Journal of Medicinal Chemistry
Article
AAV-qC8 (5). Yield 40%; HPLC purity 95%; 1H NMR (DMSO-d6,
400 MHz, 298 K) δ/ppm: 9.42 (s, 1H), 9.15 (s, 1H), 9.07 (s, 1H),
8.65 (bs, 2H), 8.53−8.46 (m, 2H), 7.85 (s, 3H), 7.58−7.51 (m, 2H),
7.48−7.42 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 7.6 Hz,
1H), 7.18 (s, 1H), 6.96 (bs, 1H), 6.81−6.78 (m, 1H), 6.73−6.68 (m,
2H), 6.58 (bs, 1H), 6.39 (m. 1H), 6.23 (m, 1H), 5.95 (d, J = 6.8 Hz,
1H), 5.82 (bs, 1H), 5.78−5.76 (m, 2H), 5.6 (s, 1H), 5.37 (d, J = 7.6
Hz, 1H), 5.30 (bs, 2H), 5.21−5.15 (m, 2H), 5.11−5.09 (m, 2H), 4.89
(bs, 1H), 4.68 (d, J = 6.4 Hz, 1H), 4.49−4.41 (m, 2H), 4.30 (s, 1H),
4.20 (d, J = 11.2 Hz, 1H), 4.10−4.02 (m, 1H), 4.02 (s, 2H), 3.72−
3.68 (m, 1H), 3.6−3.43 (m, 4H), 3.18 (s, 6H), 3.06 (q, J = 6.8 Hz,
3H), 2.33−2.32 (m, 1H), 2.20−2.08 (m, 2H), 1.96 (t, J = 8.0 Hz,
3H), 1.82−1.81 (m, 1H), 1.73−1.66 (m, 1H), 1.54−1.44 (m, 3H),
1.39 (t, J = 6.4 Hz, 2H), 1.24 (bs, 10H), 1.13 (d, J = 5.2 Hz, 3H),
0.92−0.84 (m, 9H). HRMS: (ESI+) 919.3680 (observed), 919.3700
(calced for [M + H]2).
= 5.2 Hz, 1H), 4.04−3.96 (m, 2H), 3.75−3.66 (m, 1H), 3.62−3.50
(m, 2H),3.49−3.43 (m, 2H), 2.99 (s, 1H), 2.91−2.83 (m, 1H), 2.67
(s, 2H), 2.55 (s, 6H), 2.33 (s, 1H), 2.19−2.06 (m, 2H), 1.83−1.80
(m, 1H), 1.71−1.59 (bs, 2H), 1.51−1.47 (bs, 4H), 1.24 (bs, 2H),
1.13 (d, J = 5.6 Hz, 3H), 0.89 (dd, J = 18.8 Hz, 5.6 Hz, 6H). HRMS:
(ESI+) 879.8193 (observed), 879.8154 (calcd for [M+ + H]2+).
AAV-qNaph (10). Yield 46%; HPLC purity 92%; 1H NMR
(DMSO-d6, 400 MHz, 298 K) δ/ppm: 9.45 (s, 1H), 8.70−8.64 (m,
2H), 8.50−8.47 (m, 2H), 8.12 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0
Hz, 1H), 7.88−7.84 (m, 2H), 7.80 (d, J = 7.2 Hz, 1H), 7.69−7.53 (m,
6H), 7.5−7.41 (m, 1H), 7.44−7.36 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H),
7.26 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 6.94 (s, 1H), 6.79−6.77 (m,
1H), 6.73−6.69 (m, 2H), 6.61 (s, 1H), 6.4 (s, 1H), 6.25 (s, 1H), 5.95
(d, J = 5.6 Hz, 2H), 5.86 (s, 1H), 5.75 (d, J = 7.6 Hz, 1H), 5.59 (s,
1H), 5.39−5.33 (m, 2H), 5.28 (s, 1H), 5.22−5.12 (m, 2H), 5.06 (s,
2H), 4.69 (d, J = 6.4 Hz, 1H), 4.44−4.42 (m, 2H), 4.22−4.20 (m,
1H), 4.09−4.08 (m, 1H), 3.97 (bs, 1H), 3.71−3.69 (m, 1H), 3.56−
3.49 (m, 4H), 3.00 (s, 6H), 2.44 (s, 3H), 2.19−2.08 (m, 4H), 1.87−
1.79 (m, 1H), 1.7−1.59 (m, 2H),1.51−1.37 (m, 3H), 1.14−1.12 (m,
3H), 0.88 (dd, J = 18.4 Hz, 6.4 Hz, 6H). HRMS: (ESI+) 904.8256
(observed), 904.8280 (calcd for [M++H]2+).
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AAV-qC10 (6). Yield 42%; HPLC purity 98%; H NMR (DMSO-
d6, 400 MHz, 298 K) δ/ppm: 9.44 (br, 1H), 9.16 (s, 1H), 9.07 (s,
1H), 8.81 (bs, 1H), 8.70 (bs, 2H), 8.59−8.49 (m, 2H), 8.27 (bs, 1H),
7.91−7.83 (m, 3H), 7.61−7.54 (m, 3H), 7.51−7.46 (m, 3H), 7.33 (d,
J = 8.4 Hz, 1H), 7.22−7.17 (m, 2H), 7.05 (s, 1H), 6.80−6.76 (m,
1H), 6.72−6.68 (m, 2H), 6.55−6.53 (m, 1H), 6.25 (s, 1H), 6.00−
5.94 (m, 2H), 5.84 (bs, 1H), 5.68 (d, J = 8.0 Hz, 1H), 5.63 (s, 1H),
5.38−5.33 (d, 2H), 5.31 (s, 1H), 5.22−5.16 (m, 2H), 5.12−5.10 (m,
2H), 4.93 (bs, 1H), 4.69 (d, J = 6.4 Hz, 1H), 4.49−4.41 (m, 2H),
4.28−4.16 (m, 2H), 4.13−4.01 (m, 5H), 3.95 (bs, 1H), 3.7 (m, 1H),
3.62−3.49 (m, 4H), 3.18 (s, 6H), 3.07 (d, J = 6.4 Hz, 2H), 2.63 (bs,
3H), 2.55 (s, 1H), 2.33−2.32 (m, 1H), 2.21−2.08 (m, 2H), 2.00−
1.95 (m, 2H), 1.88−1.80 (m, 1H), 1.73−1.55 (m, 3H), 1.49 (s, 2H),
1.40 (t, J = 6.0 Hz, 2H), 1.24 (bs, 15H), 1.13 (d, J = 6.0 Hz, 3H), 0.91
(d, J = 5.6 Hz, 3H), 0.88−0.83 (m, 6H). HRMS: (ESI+) 933.3817
(observed), 933.3825 (calcd for [M + H]2+).
AAV-qBiph (11). Yield 42%; HPLC purity 96%; 1H NMR (DMSO-
d6, 400 MHz, 298 K) δ/ppm: 9.45 (s, 1H), 9.17 (s, 1H), 9.09 (s, 1H),
8.75 (bs, 1H), 8.68 (s, 2H), 8.52−8.51 (m, 1H), 7.89 (t, J = 8.0 Hz,
2H), 7.73−7.59 (m, 6H), 7.55 (d, J = 6.0 Hz, 3H), 7.51−7.47 (m,
4H), 7.44−7.38 (m, 1H), 7.34 (d, J = 6.0 Hz, 1H), 7.23 (d, J = 8.4 Hz
2H), 7.18 (bs, 1H), 7.02 (bs, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.73−
6.69 (m, 2H), 6.57 (s, 1H), 6.4 (s, 1H), 6.25 (s, 1H), 5.98−5.96 (m,
2H), 5.70 (d, J = 7.6 Hz 1H), 5.62 (s, 1H), 5.37−5.35 (m, 2H), 5.30
(s, 1H), 5.19 (s, 2H), 4.93 (bs, 1H), 4.70 (d, J = 6.4 Hz, 1H), 4.47
4.43 (m, 2H), 4.28−4.19 (m, 2H), 4.09 (t, J = 5.2 Hz, 1H), 4.04−
4.00 (m, 1H), 3.77−3.70 (m, 1H), 3.72−3.69 (m, 2H), 3.63−3.45
(m, 3H), 3.01 (s, 6H), 2.57 (s, 2H), 2.19−2.07 (m, 4H),1.84 (d, J =
12.0 Hz, 1H), 1.71−1.64 (m, 2H), 1.53−1.43 (m,3H), 1.14 (d, J = 6.4
Hz, 3H), 0.88 (dd, J = 19.6 Hz,6.0 Hz 6H). HRMS: (ESI+) 917.8320
(observed), 917.8310 (calcd for [M + H]2+).
1
AAV-qC12 (7). Yield 43%; HPLC purity 98%; H NMR (DMSO-
d6, 400 MHz, 298 K) δ/ppm: 9.44 (bs, 1H), 9.16 (s, 1H), 9.07 (s,
1H), 8.69 (s, 1H), 8.57−8.48 (m, 2H), 8.25 (br, 2H), 7.9−7.82 (m,
3H), 7.6−7.53 (m, 3H), 7.51−7.42 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H),
7.23 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.01 (bs, 1H), 6.82−6.77 (m,
1H), 6.73−6.67 (m, 1H), 6.55 (s, 1H), 6.39 (bs, 1H), 6.24 (s, 1H),
5.99−5.91 (m, 2H), 5.83 (bs, 1H), 5.76 (d, J = 7.6 Hz, 1H), 5.62 (s,
1H), 5.4−5.28 (m, 3H), 5.19 (s, 2H), 5.12 (s, 2H), 4.93−4.92 (m,
1H), 4.72−4.65 (m, 1H), 4.49−4.41 (m, 2H), 4.29−4.16 (m, 2H),
4.13−3.99 (m, 4H), 3.74−3.66 (m, 1H), 3.59−3.50 (m, 5H), 3.18 (s,
6H), 3.07 (q, J = 6.4 Hz, 2H), 2.57 (m, 2H), 2.34−2.31 (m, 1H),
2.17−2.07 (m, 2H), 2.0−1.95 (m, 2H), 1.88−1.79 (m, 1H), 1.7−1.6
(m, 2H), 1.53−1.45 (m, 2H),1.43−1.36 (m,2H) 1.24 (br,18H), 1.13
(d, J = 6.0 Hz, 3H), 0.92−0.83 (m, 9H). HRMS: (ESI+) 947.3984
(observed), 947.3965 (calcd for [M + H]2+).
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CBP-Van (12). Yield 45%; HPLC purity 95%; H NMR (DMSO-
d6, 400 MHz, 298 K) δ/ppm: 9.45 (s, 1H), 8.58 (bs, 1H), 8.43−8.21
(m, 1H), 8.05−7.79 (m, 2H), 7.78−7.56 (m, 5H), 7.55−7.43 (m,
4H), 7.43−7.19 (m, 3H), 6.89−6.64 (m, 2H), 6.36 (d, J = 14.8 Hz,
1H), 5.87−5.70 (m, 1H), 5.55−5.52 (m, 1H), 5.42−5.12 (m, 4H),
4.94−4.68 (m, 2H), 4.61−4.36 (m, 2H), 4.33 (d, 1H), 4,.17 (bs, 1H),
4.00 (bs, 2H), 3.85 (d, J = 13.2 Hz, 1H), 3.73−3.62 (m, 1H), 3.6−
3.51 (m, 2H), 3.12 (s, 1H), 3.03−2.98 (m, 1H), 2.54 (s, 2H), 2.33−
2.16 (m, 2H),1.77−1.56 (m, 2H), 1.28−1.19 (bs, 2H), 1.1−1.01 (m,
3H), 0.99−0.82 (m, 6H). HRMS ESI+m/z: 825.7471 (observed),
825.7454 (calcd for [M + 2H]2+).
1
AAV-qC14 (8). Yield 45%; HPLC purity 99; H NMR (DMSO-d6,
Protocol for the Synthesis of Control Compound 13. p-Toluic
acid (1 equiv) and DIPEA (5.0 equiv) were dissolved in a 4:1 mixture
of DCM/DMF. The reaction mixture was cooled to 4 °C and HBTU
(1.2 equiv) was added. Compound 3c (1.1 equiv) was then added to
the reaction mixture and allowed to stir for 24 h at room temperature.
Following this, the reaction mixture was diluted with DCM and was
washed sequentially with water, 1 N HCl solution, and aqueous
saturated bicarbonate solution. The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo. A pure
product was obtained through column chromatography using silica as
the stationary phase (gradient: 60%−70% ethyl acetate/hexane).
N-(2-(Decylamino)-2-oxoethyl)-N,N-dimethyl-3-(4-
methylbenzamido)propan-1-aminium Trifluoroacetate (13). Yield
400 MHz, 298 K) δ/ppm: 9.44 (bs, 1H), 9.16 (s, 1H), 9.08 (s, 1H),
8.69 (s, 1H), 8.54 (t, J = 5.6 Hz, 2H), 8.25 (bs, 2H), 7.89−7.84 (m,
3H), 7.59−7.52 (m, 3H), 7.50−7.41 (m, 2H), 7.32 (d, J = 8.4 Hz,
1H), 7.24 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 7.00 (s, 1H), 6.79−6.77
(m, 1H), 6.73−6.68 (m, 2H), 6.55 (s, 1H), 6.39 (s, 1H), 6.25 (s, 1H),
5.95 (d, J = 6.4 Hz, 1H), 5.91 (s, 1H), 5.76 (d, J = 8.0 Hz, 1H), 5.61
(s, 1H), 5.41−5.27 (m, 3H), 5.19 (s, 2H), 5.11 (s, 2H), 4.92 (bs,
1H), 4.73−4.64 (m, 1H), 4.49−4.41 (m, 2H), 4.32−4.17 (m, 2H),
4.11−4.09 (m, 1H), 4.03 (s, 3H), 3.75−3.65 (m, 1H), 3.59−3.44 (m,
3H), 3.18 (s, 6H), 3.07 (q, J = 6.4 Hz, 2H), 2.54 (m, 2H), 2.34−2.31
(m, 1H), 2.19−2.07 (m, 2H), 1.99−1.92 (m, 2H), 1.87−1.79 (m,
1H), 1.70−1.59 (m, 2H), 1.48 (s, 2H), 1.40 (s, 2H), 1.24 (bs, 22H),
1.13 (d, J = 6.0 Hz, 3H), 0.93−0.80 (m, 9H). HRMS: (ESI+)
961.4145 (observed), 961.4122 (calcd for [M+ + H]2+).
1
65%; H NMR (DMSO-d6, 400 MHz, 298 K) δ/ppm: 8.53 (s, 1H;
NH), 8.46 (s, 1H; NH), 7.74 (d, J = 6.8 Hz, 1H; ArH), 7.27 (s, 2H;
+
+
AAV-qPh (9). Yield 44%; HPLC purity 94%; 1H NMR (DMSO-d6,
400 MHz, 298 K) δ/ppm: 9.43 (s, 1H), 9.17 (s, 1H), 9.06 (s, 1H),
8.73−8.47 (m, 3H), 8.17 (bs, 2H), 7.86 (s, 1H), 7.57−7.42 (m, 8H),
7.33 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.05
(s, 1H), 6.80−6.68 (m, 2H), 6.53 (m, 1H), 6.39 (d, 1H), 6.25 (s,
1H), 5.97 (d, J = 6.4 Hz, 1H) 5.90 (s, 1H), 5.79−5.75 (m, 1H), 5.63
(s, 1H), 5.37−5.30 (m, 2H), 5.18−5.10 (m, 3H), 4.92 (bs, 1H), 4.68
(d, J = 6.0 Hz, 1H), 4.44−4.42 (m, 2H),4.29−4.16 (m, 1H), 4.10 (t, J
HAr), 4.00 (s, 2H; COCH2NMe2 ), 3.56−3.52 (m, 2H; CH2NMe2 ),
3.18 (s, 6H; N+(CH3)2), 3.07−3.04 (m, 2H; CH2CH2NHCO), 2.35
(s, 3H; PhCH3), 1.96−1.94 (m, 2H; CH2NH), 1.38−1.36 (m, 2H;
CH2CH2CH2NHCO), 1.23 (s, 16H; CH2(alkyl chain)), 0.86−0.84
(m,3H; CH3); HRMS ESI+ m/z: 418.3434 (observed), 418.3429
(calcd for M+).
Biological Assays. Antibacterial Assay. The antibacterial
activities of the compounds are reported as their MIC, which is the
10198
J. Med. Chem. 2021, 64, 10185−10202