Arch. Pharm. Chem. Life Sci. 2010, 8, 458–464
400-O-Carbamoyl Erythromycin-A Derivatives
463
400-O-(Propenyl)carbamoyl erythromycin A 4i
(s, 1H), 2.38 (m, 1H), 2.01 (m, 1H), 1.67 (m, 4H), 1.63–1.62 (m,
2H), 1.55 (m, 1H), 1.43 (s, 3H), 1.21–1.19 (m, 3H), 1.16–1.07 (m,
21H), 0.98 (m, 3H), 0.85 (t, 3H); MS (ESI) m/z calcd.
for C46H76N2O15: 896.5; found [M þ Hþ]: 898.1. Anal. calcd.
for C46H76N2O15: C, 61.59; H, 8.54; N, 3.12. Found: C, 61.54;
H, 8.56; N, 3.10.
White crystals, yield: 61.8%; m. p.: 125–1288C; TLC Rf ¼ 0.51
(methanol/dichloromethane, 1:7); IR (KBr) cmꢁ1: 3459, 2974,
2938, 2881, 2832, 2787, 1805, 1732, 1645, 1506, 1457, 1423,
1381, 1344, 1245, 1170, 1110, 1094, 1074, 1051, 1015; 1H-NMR
(600 MHz, CDCl3) d: 5.86–5.83 (m, 1H), 5.19–5.14 (m, 3H), 5.05–
5.03 (d, J ¼ 10.9 Hz, 1H), 4.92–4.86 (m, 2H), 4.59–4.54 (m, 2H),
4.30–4.28 (m, 2H), 4.12–4.11 (m, 1H), 4.01 (d, J ¼ 9.3 Hz, 1H), 3.80
(s, 1H), 3.64 (m, 1H), 3.59–3.57 (d, J ¼ 7.2 Hz, 1H), 3.31 (m, 4H),
3.09–3.08 (m, 2H), 2.89 (m, 1H), 2.68–2.67 (m, 1H), 2.42–2.34 (m,
6H), 2.05 (s, 1H), 2.01–1.90 (m, 3H), 1.66–1.63 (m, 4H), 1.61–1.60
(m, 2H), 1.46 (s, 3H), 1.27 (m, 2H), 1.20–1.09 (m, 21H), 0.93–0.92 (t,
3H), 0.85 (t, 3H); MS (ESI) m/z calcd. for C41H72N2O14: 816.5; found
[M þ Hþ]: 818.1. Anal. calcd. for C41H72N2O14: C, 60.27; H, 8.88; N,
3.43. Found: C, 60.31; H, 8.90; N, 3.45.
400-O-(2-Chlorophenethyl)carbamoyl erythromycin A 4f
White crystals, yield: 50.7%; m. p.: 125–1288C; TLC Rf ¼ 0.58
(methanol/dichloromethane, 1:7); IR (KBr) cmꢁ1: 3451, 2974,
2938, 2878, 2831, 2786, 1805, 1731, 1635, 1509, 1457, 1380,
1343, 1244, 1170, 1111, 1073, 1051, 1035, 1015; 1H-NMR
(600 MHz, CDCl3) d: 7.22–7.20 (m, 4H), 5.05–5.04 (d, J ¼ 9.8 Hz,
1H) 4.92–4.91 (d, J ¼ 4.6 Hz, 1H), 4.55–4.53 (m, 1H), 3.87 (s, 1H),
3.81–3.79 (m, 1H), 3.57–3.55 (m, 3H), 3.50–3.48 (m, 2H), 3.31–3.30
(m, 3H), 3.28 (m, 1H), 3.09–3.08 (m, 1H), 2.99–2.97 (m, 2H), 2.80
(m, 1H), 2.41 (m, 1H), 2.38 (s, 6H), 2.33–2.32 (m, 1H), 2.01 (s, 1H),
1.91 (m, 2H), 1.63–1.62 (m, 3H), 1.60–1.59 (m, 3H), 1.57 (m, 3H),
1.45 (s, 3H), 1.19–1.18 (m, 3H), 1.16–1.12 (m, 21H), 1.10 (t, 3H),
0.86–0.84 (t, 3H); MS (ESI) m/z calcd. for C46H75ClN2O14: 914.5;
found [M þ Hþ]: 916.2. Anal. calcd. for C46H75ClN2O14: C, 60.35;
H, 8.26; N, 3.06. Found: C, 60.30; H, 8.28; N, 3.04.
400-O-(Butyl)carbamoyl erythromycin A 4j
White crystals, yield: 50.1%; m. p.: 131–1348C, TLC Rf ¼ 0.52
(methanol/dichloromethane, 1:7); IR (KBr) cmꢁ1: 3458, 2971,
2936, 2876, 2832, 2786, 1806, 1731, 1633, 1511, 1458, 1381,
1243, 1168, 1109, 1074, 1053, 1016; 1H-NMR (600 MHz, CDCl3)
d: 5.06 (d, J ¼ 6.2 Hz, 1H), 4.91 (d, J ¼ 5.0 Hz, 1H), 4.76 (m, 1H),
4.53 (m, 2H), 4.27 (m, 1H), 4.25 (m, 1H), 4.01 (d, J ¼ 9.2 Hz, 1H),
3.80 (s, 1H), 3.64 (t, 1H), 3.58 (d, J ¼ 7.7 Hz, 1H), 3.31 (s, 3H), 3.21
(m, 2H), 3.08 (m, 2H), 2.89 (m, 1H), 2.69 (m, 1H), 2.42 (s, 6H), 2.32
(m, 1H), 2.05 (s, 1H), 1.99–1.89 (m, 4H), 1.63 (m, 2H), 1.49 (m, 3H),
1.46 (s, 3H), 1.35–1.32 (m, 3H), 1.20–1.12 (m, 27H), 0.93 (t, 3H),
0.85 (t, 3H); MS (ESI) m/z calcd. for C42H76N2O14: 832.5; found
[M þ Hþ]: 834.1. Anal. calcd. for C42H76N2O14: C, 60.55; H, 9.20; N,
3.36. Found: C, 60.51; H, 9.17; N, 3.33.
400-O-(3,4-Methylenedioxyphenethyl)carbamoyl
erythromycin A 4g
White crystals, yield: 55.2%; m. p.: 129–1328C; TLC Rf ¼ 0.56
(methanol/dichloromethane, 1:7); IR (KBr) cmꢁ1: 3446, 2974,
2939, 2881, 2832, 2785, 1728, 1632, 1504, 1491, 1456, 1379,
1343, 1248, 1171, 1111, 1093, 1073, 1051, 1036, 1014; 1H-NMR
(600 MHz, CDCl3) d: 6.73–6.61 (m, 3H), 5.92 (s, 2H), 5.05–5.03 (d,
J ¼ 10.4 Hz, 1H), 4.91–4.90 (d, J ¼ 4.8 Hz, 1H), 4.53–4.53 (d,
J ¼ 9.8 Hz, 1H), 4.23 (m, 1H), 4.00–3.99 (d, J ¼ 7.5 Hz, 1H),
3.86 (s, 1H), 3.79 (s, 1H), 3.56–3.55 (m, 2H), 3.48–3.47 (m, 3H),
3.29 (s, 3H), 3.09–3.07 (m, 2H), 2.76 (m, 1H), 2.75–2.73 (m, 4H),
2.41–2.39 (m, 2H), 2.39–2.30 (m, 4H), 1.91 (m, 4H), 1.64–1.62 (m,
3H), 1.61–1.57 (m, 12H), 1.45–1.44 (m, 4H), 1.25 (m, 3H), 1.19–
1.12 (m, 21H), 1.09 (t, 3H), 0.85 (t, 3H); MS (ESI) m/z calcd.
for C47H76N2O16: 924.5; found [M þ Hþ]: 926.1. Anal. calcd.
for C47H76N2O16: C, 61.02; H, 8.28; N, 3.03. Found: C, 61.06;
H, 8.25; N, 3.00.
400-O-(Pentyl)carbamoyl erythromycin A 4k
White crystals, yield: 53.1%; m. p.: 129–1328C; TLC Rf ¼ 0.53
(methanol/dichloromethane, 1:7); IR (KBr) cmꢁ1: 3445, 2971,
2936, 2876, 2832, 2786, 1804, 1727, 1633, 1510, 1458, 1379,
1344, 1278, 1252, 1170, 1109, 1073, 1051, 1015; 1H-NMR
(600 MHz, CDCl3) d: 5.06–5.04 (d, J ¼ 10.7 Hz, 1H), 4.92–4.91
(m, 1H), 4.54–4.53 (d, J ¼ 9.7 Hz, 1H), 3.86 (s, 1H), 3.80 (s, 1H),
3.58–3.57 (d, J ¼ 7.3 Hz, 1H), 3.32–3.31 (m, 4H), 3.22–3.18 (m, 3H),
3.09–3.07 (m, 2H), 2.88 (m, 1H), 2.69 (m, 1H), 2.42–2.40 (m, 3H),
2.01 (m, 1H), 1.93–1.91 (m, 3H), 1.65 (m, 2H), 1.60–1.59 (m, 3H),
1,47–1.45 (m, 6H), 1.32–1.28 (m, 7H), 1.20–1.11 (m, 30H), 0.90–
400-O-(Propyl)carbamoyl erythromycin A 4h
0.87 (t, 3H), 0.86–0,84 (t, 3H); MS (ESI) m/z calcd. for C43H78N2O14
:
White crystals, yield: 61.2%; m. p.: 150–1538C; TLC Rf ¼ 0.56
(methanol/dichloromethane, 1:7); IR (KBr) cmꢁ1: 3459, 2972,
2938, 2878, 2831, 2786, 1802, 1728, 1631, 1510, 1459, 1379,
1343, 1263, 1170, 1110, 1093, 1051, 1014; 1H-NMR (600 MHz,
CDCl3) d: 5.06–5.04 (d, J ¼ 10.9 Hz, 1H), 4.93–4.92 (d, J ¼ 4.8 Hz,
1H), 4.86 (m, 1H), 4.55–4.51 (m, 2H), 4.28–4.25 (m, 1H), 4.14–4.11
(m, 1H), 4.01 (d, J ¼ 9.6 Hz, 1H), 3.80 (s, 1H), 3.67–3.65 (m, 1H),
3.59–3.58 (d, J ¼ 7.4 Hz, 1H), 3.31–3.29 (s, 3H), 3.19–3.16 (m, 2H),
3.10–3.08 (m, 2H), 2.90–2.87 (m, 1H), 2.69–2.68 (m, 2H), 2.40–2.35
(m, 6H), 2.05 (s, 1H), 2.01–1.90 (m, 4H), 1.69–1.63 (m, 2H), 1.53–
1.50 (m, 3H), 1.46 (s, 3H), 1.27–1.25 (m, 2H), 1.20–1.09 (m, 24H),
0.93–0.91 (t, 3H), 0.85 (t, 3H); 13C-NMR (600 MHz, CDCl3) d: 175.56,
156.29, 102.42, 96.52, 83.21, 79.87, 78.78, 77.02, 75.02, 73.04,
71.03, 68.95, 68.07, 65.07, 63.40, 49.61, 45.26, 44.79, 42.87, 39.11,
38.51, 37.75, 35.41, 23.1, 21.44, 21.08, 20.85, 18.27, 18.18, 16.18,
16.05, 12.01, 11.14, 10.65, 9.35; MS (ESI) m/z calcd.
for C41H74N2O14: 818.5; found [M þ Hþ]: 820.2. Anal. calcd.
for C41H74N2O14: C, 60.12; H, 9.11; N, 3.42. Found: C, 60.08; H,
9.09; N, 3.44.
846.6; found [M þ Hþ]: 848.3. Anal. calcd. for C43H78N2O14: C,
60.97; H, 9.28; N, 3.31. Found: C, 61.01; H, 9.31; N, 3.28.
Microbiology
The MIC values for all 400-O-carbamoyl erythromycin-A derivatives
were determined by the dilution method. For sample prep-
aration, each of the test compounds and references (EMA,
CAM, and AZM) was dissolved in 75% ethanol at a concentration
of 512 mg/mL. Further dilutions of the compounds and referen-
ces in the test medium were prepared at the required quantities
of 256, 128, etc. down to 0.03 and 0.015 mg/mL.
Culture of microorganisms and assay for in-vitro
antimicrobial activity
Bacterial strains were maintained on MHA (Mu¨ller–Hinton Agar)
medium for 24 h at 378C. The bacteria were prepared by suspen-
sion in 10 mL of sterile water for colonies from culture on MHA
ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com