)
Exc.b (%)
CYP2C9 IC50 (μM)
3f
6c
2.61
2.22
3.70
–
9.14
4.42
23
10
9.0
9.5
1.1
0
52
94
6d
> 100
–
6f
dotinurad
5.7
BBR
0.041
a
b
Maximum concentration (Cmax); Excretion rate in urine (%, 0–4 h) after
oral administration of 3 mg/kg to rats.
inhibition. Although 3f had an approximately 100-fold lower UUI ac-
tivity than dotinurad (UUI in RPTEC assay: IC50 = 6.8
μ
M)20, its urinary
excretion was several tens of times higher than that of the control agent.
These results suggested that 3f was present as a parent compound in
urine at a larger ratio and may possess true uricosuric activity. There-
fore, we decided to investigate the activity of 3f in Cebus apella, whose
uricosuric mechanisms can be extrapolated to humans (Fig. 3). In this
experiment, 3f treatment decreased plasma urate concentrations, asso-
ciated with an excretion rate of 9.0% of the compound dose in 24 h
urine. Our observations indicated that the large proportion of parent
compound 3f in the urine might enhance the compound’s effect and
overcome its moderate intrinsic activity. Thus, these data supported our
hypothesis that active compounds in the urine could contribute to the
pharmacological effect.
Although the monocyclic derivatives discussed here had a much
lower UUI activity than the bicyclic compounds, the new derivatives
also displayed a divergence between UUI and MIA, and representative
compound 3f showed moderate activity in Cebus apella. This charac-
teristic is a promising property of potential uricosuric agents, which
applied also to the bicyclic compounds.
the conjugated ketone radicals and that the lipophilicity of compounds
affects MIA. However, the UUI activity, especially in RPTECs, tended to
be reduced by lowering the lipophilicity of the test compounds.
This structural property may have contributed to the results seen in
Cebus apella, in which 3f caused a moderate decrease of plasma urate
concentrations, compared to that of dotinurad, which had a significant
pharmacological effect at > 5 mg/kg (p.o.), as reported previously.20
Thus, we have identified new compounds with potency as real uricosuric
agents without the negative consequences of MIA. The series could
In conclusion, we initially focused on designing compounds that do
not exhibit MIA while retaining relevant uricosuric activity. We pursued
this aim by synthesizing phenol derivatives with amide-linked mono-
cyclic core rings to eliminate the adverse effects associated with bis-aryl
ketone-containing compounds, such as BBR. This approach resulted in
compounds with low hydrophobicity and no MIA. In addition, we
demonstrated that bis-aryl ketones or aryl vinyl ketones could stabilize
4

J. Uda et al.
Bioorganic & Medicinal Chemistry Letters 40 (2021) 127900
12 McDonald MG, Rettie AE. Sequential metabolism and bioactivation of the
hepatotoxin benzbromarone: Formation of glutathione adducts from a catechol
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Declaration of Competing Interest
¨
13 Spaniol M, Bracher R, Ha HR, Follath F, Krahenbühl S. Toxicity of amiodarone and
amiodarone analogues on isolated rat liver mitochondria. J Hepatol. 2001;35:
628–636. https://doi.org/10.1016/s0168-8278(01)00189-1.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
¨ ¨
¨
¨
14 Kaufmann P, Torok M, Hanni A, Roberts P, Gasser R, Krahenbühl S. Mechanisms of
benzarone and benzbromarone-induced hepatic toxicity. Toxicity of amiodarone and
amiodarone analogues on isolated rat liver mitochondria. Hepatology. 2005;41:
925–935. https://doi.org/10.1016/s0168-8278(01)00189-1.
Acknowledgment
¨ ¨
15 Waldhauser KM, Torok M, Ha HR, et al. Hepatocellular toxicity and pharmacological
effect of amiodarone and amiodarone derivatives. J Pharmacol Exp Ther. 2006;319:
1413–1423. https://doi.org/10.1124/jpet.106.108993.
We thank Koichi Omura for his contribution to the analytical work.
Appendix A. Supplementary data
16 Ramachandran A, Visschers RGJ, Duan L, Akakpo JY, Jaeschke H. Mitochondrial
dysfunction as a mechanism of drug-induced hepatotoxicity: Current understanding
and future perspectives. J Clin Transl Res. 2018;4(75–100). https://doi.org/
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17 Ai Q, Jing Y, Jiang R, et al. Rotenone, a mitochondrial respiratory complex I
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Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.127900.
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18 Grünig D, Felser A, Bouitbir J, Krahenbühl S. The catechol-O-methyltransferase
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