Potent inhibitors of the Qi site of the mitochondrial respiration complex III

Article abstract of DOI:10.1021/jm060408s

A series of azole-fused salicylamides were prepared as analogues of antimycin and assayed for activity at complex III of the mitochondrial respiratory chain. The activity of these compounds approached that of antimycin in inhibitory potency and some showe

Full text of DOI:10.1021/jm060408s

4762
J. Med. Chem. 2006, 49, 4762-4766
Potent Inhibitors of the Qi Site of the Mitochondrial Respiration Complex III
Stephen Bolgunas, David A. Clark,* Wayne S. Hanna, Patricia A. Mauvais, and Steve O. Pember
DuPont Agricultural Products, Stine/Haskell Research Center, Post Office Box 30, Newark, Delaware 19714
ReceiVed April 6, 2006
A series of azole-fused salicylamides were prepared as analogues of antimycin and assayed for activity at
complex III of the mitochondrial respiratory chain. The activity of these compounds approached that of
antimycin in inhibitory potency and some showed growth reduction of Septoria nodorum in vitro. Compound
8a was shown to bind at the Qi site of complex III by red-shift titration of the bc1 complex.
Introduction
Antimycin A1 (1, Figure 1, antimycin) is a dilactone salicyl-
amide that was isolated from Streptomyces sp.1 It is a potent
inhibitor of the Qi site of complex III (bc1 complex) in the
mitochondrial respiratory chain, with a dissociation constant with
bovine heart mitochondrial particles of 32 pM.2 It and the related
blastomycins and UK-2A have attracted interest as antifungal
agents from the pharmaceutical arena3 and have also served as
a starting point for the synthesis of agricultural insecticides and
fungicides.4 However, unlike the Qo site of the bc1 complex,
Figure 1. Structure of antimycin A1 (1) showing binding interactions
with the bc1 complex.10b
which is the target of inhibitors such as myxothiazole and
strobilurins5 and commercial agricultural fungicides developed
from these such as Azoxystrobin6 and Kresoxim-methyl,7 the
Qi site has witnessed only limited commercial exploitation.8
As such it represents an attractive target that might not suffer
resistance issues that surround the Qo site inhibitors.9
Two recent crystal structure determinations of the bc1
complex bound to antimycin illuminate the binding mode of
antimycin but differ in their assessment of the conformation of
the ligand.10 In the structure with the higher resolution of 2.28
Å,10b it can be seen that antimycin forms an extensive hydrogen-
bonded network to the enzyme as shown in Figure 1. The
formamide oxygen receives a water-mediated hydrogen bond
from Lys227 The formamide NH acts as a hydrogen-bond donor
to Asp228, which also forms a hydrogen bond with the phenol.
The formamide oxygen is bent back toward and coplanar with
the benzene ring as in the crystal structure of the unbound
ligand.11 A hydrogen bond between the phenolic oxygen and
the benzamide NH maintains a coplanar arrangement of these
two groups, and the benzamide oxygen is then involved in a
water-mediated hydrogen bond to His201. With respect to the
native ligand in the solid state, the benzamide has been rotated
180° in binding to the bc1 complex.
Figure 2. Structure of functional antimycin equivalent (2).12a
Figure 3. Designed benzazole mimics of formamidosalicylamide 2
(A ) CH or N).
group that were also free of patent protection. Inspired by the
conformation of the formamide group in the crystal structure,
we conceived the azole-fused salicylamides shown in Figure 3.
These analogues would span a range of NH pKas14 that would
approach that of the formamide group and incorporate the
biphenyl ether amides as previously described by Tokutake et
al.12a
Tokutake et al.12a have prepared simpler analogues of the
natural product that possess comparable in vitro activity by
replacing the dilactone portion of the molecule with biphenyl
and biphenyl ether groups such as compound 2 (Figure 2). These
analogues also possess moderate to good levels of in vivo
activity on a range of agricultural pathogens but fall short of
commercial standards such as Azoxystrobin.4
The formamide group is an important element of the
pharmacophore13 but one which represents a potential metabolic
liability that could result in lower in vivo efficacy than might
be expected on the basis of the intrinsic activity of these
compounds. As such we sought potential replacements for this
Chemistry
The synthesis of these targets is shown in Scheme 1.
Compound 5 was prepared analogously to that described by
Poupart et al.,15 with chlorine as protection for the 5-position
rather than bromine. Treatment of the amino toluene 5 with
isoamyl nitrite gave the indazole 6 in good yield, which was
then demethylated by use of concentrated HBr to yield the
phenol-acid 7, which could be coupled to a variety of anilines
to give the targets 8.
Using a similar sequence from the diamine 9,16 we prepared
the benzotriazole analogue 12 (Scheme 2), and similarly,
reduction of the nitro aniline 13 with Pd and formic acid gave
the benzimidazole 14, which was carried on to the final targets
as described above (Scheme 3).
* Corresponding author: phone 302-451-4846; fax 302-366-5738;
e-mail david.a.clark@usa.dupont.com.
10.1021/jm060408s CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/30/2006

Inhibitors of Mitochondrial Respiration Complex III
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4763
Scheme 4a
Scheme 1a
a Reagents and conditions: (a) NCS, DMF, 20 °C, 3 days; (b) HNO3,
Ac2O, AcOH, 25 °C, 18 h; (c) 50 psi H2, NEt3, Pd(OH2)/C, EtOH, 20 °C,
8 h; (d) i-amyl nitrite, HOAc, 20 f 117 °C, 1 h; (e) cHBr, 80 °C, 18 h; (f)
EDC.HCl, HOBt, 4-(4R-phenoxy)phenylaniline, pyridine, 90 °C, 18 h.
Scheme 2a
a Reagents and conditions: (a) EtO2CCH2SH, pyridine, -35 f 15 °C;
(b) DMFDMA, 25 °C, 2 h; (c) NH2NH2, EtOH, 20 °C; (d) NH2NH2‚HCl,
NaOAc, EtOH, 20 °C, 1.5 h; (e) NaHMDS, SEMCl, THF, 20 °C, 1 h; (f)
KO-t-Bu, THF, 5 °C, 1 h; (g) NaHMDS, SEMCl, THF, 20 °C, 2 h; (h)
NaOH, EtOH, 78 °C; (i) EDC‚HCl, HOBt, 4-(4-trifluoromethylphenoxy)-
phenylaniline, pyridine, 85 °C, 2 h; (j) TFA, H2O, 20 °C, 40 min.
Table 1. Inhibitory Effect of Target Compounds against Mitochondrial
Electron Transport and Cellular Growth of Septoria nodoruma
FMET2-3
(I50, nM)
FMET2
(I50, nM)
growth inhibition
(GR50, nM)
compd
8a
8b
17
12a
12b
28
127 (19)
26 (7)
>30 000
32 (2)
5 (1)
>30 000
>30 000
>30 000
>30 000
1815 (613)
>30 000
>30 000
1909 (1928)
343 (241)
>30 000
>30 000
>30 000
a Reagents and conditions: (a) i-amyl nitrite, HOAc, 20 °C, 0.5 h; (b)
cHBr, 80 °C, 6 h; (c) EDC‚HCl, HOBt, 4-(4R-phenoxy)phenylaniline,
pyridine, 90 °C, 7 h.
Scheme 3a
26 (4)
2 (1)
11 517 (1962)
33 (20)
antimycin
a Standard deviations are shown in parentheses. Growth inhibition data
are the mean of 8 replicates.
protection of the hydroxy group to allow saponification of the
ester. The conversion of 23 to 25 could be accomplished in
one pot in an overall 95% yield. Amide formation under standard
conditions was accompanied by loss of the SEM ether. Finally,
the remaining SEM group was removed by careful treatment
with TFA to give the target compound 28.
Results and Discussion
a Reagents and conditions: (a) HCO2H, Pd/C, 100 °C, 3 days; (b) 50
psi H2, NEt3, Pd/C, EtOH, 20 °C, 18 h; (c) cHBr, 85 °C, 6 h; (d) EDC‚HCl,
HOBt, 4-phenoxyphenylaniline, pyridine, 85 °C, 6 h.
The in vitro activity of the compounds prepared is shown in
Table 1. All assays were performed on the plant pathogen
Septoria nodorum or on submitochondrial particles derived
therefrom. The first assay (FMET2-3) gives a measure of
inhibition versus both complex 2 (succinate dehydrogenase) and
complex 3 (bc1 complex). The second assay (FMET2) shows
inhibitory activity against complex 2 only. The third column
shows the growth inhibition of cells cultured in a Petri dish.19
As can be seen from the table, all compounds are inactive
against complex 2 and therefore activity shown in assay 1 is
due solely to activity at the bc1 complex. It can also be seen
that the indazole analogues 8 have good to excellent activity in
comparison with antimycin, with the 4′CF3 substitution (8b)
enhancing the level of activity 5-fold over that of the unsub-
Since thiophenes are common bioisosteres of phenyl groups,
we also targeted the pyrazolothiophene 28, which was prepared
as described in Scheme 4. Ethyl bromopyruvate was reacted
with ethyl thioacetate according to a modified procedure as
described by Titus and Titus.17a Formation of the enamine 20
was accomplished by reaction with DMFDMA, which reacted
with hydrazine to give predominantly the pyridazinone 21.
Selectivity for the pyrazole 22 could be achieved under mildly
acidic conditions with hydrazine hydrochloride and sodium
acetate. Dieckmann condensation took place readily18 after
N-protection to give the thiophene 24. This was followed by

4764 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15
Bolgunas et al.
Experimental Section
General Techniques. Reactions were carried out under an
atmosphere of dry nitrogen with anhydrous solvents purchased from
the Aldrich Chemical Co. Inc. where appropriate. Amine bases were
dried and stored over potassium hydroxide. Reactions were
monitored by thin-layer chromatography (TLC) on E. Merck silica
gel plates (0.25 mm) and visualized under UV light (254 nm) and/
or by heating with phosphomolybdic acid ethanol solution. Solvents
used for workup and chromatography were reagent-grade from E.
Merck or VWR Scientific. Flash chromatography was performed
on E. Merck silica gel (60, particle size 0.040-0.063 mm). Yields
refer to chromatographically and spectroscopically (1H NMR) pure
materials.
1H NMR spectra were recorded on a Varian 400 MHz instrument
at 25 °C. 13C NMR spectra are recorded at 100 MHz. Chemical
shifts are reported relative to TMS internal standard. Multiplicities
are designated singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), or broad singlet/multiplet (br s/br m). IR samples
were prepared by evaporation of a solution of the compound from
CDCl3 onto a NaCl plate under a stream of nitrogen. IR spectra
were recorded on a Nicolet Avatar 330 spectrometer. Mass spectra
were recorded on a Waters Micromass spectrometer under fast atom
bombardment (FAB) conditions. HRMS were acquired on a
Micromass LCT time-of-flight mass spectrometer interfaced with
a Agilent 1100 liquid chromatograph. Melting points were recorded
on a Thomas-Hoover Unimelt apparatus and are uncorrected.
Microanalyses were performed at Quantitative Technologies Inc.,
Whitehouse, NJ.
Figure 4. Difference spectrum of inhibitor binding to reduced bc1
complex minus reduced enzyme in absence of the inhibitor: (A) 10
µM; (B) 20 µM, and (C) 40 µM compound 8a. (D) Addition of 20 µM
antimycin A. Titration mixtures contained 4 µM bc1 complex, 0.2 mM
EDTA, 2 mM NaN3, and 0.02% Triton X-100 in 50 mM sodium
phosphate, pH 7.2.
stituted compound (8a). The activity of the benzotriazole
analogue 12b increases a further 5-fold over 8b and is nearly
equipotent with the natural product. However, the benzimidazole
analogue 17 is completely inactive, despite its apparent good
electrostatic mimicry of the formamide group. The superior
activity of the benzotriazole analogue might be due to the
increased NH acidity versus the indazole or might be a result
of increased acidity of the phenol. The activity of the thienopy-
razole 28 matches that of the indazole 8b.
The indazole compounds 8 displayed good in vivo activity
against Septoria nodorum, with 8b having a submicromolar
GR50 (Table 1); however, the benzotriazole analogues 12 were
inactive in this assay, possibly due to poor cell penetration of
these compounds. Three membranes must be crossed to access
the Qi site, and good fungicidal compounds acting at this site
must therefore possess excellent translational properties. The
activity of the thienopyrazole 28 was also much lower than
might be expected from its intrinsic potency.
Unfortunately, none of the above compounds controlled
Septoria nodorum grown on wheat when applied at 40 ppm.
The unsubstituted indazole (8a) was used as a representative
analogue to confirm binding of the inhibitors to the Qi domain
by use of purified bovine enzyme. The Qi domain and the Qo
domain of cytochrome b are located near the bH and bL hemes,
respectively. Tightly associating Qi inhibitors, such as antimycin,
perturb the optical spectrum of the reduced enzyme, causing a
red shift in the Soret region of the bH heme2. Many, but not all,
Qo domain inhibitors also elicit a red shift in the reduced optical
spectrum of the bL heme.20 Because the wavelength transitions
differ for Qi and Qo red-shifted spectra, the general localization
of inhibitor binding can be distinguished. Figure 4 depicts the
difference spectrum of compound 8a binding to reduced
cytochrome bc1 upon sequential titration. Characteristic red-
shift peaks and troughs were observed at 564 and 558 nm,
respectively. These transitions are identical to those observed
when antimycin was added to fully saturate the site, therefore
confirming Qi site occupancy. It should be noted that some Qi
inhibitors, such as the hydroxyquinoline N-oxides, also bind
weakly to the Qo domain,10a and this possibility cannot be ruled
out for the indazole compounds based on the current analysis.
7-Methoxyindazole-6-carboxylic Acid, Methyl Ester (6). To
a solution of 3-amino-2-methoxy-4-methylbenzoic acid, methyl ester
(5) (0.64 g, 3.28 mmol) in acetic acid (20 mL) was added
i-amylnitrite (0.476 mL, 1.1 equiv). The mixture was stirred at
ambient temperature for 30 min before being heated to reflux for
1 h. Upon cooling, the mixture was concentrated and purified by
flash chromatography (silica gel, 30-40% ethyl acetate in hexane)
to yield the indazole 6 (0.50 g, 74%) as a pale yellow solid: mp
1
118-121 °C; Rf 0.57 (silica, 40% ethyl acetate in hexanes). H
NMR (CDCl3) δ 8.11 (s, 1H), 7.60 (d, 2H), 7.49 (d, 1H), 4.09 (s,
3H), 3.97 (s, 3H). 13C NMR (CDCl3) δ 166.7, 133.5, 127.8, 123.6,
119.6, 115.7, 105.1, 62.4, 52.3. IR 3361, 2950, 2918, 1714 cm-1
.
MS 207.3 (M + H+). Anal. (C10H10N2O3) C,H,N.
7-Hydroxyindazole-6-carboxylic Acid (7). 7-Methoxyindazole-
6-carboxylic acid, methyl ester (6) (0.6 g), was heated in 48% HBr
(3 mL) at 80 °C for 18 h. Upon cooling, the precipitate was filtered,
washed with a small amount of water, and dried in vacuo at 60 °C
to give acid 7 as a white solid (0.49 g, 96%): white solid, mp
1
232-233 °C (decomp). H NMR (DMSO-d6) δ 12.4-12.0 (br s,
1H), 8.11 (s, 1H), 7.43 (d, 2H), 7.24 (d, 1H). 13C NMR (DMSO-
d6) δ 173.7, 150.2, 134.4, 131.9, 128.2, 121.4, 111.5, 107.3. MS
177.1 (M - H+).
7-Hydroxyindazole-6-carboxylic Acid, 4-(4-Trifluorometh-
ylphenoxy)phenylamide (8b). To a mixture of 7-hydroxyindazole-
6-carboxylic acid (7) (129 mg, 0.5 mmol), HOBt (71 mg, 1.05
equiv), EDC‚HCl (125 mg, 1.3 equiv), and 4-(4-trifluorometh-
ylphenoxy)aniline (152 mg, 1.2 equiv) was added pyridine (5 mL),
and the mixture was heated at 90 °C for 18 h. The mixture was
then cooled, acidified with 1 N HCl, extracted with methylene
chloride 3×, and dried (MgSO4). Upon concentration, the residue
was purified by flash chromatography (silica gel, 30-40% ethyl
acetate in hexane) to yield the amide 8b (0.14 g, 68%): white solid,
mp 204-205 °C; Rf 0.26 (silica, 40% ethyl acetate in hexanes). 1H
NMR (CDCl3) δ 13.3-12.9 (br s, 1H), 8.13 (s, 1H), 8.10 (s, 1H),
7.63 (d, 2H), 7.58 (d, 2H), 7.29-7.22 (m, 3H), 7.10 (d, 2H), 7.06
(d, 2H). 13C NMR (CDCl3) δ 160.6, 153.2, 150.1, 135.3, 133.2,
132.5, 127.4 (q)+, 127.2, 125.3, (q), 123.5, 120.8, 118.0, 117.5,
111.6, 108.7. IR 1608 cm-1. HRMS Calcd. for C21H14N3O3F3
(M + H+): 414.1066. Found: 414.1057.
Conclusion
A series of azole-fused salicylamides have been prepared
wherein the azole NH is designed to replace the formamide NH
in antimycin. These functional mimics have been shown to have
excellent activity at the Qi site of the bc1 complex. Potent control
of cell growth was also observed for the indazole analogues 8.
These functional mimics might find application elsewhere such
as in Bcl2 binding for cancer chemotherapy.21
6-[2-(Trimethylsilanyl)ethoxymethoxy]-1-[2-(trimethylsilanyl)-
ethoxymethyl]-1H-thieno[3,2-c]pyrazole-5-carboxylic Acid (26).
To a solution of ester 25 (0.44 g) in ethanol (15 mL) was added

Inhibitors of Mitochondrial Respiration Complex III
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 15 4765
K. Preparation of N-phenoxypyrimidinyloxyphenyl-3-formylamino-
2-hydroxybenzamides and related compounds as pesticides. DE
19710609, 1998. (c) Imamura, K.; Mitomo, K.; Yamada, N.;
Yamamoto, K.; Teraoka, T.; Sakanaka, O.; Kurihara, H.; Taniguchi,
M. Preparation of picolinamide derivatives and pest controllers
containing the same as the active ingredient. WO 2000026191, 2000.
(d) Nieto-Roman, F.; Vors, J.-P.; Villier, A.; Lachaise, H.; Mousques,
A.; Hartmann, B.; Hutin, P.; Molina, J. L.; Muller, B. Preparation of
picolinic acid derivatives for agrochemical and therapeutic use as
fungicides. WO 2001049666, 2001. (e) Bacque, E.; Barriere, J.-C.;
Vors, J.-P.; Nieto-Roman, F.; Villier, A. Preparation of hydroxy-
picolinic acid derivatives for agrochemical and pharmaceutical use
as fungicides. WO 2001049667, 2001.
NaOH (1.0 N, 1.4 mL, 1.5 equiv) and the mixture was heated at
reflux for 0.5 h before being cooled and concentrated in vacuo.
The resulting oil was redissolved in water (10 mL) and neutralized
by the dropwise addition of HCl (1.0 N). The precipated white solid
was collected, washed with water, and dried in vacuo to give acid
26 (0.37 g, 89%): mp 67-68 °C; Rf 0.31 (silica, 80% ethyl acetate
1
in hexanes). H NMR (CDCl3) δ 7.81 (s, 1H), 6.01 (s, 2H), 5.63
(s, 1H), 3.92 (t, 2H), 3.65 (t, 2H), 0.98 (m, 4H), 0.02 (s, 9H), 0.00
(s, 9H). 13C NMR (CDCl3) δ 165.9, 150.4, 148.4, 123.6, 122.0,
118.4, 97.7, 83.4, 69.5, 69.0, 19.5, 19.3, 0.1, 0.0. IR 3800-2500,
2953, 1671 cm-1. MS 444.91 (M + H+), 443.06 (M - H+). Anal.
(C18H32N2O5SSi2) C, H, N.
(5) (a) Clough, J. M. The strobilurins, oudemansins, and myxothiazols,
fungicidal derivatives of â-methoxyacrylic acids. Nat. Prod. Rep.
1993, 10 (6), 565-574. (b) Sauter, H.; Steglich, W.; Anke, T.
Strobilurins: volution of a new class of active substances. Angew.
Chem., Int. Ed. 1999, 38 (10), 1329-1349.
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I.; Spinks, C. Azoxystrobin: A novel broad-spectrum systemic
fungicide. Pesticide Outlook 1996, 7 (4), 16-20. (b) Clough, J. M.
The strobilurin fungicides - from mushroom to molecule to market.
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Development of a novel fungicide, cyazofamid. J. Pestic. Sci. 2004,
29 (2), 147-152, 136-138. (b) Mitani, S.; Araki, S.; Takii, Y.;
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6-Hydroxy-1-[2-(trimethylsilanyl)ethoxymethyl]-1H-thieno-
[3,2-c]pyrazole-5-carboxylic Acid, 4-(4-Trifluoromethylphen-
oxy)phenyl Amide (27). To a solution of acid 26 (554 mg) in
pyridine (10 mL) were added HOBt (177 mg, 1.05 equiv), EDC
(311 mg, 1.3 equiv), and 4-(4-trifluoromethylphenoxy)aniline (347
mg, 1.2 equiv), and the mixture was heated at 85 °C for 2 h. The
mixture was then cooled, concentrated, diluted with 1 N HCl, and
twice extracted with methylene chloride. The organic phase was
dried (MgSO4), concentrated, and purified by flash chromatography
(silica gel, 20-40% ethyl acetate in hexane). The residue obtained
is dissolved in ethyl ether (3 mL) and precipitated with hexanes to
afford the amide 27 as an off white solid (90 mg, 13%): mp 158-
1
160 °C; Rf 0.56 (silica, 60% ethyl acetate in hexanes). H NMR
(CDCl3) δ 11.53 (br s, 1H), 7.80 (s, 1H), 7.63 (d, 2H), 7.60 (d,
2H), 7.40 (br s, 1H), 7.10 (d, 2H), 7.07 (d, 2H), 5.65 (s, 2H), 3.65
(t, 2H), 0.95 (t, 2H), 0.02 (s, 9H). 13C NMR (CDCl3) δ 154.0, 151.0,
135.0, 128.6 (q), 124.1, 122.1, 119.1, 83.3, 69.1, 19.3, 0.0. IR 3300,
2917, 1648 cm-1; MS 549.87 (M + H+), 547.99 (M - H+).
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fungicides in the QoI-STAR cross- resistance group: current
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6-Hydroxy-1H-thieno[3,2-c]pyrazole-5-carboxylic Acid, 4-(4-
Trifluoromethylphenoxy)phenyl Amide (28). Compound 27 (89
mg) was dissolved in TFA (3 mL) and stirred for 20 min. Water (2
mL) is then added with ice-bath cooling. After stirring for a further
5 min, an additional 1 mL of water is added and the mixture is
stirred for an additional 15 min before being filtered and washed
with water to give a beige solid (65 mg). The solid is triturated
with methylene chloride to give clean indazole 28. The methylene
chloride extract is purified by flash chromatography (silica gel,
4080% ethyl acetate in hexane) to yield additional indazole 28 (26
mg total yield, 38%). mp 221-223 °C. Rf 0.09 (silica, ethyl
acetate): 1H NMR (acetone-d6) δ 12.12 (br s, 1H), 9.35 (s, 1H),
7.93 (s, 1H), 7.84 (d, 2H), 7.72 (9d, 2H), 7.17 (d, 2H), 7.15 (d,
2H). IR 3147, 2928, 1603 cm-1. HRMS Calcd. for C19H12N3O3F3S
(M + H+): 420.0630. Found: 420.0618.
(10) (a) Gao, X.; Wen, X.; Esser, L.; Quinn, B.; Yu, L.; Yu, C.-A.; Xia,
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comparative analysis of crystal structures of mitochondrial cyto-
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Biochemistry 2003, 42 (30), 9067-9080. (b) Huang, L.-S.; Cobessi,
D.; Tung, E. Y.; Berry, E. A. Binding of the Respiratory Chain
Inhibitor Antimycin to the Mitochondrial bc1 Complex: A New
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bonding Pattern. J. Mol. Biol. 2005, 351 (3), 573-597.
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Van der Helm, D.; Deisenhofer, J. Structure of Antimycin A1, a
Specific Electron-Transfer Inhibitor of Ubiquinol-Cytochrome c
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Strong, F. M. The chemistry of antimycin A. XI. N-Substituted
3-formamidosalicylic amides. J. Med. Chem. 1963, 6 (4), 424-427.
(13) Tokutake, N.; Miyoshi, H.; Satoh, T.; Hatano, T.; Iwamura, H.
Structural factors of antimycin A molecule required for inhibitory
action. Biochim. Biophys. Acta, Bioenerg. 1994, 1185 (3), 271-278.
(14) (a) Bordwell, F. G. Equilibrium acidities in dimethyl sulfoxide
solution. Acc. Chem. Res. 1988, 21 (12), 456-463. (b) Catalan, J.;
Claramunt, R. M.; Elguero, J.; Laynez,.; Menendez, M.; Anvia, F.;
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azoles: the annelation effect in azoles. J. Am. Chem. Soc. 1988, 110
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Acknowledgment. We thank Mike Wadsley for HRMS
analyses.
Supporting Information Available: Synthetic procedures,
analytical data for compounds 4, 5, 8, 10-12, 14-17, and 20-26,
and procedure for the characterization of bc1 binding by red-shift
titration. This material is available free of charge via the Internet
at http://pubs.acs.org.
(15) Poupart, M.-A.; Beaulieu, P. L.; Rancourt, J. A preparation of
heterocyclic compounds, useful as inhibitors of RNA dependent RNA
polymerases, such as hepatitis C virus polymerase. WO 2004064925,
2004.
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