Antibacterial activities of 400-O-carbamate derivatives
C Ma et al
7
3.33–3.31 (m, 3H), 3.28–3.20 (m, 4H), 2.96–2.86 (m, 3H), 2.43–2.41 (m, 2H), J¼4.8 Hz, 1H), 4.53 (d, J¼9.6 Hz, 1H), 4.45–4.34 (m, 4H), 3.61–3.59 (m, 3H),
2.37–2.33 (m, 6H), 2.28–2.22 (m, 3H), 2.20 (m, 3H), 1.99 (m, 1H), 1.92 3.32 (m, 3H), 3.29–3.16 (m, 3H), 2.88 (m, 3H), 2.44 (m, 2H), 2.44–2.33
(m, 1H), 1.91–1.80 (m, 4H), 1.75 (m, 1H), 1.65–1.61 (m, 2H), 1.60–1.58 (m, 8H), 2.20 (m, 4H), 2.18 (m, 1H), 2.02 (m, 2H), 1.98 (m, 2H), 1.92–1.77
(m, 2H), 1.55–1.53 (m, 2H), 1.47–1.44 (s, 4H), 1.28–1.25 (m, 5H), 1.24–1.17 (m, 4H), 1.59–1.56 (m, 1H), 1.45 (m, 4H), 1.30–1.29 (m, 4H), 1.22–1.19
(m, 9H), 1.17–1.11 (m, 4H), 1.07–1.01 (m, 6H), 0.98–0.87 (m, 6H); ESI-MS (m, 9H), 1.16–1.14 (m, 3H), 1.07–1.05 (m, 6H), 0.93–0.89 (m, 6H); ESI-MS
m/z calculated for C52H86N4O16 1022.6; found (M+H)+ 1024.3; analysis
m/z calculated for C51H84N4O15 992.6; found (M+H)+ 994.0; analysis
calculated for C52H86N4O16: C 61.04, H 8.47, N 5.48. Found: C 60.97, calculated for C51H84N4O15: C 61.67, H 8.52, N 5.64. Found: C 61.58,
H 8.44, N 5.49.
H 8.57, N 5.69.
400-O-(((Phenethyl)amino)-4-oxobutyl)carbamoylazithromycin
11,12-cyclic carbonate (7g)
400-O-(((4-Fluorobenzyl)amino)-4-oxobutyl)carbamoylazithromycin
11,12-cyclic carbonate (7c)
White solid, yield 76.5%, m.p.: 158–1641C, TLC RF¼0.55 (dichlormethane–
White solid, yield 72.0%, m.p.: 126–1301C, TLC RF¼0.56 (dichlormethane–
methanol, 10:1); IR (KBr): 3411, 3063, 2971, 2933, 1812, 1721, 1653, 1524,
1456, 1379, 1353, 1239, 1167, 1109, 1044, 1014cmꢀ1 1H NMR (600MHz,
;
methanol, 10:1); IR (KBr): 3431, 2970, 2932, 1813, 1734, 1647, 1510, 1457,
1379, 1353, 1298, 1222, 1167, 1110, 1074, 1046, 1015 cmꢀ1 1H NMR
;
CDCl3) d 7.31–7.28 (m, 2H), 7.27–7.20 (m, 3H), 5.03 (d, J¼4.2Hz, 1H), 4.88
(dd, J¼9.0 Hz, J ¼3 .0Hz, 1H), 4.58–4.52 (m, 1H), 4.40–4.28 (m, 3H), 3.76
(m, 2H), 3.65–3.53 (m, 4H), 3.35–3.30 (m, 3H), 3.22–3.19 (m, 3H), 2.85–2.83
(m, 3H), 2.78 (m, 5H), 2.46–2.42 (m, 1H), 2.38–2.31 (m, 3H), 2.22–2.02
(m, 9H), 1.92 (m, 3H), 1.87–1.73 (m, 3H), 1.70–1.56 (m, 3H), 1.45 (m, 4H),
1.41–1.35 (m, 3H), 1.28 (m, 3H), 1.23 (m, 4H), 1.20–1.18 (m, 3H), 1.16
(m, 3H), 1.01–0.96 (m, 3H), 0.96–0.86 (m, 6H); ESI-MS m/z calculated
for C52H86N4O15 1006.6; found (M+H)+ 1007.9; analysis calculated for
C52H86N4O15: C 62.01, H 8.61, N 5.56. Found: C 61.96, H 8.57, N 5.59.
(600 MHz, CDCl3) d 7.27–7.25 (m, 2H), 7.03–7.00 (m, 2H), 5.08 (m, 1H),
4.89 (dd, J¼9.0 Hz, J¼3.0 Hz, 1H), 4.54–4.52 (m, 1H), 4.47–4.44 (m, 1H),
4.41–4.35 (m, 2H), 4.31–4.28 (m, 1H), 4.16–4.13 (m, 1H), 3.80 (m, 1H),
3.66–3.59 (m, 2H), 3.37–3.29 (m, 3H), 3.27–3.13 (m, 3H), 2.89–2.85 (m, 3H),
2.66 (m, 1H), 2.44–2.42 (m, 1H), 2.40–2.35 (m, 6H), 2.33–2.29 (m, 3H),
2.27–2.24 (m, 1H), 2.22–2.20 (m, 1H), 2.07–2.00 (m, 3H), 1.92 (m, 2H),
1.89–1.80 (m, 2H), 1.68–1.53 (m, 4H), 1.46–1.44 (m, 4H), 1.33–1.29 (m, 4H),
1.27–1.23 (m, 3H), 1.24–1.19 (m, 7H), 1.15 (m, 3H), 1.11–1.05 (m, 6H),
0.98–0.84 (m, 6H); ESI-MS m/z calculated for C51H83FN4O15 1010.6;
found (M+H)+ 1011.9; analysis calculated for C51H83FN4O15: C 60.57,
H 8.27, N 5.54. Found: C 60.44, H 8.30, N 5.50.
400-O-(((Pentyl)amino)-4-oxobutyl)carbamoylazithromycin
11,12-cyclic carbonate (7h)
400-O-(((2-Chlorophenethyl)amino)-4-oxobutyl)carbamoylazithromycin
11,12-cyclic carbonate (7d)
White solid, yield 80.7%, m.p. 132–1361C, TLC RF¼0.54 (dichlormethane–
methanol, 10:1); IR (KBr): 3419, 2934, 2872, 1814, 1724, 1653, 1518, 1457,
1
1379, 1238, 1167, 1110, 1074, 1046, 1015cmꢀ1; H NMR (600MHz, CDCl3):
White solid, yield: 77.5%, m.p.: 145–148 1C, TLC RF¼0.53 (dichlormethane–
d 5.08 (d, J¼4.2 Hz, 1H), 4.88 (dd, J¼9.0 Hz, J¼3.6Hz, 1H), 4.55 (m, 1H),
4.45 (d, J¼7.2 Hz, 1H), 4.40–4.35 (m, 2H), 3.66–3.64 (m, 1H), 3.60–3.59
(m, 1H), 3.34–3.29 (m, 4H), 3.29–3.20 (m, 5H), 2.87–2.86 (m, 3H), 2.43–2.41
(m, 1H), 2.38–2.35 (m, 6H), 2.41–2.35 (m, 6H), 2.26 (m, 1H), 2.22–2.18
(m, 6H), 1.92 (m, 1H), 1.87–1.79 (m, 4H), 1.66–1.55 (m, 4H), 1.53–1.46
(m, 4H), 1.48–1.41 (m, 2H), 1.36–1.27 (m, 5H), 1.22–1.20 (m, 9H), 1.16
(m, 3H), 1.07 (m, 3H), 0.93–0.86 (m, 9H); ESI-MS m/z calculated
for C49H88N4O15 972.6; found (M+H)+ 974.0; analysis calculated for
C49H88N4O15: C 60.47, H 9.11, N 5.76. Found: C 60.57, H 9.08, N 5.71.
methanol, 10:1); IR (KBr): 3428, 2972, 2936, 1812, 1723, 1656, 1517, 1456,
1379, 1353, 1335, 1298, 1237, 1167, 1109, 1074, 1046, 1015cmꢀ1 1H NMR
;
(600 MHz, CDCl3) d 7.36 (m, 1H), 7.24–7.16 (m, 3H), 5.11–5.08 (m, 2H), 4.88
(dd, J¼9.0 Hz, J¼3.0 Hz, 1H), 4.54–4.50 (m, 1H), 4.45–4.35 (m, 3H), 3.66–3.59
(m, 1H), 3.56–3.53 (m, 2H), 3.31 (m, 3H), 3.29–3.26 (m, 2H), 3.23–3.19
(m, 3H), 2.98–2.96 (t, 3H), 2.89–2.84 (m, 3H), 2.64 (m, 2H), 2.43–2.41
(m, 1H,), 2.38–2.31 (m, 6H), 2.26–2.20 (m, 3H), 2.18–2.16 (m, 2H),
2.07–2.00 (m, 2H), 1.91 (m, 1H), 1.86–1.76 (m, 2H), 1.65–1.59 (m, 2H),
1.45 (m, 4H), 1.31–1.29 (m, 4H), 1.29–1.25 (m, 2H), 1.22–1.19 (m, 7H),
1.15 (m, 3H), 1.07 (m, 6H), 0.93–0.87 (m, 6H); ESI-MS m/z calculated
for C52H85ClN4O15 1040.6; found (M+H)+ 1041.9; analysis calculated for
C52H85ClN4O15: C 59.96, H 8.22, N 5.38. Found: C 60.06, H 8.20, N 5.40.
ACKNOWLEDGEMENTS
This research was supported by the Major R&D Program of New
Drugs—National S&T Key Special Subject of China (2009ZX09103-115)
and National Natural Science Foundation of China (20872081).
400-O-(((3-Chlorobenzyl)amino)-4-oxobutyl)carbamoylazithromycin
11,12-cyclic carbonate (7e)
White solid, yield 76.5%, m.p.: 145–1481C, TLC RF¼0.52 (dichlormethane–
methanol, 10:1); IR (KBr): 3427, 2972, 2935, 1812, 1723, 1656, 1599, 1575,
1521, 1459, 1380, 1353, 1238, 1167, 1109, 1076, 1045, 1015cmꢀ1 1H NMR
;
1
Itoh, Z., Nakaya, K., Suzuki, H., Aria, H. & Wakabayashi, K. Erythromycin mimics
exogenous motilin in gastrointestinal contractile activity in the dog. Am. J. Physiol.
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Katz, L., Chu, D. T. W. & Plattner, J. J. New directions in antibacterial research. J. Med.
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Lai, C. J. & Weisblum, B. Altered methylation of ribosomal RNA in an erythromycin-
resistant strain of Staphylococcus aureus. Proc. Natl Acad. Sci. USA 68, 856–860 (1971).
Weisblum, B. Erythromycin resistance by ribosome modification. Antimicrob. Agents
Chemother. 39, 577–585 (1995).
Zhanel, G. G. et al. The ketolides: a critical review. Drugs 62, 1771–1804 (2002).
Bryskier, A. Novelties in the field of anti-infectives in 1997. Clin. Infect. Dis. 27,
865–883 (1998).
Xiong, L., Shah, S., Mauvais, P. & Mankin, A. S. A ketolide resistance mutation in
domain II of 23S rRNA reveals the proximity of hairpin 35 to the peptidyl transferase
centre. Mol. Microbiol. 31, 633–639 (1999).
Hansen, L. H., Mauvais, P. & Douthwaite, S. The macrolide-ketolide antibiotic binding
site is formed by structures in domains II and V of 23S ribosomal RNA. Mol. Microbiol.
31, 623–631 (1999).
(600 MHz, CDCl3) d 7.31 (m, 1H), 7.27–7.22 (m, 2H), 7.20–7.18 (m, 1H),
5.04 (d, J¼4.2 Hz, 1H), 4.88 (dd, J¼9.0 Hz, J¼3.0 Hz, 1H), 4.58–4.53 (m, 2H),
4.47–4.39 (m, 3H), 4.30 (m, 2H), 4.07 (t, 1H), 3.60–3.59 (d, J¼6.0 Hz, 1H),
3.45–3.42 (m, 2H) 3.30–3.28 (m, 3H), 3.28–3.18 (m, 2H), 2.88–2.78 (m, 3H),
2.69 (m, 6H), 2.46–2.44 (m, 1H), 2.37–2.35 (m, 2H), 2.31–2.28 (m, 2H),
2.23–2.21 (m, 3H), 2.06–2.02 (m, 1H), 1.93–1.81 (m, 4H), 1.65–1.60 (m, 3H),
1.51 (m, 1H), 1.45 (m, 3H), 1.42–1.34 (m, 3H), 1.28 (m, 3H), 1.25–1.19
(m, 8H), 1.17 ( m, 3H), 1.11–1.07 (m, 3H), 1.02–0.87 (m, 9H); ESI-MS
m/z calculated for C51H83ClN4O15 1026.6; found (M+H)+ 1028.0; analysis
calculated for C51H83ClN4O15: C 59.60, H 8.14, N 5.45. Found: C 59.50,
H 8.18, N 5.41.
2
3
4
5
6
7
8
9
400-O-(((Benzyl)amino)-4-oxobutyl)carbamoylazithromycin
11,12-cyclic carbonate (7f)
White solid, yield 73.5%, m.p.: 120–1221C, TLC RF¼0.53 (dichlormethane–
10 Champney, W. S.
& Tober, C. L. Structure-activity relationships for six ketolide
methanol, 10:1); IR (KBr): 3423, 2972, 1813, 1725, 1659, 1514, 1455, 1379,
antibiotics. Curr. Microbiol. 42, 203–210 (2001).
;
1353, 1299, 1238, 1167, 1110, 1074, 1046, 1015 cmꢀ1 1H NMR (600MHz,
11 Schlunzen, F. et al. Structural basis for the interaction of antibiotics with the peptidyl
transferase centre in eubacteria. Nature 413, 814–821 (2001).
CDCl3): d 7.34–7.27 (m, 5H), 5.07 (d, J¼4.8 Hz, 1H), 4.88 (dd, J¼4.0 Hz,
The Journal of Antibiotics