Azoles as Mimics of the Turn Region of Gramicidin S
Leu, 4H), 1.40 (Hg Leu, 2H), 0.96 (Hg Val, 6H), 0.89 (Hd Leu, 12H),
0.87 ppm (Hg Val, 6H); 13C NMR (150 MHz, CD3OH): d=173.5,
172.4, 172.4, 136.8, 136.8, 130.4, 130.0, 129.7, 129.7, 129.2, 128.5,
124.5, 62.1, 62.0, 60.4, 60.4, 55.9, 54.9, 54.1, 52.4, 51.4, 51.3, 47.9,
40.6, 31.9, 31.9, 25.6, 25.6, 24.6, 23.2, 23.2, 23.0, 22.9, 19.6,
19.5 ppm; LC/MS: tR =8.06 min (10!90% CH3CN, 15 min run); MS
(ESI): m/z: 1222.73 [M+H]+; HRMS calculated for C63H96N15O10
[M+H]+: 1222.74591, found: 1222.74704.
CH3CN, 15 min run); MS (ESI): m/z: 1323.1 [M+H]+; HRMS calculat-
ed for C71H100N15O10 [M+H]+: 1322.77721, found: 1322.77827.
Peptide 2e: Yield: 36% (14 mmol, 19 mg): 1H NMR (750 MHz,
CD3OH): d=8.92–8.07 (Ar pyr, m, 9H), 8.88 (NH Phe, d, J=2.53 Hz,
1H), 8.77 (NH TrA, d, J=2.40 Hz, 1H), 8.67 (NH Leu, d, J=9.17 Hz,
1H), 8.66 (NH Leu, d, J=9.72 Hz, 1H), 8.65 (NH Orn, d, J=9.82 Hz,
1H), 8.62 (NH Orn, d, J=9.29 Hz, 1H), 7.90 (triazole, s, 1H), 7.80
(NH2 Orn, brs, 2H), 7.68 (NH Val, d, J=8.90 Hz, 1H), 7.64 (NH2 Orn,
brs, 2H), 7.44 (NH Val, d, J=8.86 Hz, 1H), 7.31–7.23 (Ar Phe, m,
5H), 6.36 (CH2pyr, dd, J=14.89 Hz, J=72.78 Hz, 2H), 4.90 (Ha Orn,
1H), 4.88 (Ha Orn, 1H), 4.62 (Ha Leu, 1H), 4.55 (Ha Leu, 1H), 4.48
(Ha Phe, 1H), 4.36 (Ha TrA, 1H), 4.32 (Ha Pro, 1H), 4.11 (Ha Val, 1H),
4.01 (Ha Pro, 1H), 3.98 (Ha Val, 1H), 3.72 (Hd Pro, 1H), 3.47 (Hd Pro,
1H), 3.10 (Hb Phe, 1H), 3.08 (Hb Phe, 1H), 3.00 (Hb Phe, 1H), 2.99
(Hd Orn, 1H), 2.92 (Hd Orn, 1H), 2.92 (Hb Phe, 1H), 2.81 (Hd Orn,
1H), 2.76 (Hd Orn, 1H), 2.47 (Hd Pro, 1H), 2.23 (Hb Val, 1H), 2.17 (Hd
Pro, 1H), 2.13 (Hb Val, 1H), 2.00 (Hb Orn, 1H), 1.98 (Hb Orn, 1H),
1.97 (Hb Pro, 1H), 1.72 (Hg Orn, 2H), 1.68 (Hg Pro, 1H), 1.68 (Hg Orn,
2H), 1.66 (Hb Pro, 1H), 1.56 (Hg Pro, 1H), 1.53 (Hb Orn, 1H), 1.52 (Hb
Orn, 1H), 1.50 (Hb Leu, 2H), 1.42 (Hg Leu, 1H), 1.35 (Hb Leu, 2H),
1.31 (Hg Leu, 1H), 1.30 (Hg Pro, 1H), 1.15 (Hg Pro, 1H), 0.93 (Hg Val,
3H), 0.85 (Hd Leu, 6H), 0.84 (Hg Val, 3H), 0.80 (Hd Leu, 6H), 0.80 (Hg
Val, 6H), 0.72 (Hb Pro, 1H), 0.59 ppm (Hb Pro, 1H); 13C NMR
(187 MHz, CD3OH): d=173.5, 173.4, 173.4, 172.7, 172.7, 172.3,
143.4, 136.8, 133.5, 132.5, 131.9, 130.3, 129.7, 129.6, 129.4, 129.2,
128.5, 128.2, 127.6, 127.0, 126.8, 126.1, 125.5, 124.3, 123.4, 61.9,
61.7, 60.4, 60.3, 55.9, 54.0, 53.0, 52.3, 51.4, 51.2, 49.9, 47.9, 47.7,
41.9, 41.6, 40.5, 31.9, 31.7, 30.6, 25.6, 25.5, 24.5, 23.1, 23.0, 22.8,
19.5, 19.4, 19.4 ppm; LC/MS: tR =9.21 min (10!90% CH3CN,
15 min run); MS (ESI): m/z: 1346.80 [M+H]+; HRMS calculated for
C73H100N15O10 [M+H]+: 1346.77721, found: 1346.77851.
Peptide 2c: Yield: 37% (14 mmol, 18 mg): 1H NMR (600 MHz,
CD3OH): d=8.92 (NH Phe, d, J=3.30 Hz, 1H), 8.82 (NH TrA, d, J=
3.32 Hz, 1H), 8.71 (NH Leu, d, J=9.37 Hz, 1H), 8.70 (NH Leu, d, J=
9.43, 1H), 8.67 (NH Orn, d, J=9.42 Hz, 2H), 8.25–7.51 (naph, m,
7H), 7.85 (triazole, s, 1H), 7.82 (NH2 Orn, brs, 2H), 7.70 (NH2 Orn,
brs, 2H), 7.69 (NH Val, d, J=8.97 Hz, 1H), 7.54 (NH Val, 1H), 7.33–
7.23 (Ar Phe, m, 5H), 6.07 (CH2Naph, dd, J=14.4 Hz, J=41.4 Hz,
2H), 4.95 (Ha Orn, 2H), 4.64 (Ha Leu, 1H), 4.59 (Ha Leu, 1H), 4.49
(Ha Phe, 1H), 4.41 (Ha TrA, 1H), 4.33 (Ha Pro, 1H), 4.15 (Ha Pro, 1H),
4.13 (Ha Val, 1H), 4.07 (Ha Val, 1H), 3.72 (Hd Pro, 1H), 3.61 (Hd Pro,
1H), 3.09 (Hb TrA, 1H), 3.08 (Hb Phe, 1H), 3.02 (Hd Orn, 1H), 3.01 (Hb
TrA, 1H), 2.96 (Hd Orn, 1H), 2.92 (Hb Phe, 1H), 2.84 (Hd Orn, 1H),
2.79 (Hd Orn, 1H), 2.46 (Hd Pro, 1H), 2.32 (Hd Pro, 1H), 2.24 (Hb Val,
1H), 2.20 (Hb Val, 1H), 2.03 (Hb Orn, 2H), 2.01 (Hb Orn, 2H), 1.99 (Hb
Pro, 1H), 1.75 (Hg Orn, 1H), 1.73 (Hb Pro, 1H), 1.70 (Hg Orn, 1H),
1.68 (Hg Pro, 1H), 1.68 (Hb Pro, 1H), 1.57 (Hg Pro, 1H), 1.56 (Hg Orn,
1H), 1.54 (Hg Orn, 1H), 1.52 (Hb Leu, 2H), 1.47 (Hg Pro, 1H), 1.46 (Hb
Leu, 2H), 1.37 (Hg Leu, 1H), 1.36 (Hg Leu, 1H), 1.09 (Hb Pro, 1H),
1.07 (Hg Pro, 1H), 0.94 (Hg Val, 3H), 0.88 (Hd Leu, 12H), 0.86 (Hg Val,
6H), 0.85 ppm (Hg Val, 3H); 13C NMR (150 MHz, CD3OH): d=173.6,
173.5, 173.4, 173.3, 172.8, 172.7, 172.4, 172.3, 161.2, 143.3, 136.8,
135.5, 132.4, 132.0, 131.0, 130.4, 130.0, 129.7, 129.4, 128.5, 128.0,
127.4, 126.6, 124.4, 124.1, 105.4, 67.9, 61.9, 60.4, 55.9, 54.0, 52.9,
52.4, 51.4, 51.3, 47.9, 41.9, 41.7, 40.5, 40.5, 37.2, 31.9, 31.8, 30.8,
30.7, 30.6, 30.4, 27.0, 25.6, 25.5, 24.6, 24.4, 24.2, 23.2, 23.2, 23.0,
22.9 ppm; LC/MS: tR =7.66 min (10!90% CH3CN, 15 min run); MS
(ESI): m/z: 1273.1 [M+H]+; HRMS calculated for C67H98N15O10
[M+H]+: 1272.76156, found: 1272.76242.
cyclo-(DPhe-Pro-Val-Orn-Leu-DHis-Pro-Val-Orn-Leu) (3): Yield: 43%
1
(17 mmol, 19 mg): H NMR (600 MHz, CD3OH): d=8.94 (NH, Phe, d,
J=3.12 Hz, 1H), 8.86 (NH His, d, J=3.60 Hz, 1H), 8.82 (2-CH im, s,
1H), 8.74 (NH Leu, d, J=8.77 Hz, 2H), 8.74 (NH Orn, d, J=8.88 Hz,
2H), 7.70 (NH Val, d, J=8.97 Hz, 1H), 7.63 (NH Val, d, J=8.97 Hz,
1H), 7.45 (5-CH im, s, 1H), 7.32–7.24 (Ar Phe, m, 5H), 4.98 (Ha Orn,
2H), 4.71 (Ha His, 1H), 4.63 (Ha Leu, 2H), 4.51 (Ha Pro, 1H), 4.49 (Ha
Phe, 1H), 4.34 (Ha Pro, 1H), 4.19 (Ha Val, 1H), 4.14 (Ha Val, 1H), 4.09
(Hd Pro, 1H), 3.74 (Hd Pro, 1H), 3.37 (Hd Pro, 1H), 3.18 (Hb His, 2H),
3.10 (Hb Phe, 1H), 3.02 (Hd Orn, 2H), 2.95 (Hb Phe, 1H), 2.88 (Hd
Orn, 2H), 2.48 (Hd Pro, 1H), 2.29 (Hd Val, 1H), 2.26 (Hb Val, 1H), 2.17
(Hb Pro, 1H), 2.06 (Hb Pro, 1H), 2.06 (Hb Orn, 2H), 2.01 (Hb Pro, 1H),
2.00 (Hg Pro, 1H), 1.92 (Hg Pro, 1H), 1.73 (Hg Orn, 4H), 1.69 (Hg Pro,
1H), 1.69 (Hb Pro, 1H), 1.63 (Hb Orn, 2H), 1.57 (Hg Pro, 1H), 1.53 (Hb
Leu, 2H), 1.49 (Hg Leu, 2H), 1.42 (Hb Leu, 2H), 0.99 (Hg Val, 3H),
0.95 (Hg Val, 3H), 0.91 (Hg Val, 3H), 0.88 (Hd Leu, 12H), 0.86 ppm (Hg
Val, 3H); 13C NMR (150 MHz, CD3OH): d=173.5, 173.5, 173.4, 172.7,
172.5, 172.4, 172.3, 136.9, 130.4, 130.1, 129.6, 128.4, 118.9, 62.3,
61.9, 60.4, 60.4, 55.9, 53.2, 52.4, 51.4, 51.3, 48.4, 47.9, 42.0, 41.7,
40.5, 37.2, 31.9, 31.9, 30.9, 30.7, 30.7, 30.6, 25.7, 25.6, 25.5, 24.7,
24.6, 24.4, 23.2, 23.1, 23.0, 22.9, 19.6 ppm; LC/MS: tR =6.81 min
(10!90% CH3CN, 15 min run); MS (ESI): m/z: 1131.53 [M+H]+;
HRMS calculated for C57H91N14O10 [M+H]+: 1131.70371, found:
1131.70509.
Peptide 2d: Yield: 31% (12 mmol, 16 mg): 1H NMR (600 MHz,
CD3OH): d=8.92 (NH Phe, d, J=3.30 Hz, 1H), 8.85–7.64 (phen, m,
9H), 8.82 (NH TrA, d, J=3.32 Hz, 1H), 8.71 (NH Leu, d, J=9.37 Hz,
1H), 8.70 (NH Leu, d, J=9.43 Hz, 1H), 8.67 (NH Orn, d, J=9.42 Hz,
2H), 7.89 (triazole, s, 1H), 7.82 (NH2 Orn, brs, 2H), 7.70 (NH2 Orn,
brs, 2H), 7.69 (NH Val, d, J=8.97 Hz, 1H), 7.54 (NH Val, 1H), 7.33–
7.23 (Ar Phe, m, 5H), 6.12 (CH2Phen, dd, J=14.77 Hz, J=38.75 Hz,
2H), 4.95 (Ha Orn, 2H), 4.64 (Ha Leu, 1H), 4.59 (Ha Leu, 1H), 4.49
(Ha Phe, 1H), 4.41 (Ha TrA, 1H), 4.33 (Ha Pro, 1H), 4.15 (Ha Pro, 1H),
4.13 (Ha Val, 1H), 4.07 (Ha Val, 1H), 3.72 (Hd Pro, 1H), 3.61 (Hd Pro,
1H), 3.09 (Hb Phe, 1H), 3.08 (Hb Phe, 1H), 3.02 (Hd Orn, 1H), 3.01
(Hb Phe, 1H), 2.92 (Hb Phe, 1H), 2.96 (Hd Orn, 1H), 2.84 (Hd Orn,
1H), 2.79 (Hd Orn, 1H), 2.46 (Hd Pro, 1H), 2.32 (Hd Pro, 1H), 2.24 (Hb
Val, 1H), 2.20 (Hb Val, 1H), 2.03 (Hb Orn, 2H), 2.01 (Hb Orn, 2H), 1.99
(Hb Pro, 1H), 1.75 (Hg Orn, 1H), 1.73 (Hb Pro, 1H), 1.70 (Hg Orn, 1H),
1.68 (Hb Pro, 1H), 1.68 (Hg Pro, 1H), 1.57 (Hg Pro, 1H), 1.56 (Hg Orn,
1H), 1.54 (Hg Orn, 1H), 1.52 (Hb Leu, 2H), 1.47 (Hg Pro, 1H), 1.46 (Hb
Leu, 2H), 1.37 (Hg Leu, 1H), 1.36 (Hg Leu, 1H), 1.09 (Hb Pro, 1H),
1.07 (Hg Pro, 1H), 0.94 (Hg Val, 3H), 0.88 (Hd Leu, 12H),0.86 (Hg Val,
6H), 0.85 ppm (Hg Val, 3H); 13C NMR (150 MHz, CD3OH): d=173.5,
173.4, 172.7, 172.4, 172.3, 143.4, 136.8, 132.4, 132.3, 132.1, 131.0,
130.9, 130.3, 129.9, 129.6, 128.9, 128.5, 128.3, 128.3, 128.2, 125.0,
124.6, 124.4, 123.7, 61.9, 61.9, 60.4, 55.9, 54.0, 53.5, 52.3, 51.4, 51.2,
47.9, 47.8, 41.9, 40.5, 31.9, 31.8, 30.6, 25.6, 25.5, 24.5, 23.2, 23.1,
23.0, 22.9, 19.6, 19.5, 19.4 ppm; LC/MS: tR =8.36 min (10!90%
Biology
Antibacterial screening: Bacteria were stored at ꢀ708C and grown
at 308C on Columbia agar with sheep blood (Oxoid, Wesel, Germa-
ny) suspended in physiological saline solution (PSS) until an optical
density of 0.1 AU was reached (at 595 nm, 1 cm cuvette). The sus-
ChemMedChem 2011, 6, 840 – 847
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
845