N-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)phenyl ... · N-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide as a new inhibitors of mitochondrial complex III: Synthesis,

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Supporting Information for

N-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide

as a new inhibitors of mitochondrial complex III: Synthesis,

biological evaluation and computational simulations

Hua Chenga, 1, Lu Yanga, 1, Hong-Fu Liua, Rui Zhanga, *, Cheng Chenb, *, Yuan Wuc,

Wen Jiangc

a Department of Chemical Engineering and Food Science, Hubei University of Arts

and Science, 296 Longzhong Road, Xiangyang 441053, P. R. China;

b State Key Laboratory of Advanced Technology for Materials Synthesis and

Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070, P. R.

China.

c Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of

Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, P. R.

China.

Contents:

1. Experimental Section ............................................................................................... S2-S5

2. Analytical data for compounds 1d’, 1e’, 3a-3e’ .................................................... S6-S12

3. 1H-NMR, 13C-NMR and HR-MS spectra for compounds 1d’, 1e’, 3a-3e’ ......... S13-S68

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1. Experimental Section

1.1 General Considerations

1H NMR spectra were obtained on a Bruker Avance 500 spectrometer in CDCl3 or

DMSO-d6 with TMS as the internal reference, while 13C NMR spectra were recorded

in CDCl3 or DMSO-d6 on a Bruker Avance 500 (125 MHz) spectrometer. The

following abbreviations were used to designate multiplicities: s = singlet, d = doublet,

t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet

of doublet of doublets, m = multiplet. HRMS were determined on a Bruker Daltonics

microTOF-QII or a Thermo Fisher Q ExactiveTM UHMR OrbitrapTM instrument.

Melting points were taken on a Buchi B-560 melting point apparatus and were

uncorrected. Ordinary reagents and solvents were purchased from commercial

suppliers and directly used without further treatment. 4-phenoxyaniline (1p),

benzoic acid (2a), 2-methylbenzoic acid (2b), 3-methylbenzoic acid (2c),

4-methylbenzoic acid (2d), 2-chlorobenzoic acid (2e), 3-chlorobenzoic acid (2f),

4-chlorobenzoic acid (2g), 2,4,6-trichlorobenzoic acid (2h),

2-chloro-4-(trifluoromethyl)benzoic acid (2i), 3-methoxybenzoic acid (2j),

3-(tert-butyl)benzoic acid (2k), 3-fluorobenzoic acid (2l), 3-bromobenzoic acid (2m),

3-(trifluoromethoxy)benzoic acid (2n), 3-(trifluoromethyl)benzoic acid (2o), picolinic

acid (2u) and pyrazine-2-carboxylic acid (2c’) were purchased from commercial

suppliers. As for compound 4-(2,4-dichlorophenoxy)aniline (1a),

3,5-dichloro-4-(2,4-dichlorophenoxy)aniline (1q),

3-chloro-4-(2,4,6-trichlorophenoxy)aniline (1r),

3,5-dichloro-4-(2,4,6-trichlorophenoxy)aniline (1s),

3,5-dichloro-4-(mesityloxy)aniline (1t), 4-((3,5-dichloropyridin-2-yl)oxy)aniline (1v),

4-(2-chloro-4-(trifluoromethyl)phenoxy)aniline (1w),

3-chloro-4-(2-chloro-4-(trifluoromethyl)phenoxy)aniline (1x),

3-chloro-4-(naphthalen-2-yloxy)aniline (1a’),

3,5-dichloro-4-(naphthalen-2-yloxy)aniline (1b’), they were prepared from a reported

procedure [1].

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1.2 General procedure for the synthesis of 1d’-1e’

A mixture of 1-fluoro-4-nitrobenzene (0.55 mL, 5.0 mmol),

2-chloro-4-methylphenol (1.43 g, 10.0 mmol), potassium carbonate (1.38 g, 10.0

mmol) and DMF (5 mL) was stirred at 100oC for 4 h. After the reaction was complete,

diethyl ether (15 mL) was added and the solution was washed with 2 N NaOH (2 × 15

mL), water (15 mL), brine (15 mL) and dried over Na2SO4. Finally, the obtained

organic layer was concentrated to afford a crude mixture which was used directly for

the next step. Subsequently, a mixture of the above crude mixture, ammonium

chloride (0.27 g, 5.0 mmol), ethanol (25 mL) and water (3 mL) was heated to reflux,

and then powdered iron (0.27 g, 15.0 mmol) was added. The reaction mixture was

then stirred at reflux for 6 h. After the reaction was complete, the suspension was

cooled to room temperature and filtered through celite. The solvent of the filtrate was

evaporated under reduced pressure, and the residue was extracted with ethyl acetate (3

× 10 mL). Finally, the combined extracts were washed with water (2 × 15 mL), brine

(15 mL), dried and concentrated to give 4-(2-chloro-4-methylphenoxy)aniline (1d’) in

72% overall yield in two steps (0.84 g, 3.6 mmol).

4-(2-Bromo-4-(trifluoromethyl)phenoxy)aniline (1e’) was obtained in 58% overall

yield in two steps (0.96 g, 2.9 mmol), following the synthetic procedure of 1d’ by

replacing 2-bromo-4-(trifluoromethyl)phenol (2.41 g, 10.0 mmol) instead of

2-chloro-4-methylphenol (1.43 g, 10.0 mmol).

1.3 General procedure for the synthesis of 3a-3e’

A 10 mL round bottomed flask was charged with 2 (1.2 mmol), EDCI (1.2 mmol),

HOBt (1.2 mmol) and dry DMF (3 mL). The reaction mixture was stirred for 1 h

under room temperature before compound 1 (1.0 mmol) was added. After complete

consumption of 1 (as monitored by TLC), the reaction mixture was diluted with water

(30 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers

were washed with water (2 × 10 mL), brine (10 mL), dried over anhydrous Na2SO4,

filtered and concentrated under reduced pressure. The crude was then purified by

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silica-gel column chromatography to afford the desired products 3a-3e’.

1.4 Enzyme Assay

In this paper, SCR was isolated from the heart of porcine, following the reported

method in the literature [2]. The overall activity of SCR was measured by the

absorption enhancement of cytochrome c at 550 nm, with 18.5 mM-1cm-1 as the

extinction coefficient. The activity of complex II was measured by monitoring the

absorbance decrease of DCIP (2,6-dichlorophenolindophenol) at 600 nm, by using an

extinction coefficient of 21.0 mM-1cm-1. As for the activity of complex III, DBH2 and

cytochrome c were used to evaluate its activity in SCR. The total volume of the

reaction mixture was 1.8 mL with the final concentrations of PBS (pH 7.4, 100 mM),

EDTA (0.3 mM), succinate (20 mM), oxidized cytochrome c (60 mM, or DCIP 53

mM) and appropriate amounts of enzyme to initiate the reaction [1].

1.5 Molecular docking

The computational protocol is similar to the reported works [3-5]. Herein, the 3D

structure of complex III was obtained from the Protein Data Bank (PDB) database

(PDB ID: 1SQB). The AutoDock 4.2 program was utilized for the docking of

representative compound 3w and Azoxystrobin (the positive control) into the Qo site

and/or Qi site of complex III. The Gasteiger charges were applied for these inhibitors.

To select the suitable docking parameters and examine the reliability and

reproducibility of the docking results, Azoxystrobin was first docked into the Qo site.

In this docking procedure, the Soils and Wets local search method was used to carry

out the comformational search, resulting in the best conformation of 3w and

Azoxystrobin. Among a series of docking parameters, the grid size was fixed as

30*30*30 and the used grid space defaulted as 0.375 Å. The standard AutoDock

scoring function was applied to assess the interaction energy between the ligand and

complex III (PDB ID: 1SQB). Among a set of 50 candidates of the docked complex

structures, the optimized one was chosed on the basis of the binding energy.

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1.6 References

[1] H. Cheng, Y.Q. Shen, X.Y. Pan, Y.P. Hou, Q.Y. Wu, G.F. Yang, New J. Chem.,

39 (2015) 7281-7292.

[2] L. Yu, C.A. Yu, J. Biol. Chem., 257 (1982) 2016-2021.

[3] G.F. Hao, F. Wang, H. Li, X.L. Zhu, W.C. Yang, L.S. Huang, J.W. Wu, E.A.

Berry, G.F. Yang, J. Am. Chem. Soc., 134 (2012) 11168-11176.

[4] H.Y. Lin, X. Chen, J.N. Chen, D.W. Wang, F.X. Wu, S.Y. Lin, C.G. Zhan, J.W.

Wu, W.C. Yang, G.F. Yang, Research, 2019 (2019) 2602414.

[5] P.L. Zhao, L. Wang, X.L. Zhu, X. Huang, C.G. Zhan, J.W. Wu, G.F. Yang, J. Am.

Chem. Soc., 132 (2010) 185-194.

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2. Analytic data for compounds 1d’, 1e’, 3a-3e’

4-(2-Chloro-4-methylphenoxy)aniline (1d’). White solid, m.p.: 72.5-73.8℃.

Isolated yield: 72%. 1H NMR (500 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.05 (d, J = 8.4

Hz, 1H), 6.82 – 6.67 (m, 3H), 6.61 (d, J = 8.3 Hz, 2H), 5.07 (s, 2H), 2.25 (s, 3H). 13C

NMR (126 MHz, DMSO-d6) δ 152.1, 146.7, 145.6, 133.5, 131.0, 129.3, 123.0, 120.3,

118.6, 115.5, 20.4. HRMS (ESI): calc. for C13H13ClNO [M+H]+: 234.06802; Found:

234.06769.

4-(2-Bromo-4-(trifluoromethyl)phenoxy)aniline (1e’). White solid, m.p.:

67.2-68.1℃. Isolated yield: 58%. 1H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 2.3

Hz, 1H), 7.65 (dd, J = 8.8, 2.2 Hz, 1H), 6.90 – 6.79 (m, 3H), 6.65 (d, J = 8.7 Hz, 2H),

5.15 (s, 2H). 13C NMR (126 MHz, DMSO-d6) δ 159.2, 147.1, 144.4, 130.8 (q, J = 3.7

Hz), 126.9 (q, J = 3.5 Hz), 123.9 (q, J = 32.8 Hz), 123.9 (q, J = 271.9 Hz), 116.7,

115.4, 112.0. HRMS (ESI): calc. for C13H10BrF3NO [M+H]+: 331.98924; Found:

331.98861.

N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3a). White solid, m.p.:

209.5-210.3℃. Isolated yield: 33%. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 7.0 Hz,

3H), 7.62 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 6.0 Hz, 1H), 7.53 – 7.40 (m, 3H), 7.19 (d, J

= 8.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H). 13C NMR (126 MHz,

CDCl3) δ 166.2, 153.6, 152.2, 135.3, 134.3, 132.4, 131.0, 129.5, 129.3, 128.5, 127.5,

126.8, 122.6, 121.4, 119.3. HRMS (ESI): calc. for C19H14Cl2NO2 [M+H]+: 358.03961;

Found: 358.03955.

N-(4-(2,4-dichlorophenoxy)phenyl)-2-methylbenzamide (3b). White solid, m.p.:


2H), 7.56 – 7.46 (m, 3H), 7.40 (t, J = 7.5 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.21 (dd, J =

9.0, 2.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 8.5 Hz, 1H), 2.54 (s, 3H). 13C

NMR (126 MHz, CDCl3) δ 168.0, 153.0, 151.7, 136.5, 136.2, 133.9, 131.4, 130.5,

130.4, 129.0, 128.0, 126.6, 126.3, 126.0, 121.7, 120.9, 118.9, 19.9. HRMS (ESI): calc.

for C20H16Cl2NO2 [M+H]+: 372.05526; Found: 372.05523.

N-(4-(2,4-dichlorophenoxy)phenyl)-3-methylbenzamide (3c). White solid, m.p.:

140.7-141.9℃. Isolated yield: 83%. 1H NMR (500 MHz, CDCl3) δ 7.80 (s, 1H), 7.68

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(s, 1H), 7.67 – 7.58 (m, 3H), 7.47 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 5.0, 1.5 Hz, 2H),

7.18 (dd, J = 9.0, 2.5 Hz, 1H), 7.02 – 6.95 (m, 2H), 6.90 (d, J = 9.0 Hz, 1H), 2.43 (s,

3H). 13C NMR (126 MHz, CDCl3) δ 165.9, 153.0, 151.7, 138.8, 134.8, 133.9, 132.7,

130.5, 129.0, 128.7, 128.0, 127.7, 126.2, 123.9, 122.0, 120.9, 118.9, 21.4. HRMS

(ESI): calc. for C20H16Cl2NO2 [M+H]+: 372.05526; Found: 372.05517.

N-(4-(2,4-dichlorophenoxy)phenyl)-4-methylbenzamide (3d). White solid, m.p.:


(d, J = 8.0 Hz, 2H), 7.61 (d, J = 9.0 Hz, 2H), 7.46 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 8.0

Hz, 2H), 7.18 (dd, J = 9.0, 2.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0 Hz,

1H), 2.43 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.6, 152.9, 151.7, 142.5, 134.0,

131.9, 130.5, 129.5, 129.0, 128.0, 127.0, 126.2, 122.0, 120.8, 118.9, 21.5. HRMS

(ESI): calc. for C20H16Cl2NO2 [M+H]+: 372.05526; Found: 372.05517.

2-Chloro-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3e). White solid, m.p.:


(dd, J = 7.5, 2.0 Hz, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.52 – 7.39 (m, 4H), 7.22 (dd, J =

9.0, 2.5 Hz, 1H), 7.02 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H). 13C NMR (126

MHz, CDCl3) δ 164.3, 153.3, 151.6, 134.9, 133.4, 131.8, 130.6, 130.5, 130.5, 130.4,

129.1, 128.0, 127.4, 126.3, 122.0, 120.9, 118.8. HRMS (ESI): calc. for C19H13Cl3NO2

[M+H]+: 392.00064; Found: 392.00053.

3-Chloro-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3f). White solid, m.p.:


(s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H),

7.50 (d, J = 2.5 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.22 (dd, J = 9.0, 2.5 Hz, 1H), 7.00

(d, J = 8.5 Hz, 2H), 6.93 (d, J = 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.3,

153.4, 151.5, 136.5, 135.0, 133.4, 132.0, 130.5, 130.1, 129.2, 128.1, 127.3, 126.4,

125.1, 122.2, 121.1, 118.7. HRMS (ESI): calc. for C19H11Cl3NO2 [M-H]-: 389.98609;

Found: 389.98602.

4-Chloro-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3g). White solid, m.p.:


2H), 7.74 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 3.0 Hz, 3H), 7.19 (d, J = 8.5

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Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz,

CDCl3) δ 164.6, 153.3, 151.5, 138.3, 133.5, 133.1, 130.5, 129.2, 129.1, 128.4, 128.1,

126.4, 122.1, 121.0, 118.8. HRMS (ESI): calc. for C19H11Cl3NO2 [M-H]-: 389.98609;

Found: 389.98603.

2,4,6-Trichloro-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3h). White solid,

m.p.: 200.7-202.1℃. Isolated yield: 13%. 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J =

9.0 Hz, 3H), 7.47 (d, J = 2.0 Hz, 1H), 7.37 (s, 2H), 7.22 – 7.16 (m, 1H), 6.97 (d, J =

8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 161.7, 153.8,

151.4, 136.2, 134.2, 133.1, 132.7, 130.5, 129.3, 128.2, 128.1, 126.5, 122.3, 121.2,

118.7. HRMS (APCI): calc. for C19H11Cl5NO2 [M+H]+: 459.92269; Found:

459.92191.

2-Chloro-N-(4-(2,4-dichlorophenoxy)phenyl)-4-(trifluoromethyl)benzamide (3i).

White solid, m.p.: 158.9-159.5℃. Isolated yield: 76%. 1H NMR (500 MHz, CDCl3) δ

7.88 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.62 (d, J

= 9.0 Hz, 2H), 7.48 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 9.0, 2.5 Hz, 1H), 6.99 (d, J = 9.0

Hz, 2H), 6.92 (d, J = 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 163.1, 153.8, 151.4,

138.3, 133.8 (d, J = 33.5 Hz), 132.9, 131.3, 130.9, 130.6, 129.3, 128.1, 127.5 (q, J =

4.0 Hz), 126.5, 124.3 (q, J = 3.6 Hz), 122.8 (d, J = 272.9 Hz), 122.1, 121.2, 118.7.

HRMS (ESI): calc. for C20H10Cl3F3NO2 [M-H]-: 457.97347; Found: 457.97326.

N-(4-(2,4-dichlorophenoxy)phenyl)-3-methoxybenzamide (3j). White solid, m.p.:


(d, J = 9.0 Hz, 2H), 7.46 (d, J = 2.5 Hz, 1H), 7.43 (s, 1H), 7.38 (d, J = 5.0 Hz, 2H),

7.18 (dd, J = 9.0, 2.5 Hz, 1H), 7.11 – 7.05 (m, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.90 (d, J

= 9.0 Hz, 1H), 3.86 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 165.5, 160.0, 153.1, 151.7,

136.2, 133.8, 130.5, 129.8, 129.0, 128.0, 126.3, 122.0, 120.9, 118.8, 118.6, 118.0,

112.5, 55.5. HRMS (ESI): calc. for C20H16Cl2NO3 [M+H]+: 388.05018; Found:

388.05076.

3-(Tert-butyl)-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3k). Pale yellow oil.

Isolated yield: 64%. 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1H), 7.79 (s, 1H), 7.67 –

7.54 (m, 4H), 7.47 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 7.6, 7.4 Hz, 1H), 7.18 (dd, J =

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8.5, 2.4 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.90 (d, J = 8.5 Hz, 1H), 1.37 (s, 9H). 13C

NMR (126 MHz, CDCl3) δ 166.4, 153.0, 152.1, 151.7, 134.6, 134.0, 130.5, 129.1,

129.0, 128.5, 128.0, 126.2, 124.4, 123.7, 122.1, 120.8, 118.8, 34.9, 31.3. HRMS (ESI):

calc. for C23H20Cl2NO2 [M-H]-: 412.08766; Found: 412.08766.

N-(4-(2,4-dichlorophenoxy)phenyl)-3-fluorobenzamide (3l). White solid, m.p.:


– 7.56 (m, 4H), 7.49 (d, J = 2.5 Hz, 1H), 7.50 – 7.43 (m, 1H), 7.30 – 7.23 (m, 1H),

7.21 (dd, J = 9.0, 2.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 1H). 13C

NMR (126 MHz, CDCl3) δ 164.5, 162.8 (d, J = 248.4 Hz), 153.4, 151.5, 137.0 (d, J =

6.8 Hz), 133.4, 130.5, 130.4, 129.2, 128.1, 126.4, 122.4 (d, J = 3.1 Hz), 122.3, 121.1,

119.0 (d, J = 21.3 Hz), 118.7, 114.5 (d, J = 23.0 Hz). HRMS (ESI): calc. for

C19H13Cl2FNO2 [M+H]+: 376.03019; Found: 376.03063.

3-Bromo-N-(4-(2,4-dichlorophenoxy)phenyl)benzamide (3m). White solid, m.p.:


(s, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H),

7.47 (d, J = 2.0 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.5 Hz, 1H), 6.96


153.4, 151.5, 136.7, 134.9, 133.4, 130.5, 130.4, 130.2, 129.2, 128.1, 126.4, 125.6,

123.0, 122.2, 121.1, 118.7. HRMS (ESI): calc. for C19H13BrCl2NO2 [M+H]+:

435.95012; Found: 435.95030.

N-(4-(2,4-dichlorophenoxy)phenyl)-3-(trifluoromethoxy)benzamide (3n). White

solid, m.p.: 167.7-169.0℃. Isolated yield: 64%. 1H NMR (500 MHz, CDCl3) δ 7.77

(d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H),

7.47 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 6.98


153.5, 151.5, 149.6, 136.9, 133.3, 130.6, 130.4, 129.3, 128.1, 126.5, 125.0, 124.3,

122.3, 121.1, 120.4 (q, J = 258.7 Hz), 120.0, 118.8. HRMS (ESI): calc. for

C20H13Cl2F3NO3 [M+H]+: 442.02191; Found: 442.02201.

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N-(4-(2,4-dichlorophenoxy)phenyl)-3-(trifluoromethyl)benzamide (3o). White solid,

m.p.: 157.8-158.1℃. Isolated yield: 50%. 1H NMR (500 MHz, CDCl3) δ 8.11 (s, 1H),

8.05 (d, J = 7.5 Hz, 1H), 7.89 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.65 – 7.52 (m, 3H),

7.47 (d, J = 2.5 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 6.92

(d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 164.3, 153.6, 151.4, 135.6, 133.3,

131.4 (q, J = 33.0 Hz), 130.5, 130.3, 129.5, 129.3, 128.5 (q, J = 3.8 Hz), 128.1, 126.5,

124.0 (q, J = 3.6 Hz), 123.6 (q, J = 272.7 Hz), 122.3, 121.2, 118.7. HRMS (ESI): calc.

for C20H13Cl2F3NO [M+H]+ 426.02700; Found: 426.02748.

N-(4-phenoxyphenyl)benzamide (3p). White solid, m.p.: 160.0-161.1℃. Isolated

yield: 90%. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 2H), 7.84 (s, 1H), 7.60

(d, J = 9.0 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 8.0

Hz, 2H), 7.09 (t, J = 7.5 Hz, 1H), 7.06 – 7.00 (m, 4H). 13C NMR (101 MHz,

DMSO-d6) δ 165.7, 157.5, 153.7, 134.8, 133.3, 131.8, 129.7, 128.8, 127.0, 123.1,

122.0, 119.6, 118.5. HRMS (ESI): calc. for C19H14NO2 [M-H]-: 288.10300; Found:

288.10277.

N-(3,5-dichloro-4-(2,4-dichlorophenoxy)phenyl)benzamide (3q). White solid, m.p.:

200.3-201.2 ℃. Isolated yield: 23%. 1H NMR (500 MHz, CDCl3) δ 7.89 (s, 1H), 7.86

(d, J = 7.5 Hz, 2H), 7.80 (s, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H),

7.47 (d, J = 2.5 Hz, 1H), 7.09 (dd, J = 9.0, 2.5 Hz, 1H), 6.42 (d, J = 9.0 Hz, 1H). 13C

NMR (126 MHz, CDCl3) δ 165.7, 151.2, 143.1, 136.4, 133.9, 132.5, 130.5, 129.8,

129.0, 127.9, 127.6, 127.0, 123.5, 120.6, 115.1. HRMS (ESI): calc. for C19H12Cl4NO2

[M+H]+: 425.96197; Found: 425.96147.

N-(3-chloro-4-(2,4,6-trichlorophenoxy)phenyl)benzamide (3r). White solid, m.p.:

182.9-183.7℃. Isolated yield: 32%. 1H NMR (500 MHz, CDCl3) δ 7.91 – 7.84 (m,

3H), 7.81 (s, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.46 (s, 2H), 7.41

(dd, J = 9.0, 2.5 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ

165.6, 148.8, 146.2, 134.5, 133.6, 132.1, 131.5, 130.4, 129.2, 128.9, 127.0, 123.1,

123.0, 119.51, 114.5. HRMS (ESI): calc. for C19H12Cl4NO2 [M+H]+: 425.96167;

Found: 425.96144.

S11

N-(3,5-dichloro-4-(2,4,6-trichlorophenoxy)phenyl)benzamide (3s). White solid,

m.p.: 190.5-191.2℃. Isolated yield: 54%. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J =

7.5 Hz, 2H), 7.82 (s, 1H), 7.73 (s, 2H), 7.61 (dd, J = 7.6, 7.5 Hz, 1H), 7.53 (dd, J =

7.6, 7.5 Hz, 2H), 7.34 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 166.3, 148.0, 145.2,

135.3, 134.5, 132.8, 129.8, 129.5, 129.4, 127.7, 127.5, 127.3, 121.1. HRMS (ESI):

calc. for C19H11Cl5NO2 [M+H]+: 459.92269; Found: 459.92270.

N-(3,5-dichloro-4-(mesityloxy)phenyl)benzamide (3t). White solid, m.p.:


– 7.79 (m, 2H), 7.66 (s, 2H), 7.59 – 7.54 (m, 1H), 7.52 – 7.43 (m, 2H), 6.79 (s, 2H),

2.25 (s, 3H), 2.09 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 166.1, 151.9, 147.1, 134.7,

133.8, 133.6, 132.7, 130.3, 129.4, 128.7, 127.5, 127.1, 121.5, 21.1, 17.6. HRMS (ESI):

calc. for C22H20Cl2NO2 [M+H]+: 400.08656; Found: 400.08636.

N-(4-(2,4-dichlorophenoxy)phenyl)picolinamide (3u). White solid, m.p.:


(s, 1H), 8.30 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 7.5 Hz, 2H), 7.50 (s, 1H), 7.47 (s, 1H),

7.18 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 6.5 Hz, 2H), 6.90 (d, J = 8.0 Hz, 1H). 13C NMR

(126 MHz, CDCl3) δ 161.9, 152.7, 151.8, 149.7, 148.0, 137.7, 133.8, 130.4, 128.8,

128.0, 126.5, 126.1, 122.4, 121.3, 120.7, 118.9. HRMS (ESI): calc. for

C18H13Cl2N2O2 [M+H]+: 359.03486; Found: 359.03470.

N-(4-((3,5-dichloropyridin-2-yl)oxy)phenyl)picolinamide (3v). White solid, m.p.:

182.0-182.9 ℃. Isolated yield: 22%. 1H NMR (500 MHz, CDCl3) δ 10.19 (s, 1H),

8.63 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.96 – 7.91 (m, 3H), 7.61 (d, J =

2.5 Hz, 1H), 7.55 – 7.49 (m, 1H), 7.40 (dd, J = 5.5, 3.0 Hz, 3H). 13C NMR (126 MHz,

CDCl3) δ 162.7, 157.9, 149.8, 148.5, 139.0, 139.0, 138.3, 136.1, 134.6, 128.4, 127.5,

127.3, 123.0, 120.7, 111.8. HRMS (ESI): calc. for C17H12Cl2N3O2 [M+H]+: 360.03011;

Found: 360.02999.

N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide (3w). White solid,

m.p.: 113.3-114.5℃. Isolated yield: 39%. 1H NMR (500 MHz, CDCl3) δ 10.07 (s,

1H), 8.63 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.99 – 7.88 (m, 1H), 7.83 (d, J

= 9.0 Hz, 2H), 7.73 (s, 1H), 7.50 (dd, J = 7.5, 5.0 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H),

S12

7.08 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 8.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ

162.0, 156.4, 151.5, 149.6, 148.0, 137.8, 134.7, 128.1 (q, J = 3.7 Hz), 126.6, 125.9 (q,

J = 33.6 Hz), 125.1 (q, J = 3.7 Hz), 124.9, 123.4 (q, J = 271.9 Hz), 122.5, 121.4,

120.2, 118.2. HRMS (ESI): calc. for C19H13ClF3N2O2 [M+H]+: 393.06122; Found:

393.06097.

N-(3-chloro-4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide (3x).


10.11 (s, 1H), 8.63 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 2.5 Hz,

1H), 7.94 (td, J = 7.5, 1.5 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 9.0, 2.5 Hz,

1H), 7.53 (dd, J = 7.0, 5.5 Hz, 1H), 7.45 – 7.38 (m, 1H), 7.11 (d, J = 9.0 Hz, 1H), 6.77


137.9, 136.0, 128.1 (q, J = 3.8 Hz), 127.0, 126.8, 125.9 (q, J = 34.1 Hz), 125.0 (q, J =

3.7 Hz), 124.1, 123.4 (q, J = 272.0 Hz), 122.5, 122.4, 122.0, 119.4, 116.6. HRMS

(ESI): calc. for C19H12Cl2F3N2O2 [M+H]+: 427.02224; Found: 427.02192.

N-(3,5-dichloro-4-(2,4-dichlorophenoxy)phenyl)picolinamide (3y). White solid,


1H), 8.64 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.02 – 7.89 (m, 3H), 7.56 (ddd,

J = 7.5, 4.5, 1.0 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 9.0, 2.5 Hz, 1H), 6.46


137.9, 136.3, 130.5, 129.8, 127.8, 127.6, 127.0, 123.5, 122.6, 120.0, 115.1. HRMS

(ESI): calc. for C18H11Cl4N2O2 [M+H]+: 426.95691; Found: 426.95668.

N-(3,5-dichloro-4-(2,4,6-trichlorophenoxy)phenyl)picolinamide (3z). White solid,


1H), 8.59 (s, 1H), 8.26 (d, J = 6.0 Hz, 1H), 7.92 (s, 1H), 7.83 (s, 2H), 7.50 (s, 1H),

7.31 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 162.5, 149.4, 148.5, 148.0, 145.0, 138.3,

135.2, 129.7, 129.5, 127.6, 127.4, 127.4, 123.0, 120.4. HRMS (ESI): calc. for

C18H10Cl5N2O2 [M+H]+: 460.91794; Found: 460.91764.

N-(3-chloro-4-(naphthalen-2-yloxy)phenyl)picolinamide (3a'). White solid, m.p.:


(d, J = 3.5 Hz, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.07 (s, 1H), 7.93 (t, J = 7.5 Hz, 1H),

S13

7.88 – 7.77 (m, 2H), 7.69 – 7.59 (m, 2H), 7.55 – 7.48 (m, 1H), 7.45 (t, J = 7.5 Hz, 1H),

7.39 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J = 8.5 Hz,

1H). 13C NMR (126 MHz, CDCl3) δ 162.0, 155.2, 149.4, 148.4, 148.0, 137.8, 134.8,

134.2, 130.1, 130.0, 127.7, 127.1, 126.8, 126.7, 126.6, 124.6, 122.5, 122.0, 119.3,

118.9, 112.2. HRMS (ESI): calc. For C22H16ClN2O2 [M+H]+: 375.08948; Found:

375.08923.

N-(3,5-dichloro-4-(naphthalen-2-yloxy)phenyl)picolinamide (3b'). White solid,


1H), 8.63 (d, J = 3.5 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.06

– 7.89 (m, 3H), 7.87 (d, J = 7.5 Hz, 1H), 7.62 – 7.49 (m, 4H), 7.28 (d, J = 8.0 Hz, 1H),

6.45 (d, J = 7.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 162.0, 152.6, 148.9, 147.9,

143.7, 138.1, 135.8, 134.8, 130.2, 127.6, 127.0, 126.7, 125.8, 125.4, 124.8, 122.7,

122.3, 122.1, 120.1, 106.8. HRMS (ESI): calc. for C22H15Cl2N2O2 [M+H]+:

409.05051; Found: 409.05023.

N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)pyrazine-2-carboxamide (3c').


9.73 (s, 1H), 9.54 (d, J = 1.5 Hz, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.62 (dd, J = 2.5, 1.5

Hz, 1H), 7.86 – 7.79 (m, 2H), 7.76 (d, J = 2.1 Hz, 1H), 7.46 (dd, J = 8.7, 2.2 Hz, 1H),

7.13 – 7.07 (m, 2H), 6.99 (d, J = 8.6 Hz, 1H). δ 13C NMR (126 MHz, CDCl3) δ 160.6,

156.1, 152.0, 147.7, 144.7, 144.2, 142.4, 134.0, 128.1 (q, J = 3.8 Hz), 126.1 (q, J =

33.6 Hz), 125.1, 125.1 (q, J = 3.4 Hz), 123.3 (q, J = 272.0 Hz), 121.6, 120.1, 118.5.

HRMS (ESI): calc. for C18H14ClF3N3O2 [M+H]+: 394.05647; Found: 394.05566.

N-(4-(2-chloro-4-methylphenoxy)phenyl)picolinamide (3d'). White solid, m.p.:

91.5-92.3℃. Isolated yield: 63%. 1H NMR (500 MHz, CDCl3) δ 9.99 (s, 1H), 8.66 –

8.56 (m, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.96 – 7.85 (m, 1H), 7.79 – 7.68 (m, 2H), 7.52

– 7.43 (m, 1H), 7.27 (s, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 8.9 Hz, 2H), 6.90

(d, J = 8.2 Hz, 1H), 2.33 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 161.8, 153.8, 150.1,

149.7, 147.9, 137.6, 134.7, 133.1, 131.1, 128.5, 126.4, 125.4, 122.3, 121.2, 120.7,

118.1, 20.5. HRMS (ESI): calc. for C19H16ClN2O2 [M+H]+: 339.08948; Found:

339.08892.

S14

N-(4-(2-Bromo-4-(trifluoromethyl)phenoxy)phenyl)picolinamide (3e'). White solid,

m.p.: 94.1-95.6℃. Isolated yield: 38%. 1H NMR (500 MHz, CDCl3) δ 10.10 (s, 1H),

8.65 (d, J = 4.7 Hz, 1H), 8.33 (d, J = 7.8 Hz, 1H), 7.95 (td, J = 7.7, 1.7 Hz, 1H), 7.92

(d, J = 2.1 Hz, 1H), 7.88 – 7.83 (m, 2H), 7.61 – 7.45 (m, 2H), 7.19 – 7.04 (m, 2H),

6.94 (d, J = 8.6 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 162.0, 157.5, 151.5, 149.6,

148.0, 137.7, 134.7, 131.1 (q, J = 3.7 Hz), 126.6, 126.2 (q, J = 33.3 Hz), 125.8 (q, J =

3.8 Hz), 123.2 (q, J = 272.1 Hz), 122.4, 121.4, 120.4, 117.9, 113.5. HRMS (ESI): calc.

for C19H13BrF3N2O2 [M+H]+: 437.01070; Found: 437.00965.

S15

3. 1H-NMR, 13C-NMR and HR-MS spectra for compounds 1d’, 1e’ and 3a-3b’

➢ 1H-NMR spectrum for 1d’

➢ 13C-NMR spectrum for 1d’

S16

➢ HRMS (ESI) spectrum of 1d’

8 #22 RT: 0.21 AV: 1 SB: 5 0.44-0.53 NL: 3.43E9T: FTMS + c ESI Full ms [50.0000-750.0000]

60 80 100 120 140 160 180 200 220 240 260 280 300 320

m/z

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5

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20

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40

45

50

55

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234.06769

275.0939356.05029 87.08091 288.09586

238.07156

151.03500 332.14035260.0831173.06543 181.97877 221.68569101.09642

246.06758

310.30996205.08567117.10235 130.06500

S17

➢ 1H-NMR spectrum for 1e’

➢ 13C-NMR spectrum for 1e’

S18

➢ HRMS (ESI) spectrum of 1e’

11 #24 RT: 0.23 AV: 1 SB: 4 0.51-0.58 NL: 1.34E9T: FTMS + c ESI Full ms [50.0000-750.0000]

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460

m/z

0

5

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15

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30

35

40

45

50

55

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331.98861

338.34088

360.32279 384.0194487.08090 279.15852149.02307 402.18142254.07817114.09144 181.98769 310.30972219.17391 446.2597165.06042

S19

➢ 1H-NMR spectrum for 3a

➢ 13C-NMR spectrum for 3a

S20

➢ HRMS (ESI) spectrum of 3a

S21

➢ 1H-NMR spectrum for 3b

➢ 13C-NMR spectrum for 3b

S22

➢ HRMS (ESI) spectrum of 3b

S23

➢ 1H-NMR spectrum for 3c

➢ 13C-NMR spectrum for 3c

S24

➢ HRMS (ESI) spectrum of 3c

S25

➢ 1H-NMR spectrum for 3d

➢ 13C-NMR spectrum for 3d

S26

➢ HRMS (ESI) spectrum of 3d

S27

➢ 1H-NMR spectrum for 3e

➢ 13C-NMR spectrum for 3e

S28

➢ HRMS (ESI) spectrum of 3e

S29

➢ 1H-NMR spectrum for 3f

➢ 13C-NMR spectrum for 3f

S30

➢ HRMS (ESI) spectrum of 3f

S31

➢ 1H-NMR spectrum for 3g

➢ 13C-NMR spectrum for 3g

S32

➢ HRMS (ESI) spectrum of 3g

S33

➢ 1H-NMR spectrum for 3h

➢ 13C-NMR spectrum for 3h

S34

➢ HRMS (ESI) spectrum of 3h

SL44_20191029133921 #19 RT: 0.21 AV: 1 NL: 1.51E8T: FTMS + c APCI corona Full ms [50.0000-750.0000]

458 459 460 461 462 463 464 465 466 467 468 469

m/z

0

10000000

20000000

30000000

40000000

50000000

60000000

70000000

80000000

90000000

100000000

110000000

120000000

130000000

140000000

150000000

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461.91888

459.92191 463.91599

462.92215 465.91275

460.92520 464.91934

466.91626 467.90945

468.91327462.17755461.65088458.91318459.65851

464.17731 465.64474460.17902

S35

➢ 1H-NMR spectrum for 3i

➢ 13C-NMR spectrum for 3i

S36

➢ HRMS (ESI) spectrum of 3i

S37

➢ 1H-NMR spectrum for 3j

➢ 13C-NMR spectrum for 3j

S38

➢ HRMS (ESI) spectrum of 3j

S39

➢ 1H-NMR spectrum for 3k

➢ 13C-NMR spectrum for 3k

S40

➢ HRMS (ESI) spectrum of 3k

S41

➢ 1H-NMR spectrum for 3l

➢ 13C-NMR spectrum for 3l

S42

➢ HRMS (ESI) spectrum of 3l

S43

➢ 1H-NMR spectrum for 3m

➢ 13C-NMR spectrum for 3m

S44

➢ HRMS (ESI) spectrum of 3m

S45

➢ 1H-NMR spectrum for 3n

➢ 13C-NMR spectrum for 3n

S46

➢ HRMS (ESI) spectrum of 3n

S47

➢ 1H-NMR spectrum for 3o

➢ 13C-NMR spectrum for 3o

S48

➢ HRMS (ESI) spectrum of 3o

S49

➢ 1H-NMR spectrum for 3p

➢ 13C-NMR spectrum for 3p

S50

➢ HRMS (ESI) spectrum of 3p

S51

➢ 1H-NMR spectrum for 3q

➢ 13C-NMR spectrum for 3q

S52

➢ HRMS (ESI) spectrum of 3q

S53

➢ 1H-NMR spectrum for 3r

➢ 13C-NMR spectrum for 3r

S54

➢ HRMS (ESI) spectrum of 3r

S55

➢ 1H-NMR spectrum for 3s

➢ 13C-NMR spectrum for 3s

S56

➢ HRMS (ESI) spectrum of 3s

S57

➢ 1H-NMR spectrum for 3t

➢ 13C-NMR spectrum for 3t

S58

➢ HRMS (ESI) spectrum of 3t

S59

➢ 1H-NMR spectrum for 3u

➢ 13C-NMR spectrum for 3u

S60

➢ HRMS (ESI) spectrum of 3u

S61

➢ 1H-NMR spectrum for 3v

➢ 13C-NMR spectrum for 3v

S62

➢ HRMS (ESI) spectrum of 3v

S63

➢ 1H-NMR spectrum for 3w

➢ 13C-NMR spectrum for 3w

S64

➢ HRMS (ESI) spectrum of 3w

S65

➢ 1H-NMR spectrum for 3x

➢ 13C-NMR spectrum for 3x

S66

➢ HRMS (ESI) spectrum of 3x

S67

➢ 1H-NMR spectrum for 3y

➢ 13C-NMR spectrum for 3y

S68

➢ HRMS (ESI) spectrum of 3y

S69

➢ 1H-NMR spectrum for 3z

➢ 13C-NMR spectrum for 3z

S70

➢ HRMS (ESI) spectrum of 3z

S71

➢ 1H-NMR spectrum for 3a’

➢ 13C-NMR spectrum for 3a’

S72

➢ HRMS (ESI) spectrum of 3a’

S73

➢ 1H-NMR spectrum for 3b’

➢ 13C-NMR spectrum for 3b’

S74

➢ HRMS (ESI) spectrum of 3b’

S75

➢ 1H-NMR spectrum for 3c’

➢ 13C-NMR spectrum for 3c’

S76

➢ HRMS (ESI) spectrum of 3c’

3 #21 RT: 0.23 AV: 1 SB: 5 0.09-0.14 , 0.41-0.45 NL: 9.98E7T: FTMS + c APCI corona Full ms [50.0000-750.0000]

50 100 150 200 250 300 350 400 450 500

m/z

0

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30

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55

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394.05566

C 18 H12 O2 N3 Cl F 3

338.34085

79.02174

75.04463 178.15867136.07548320.33045

360.09455

C 12 H18 O4 N3 Cl F 3219.1738587.08089 108.08095 173.08051288.03903

C 11 H8 N4 Cl F 3235.16871 415.21069

445.11859

C 25 H21 O2 Cl F 3 523.47192

S77

➢ 1H-NMR spectrum for 3d’

➢ 13C-NMR spectrum for 3d’

S78

➢ HRMS (ESI) spectrum of 3d’


333 334 335 336 337 338 339 340 341 342 343 344 345 346

m/z

0

5

10

15

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25

30

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45

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55

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65

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75

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Ab

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339.08892

341.08587

340.09228

338.34100

342.08920

339.34442343.09235340.34759336.32561 337.32882334.30975 344.09506

338.08221

S79

➢ 1H-NMR spectrum for 3e’

➢ 13C-NMR spectrum for 3e’

S80

➢ HRMS (ESI) spectrum of 3e’


370 380 390 400 410 420 430 440 450 460 470 480 490

m/z

0

5

10

15

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25

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Ab

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437.00965

440.01096

391.28329

441.01428392.28622 415.21011 429.02566367.37561 389.30376 409.38058 467.40912

N-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)phenyl ... · N-(4-(2-Chloro-4-(trifluoromethyl)phenoxy)phenyl)picolinamide as a new inhibitors of mitochondrial complex III: Synthesis,

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