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Synthesis and antibacterial activity of novel 10, 11-epoxy acylide erythromycin derivatives

Ying Nie ,  Yin Sun ,  Qi-Dong You

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Citation:  Ying Nie, Yin Sun, Qi-Dong You. Synthesis and antibacterial activity of novel 10, 11-epoxy acylide erythromycin derivatives[J]. Chinese Chemical Letters, 2013, 24(3): 183-185. shu

Synthesis and antibacterial activity of novel 10, 11-epoxy acylide erythromycin derivatives

    • 通讯作者: Qi-Dong You,
摘要: A series of novel acylide derivatives have been synthesized from clarithromycin A via a facile procedure. The C-3 modifications involved replacing the natural C-3 cladinosyl group in clarithromycin core with different aryl-piperzine sidechain via chemical synthesis. Meanwhile a distinctive intermediate with 10,11-epoxy moiety was obtained. The structure and stereochemistry of this novel structure were confirmed via NMR and X-ray crystallography. Potential anti-bacterial activities against both Grampositive and Gram-negative bacteria were reported. Because of existence of C10,11-epoxide, these derivatives can be used as intermediates for further structural modification.

English

    1. [1] P. Kurath, P. Jones, R. Egan, et al., Acid degradation of erythromycin A and erythromycin B, Experentia 27 (1971) 362.[1] P. Kurath, P. Jones, R. Egan, et al., Acid degradation of erythromycin A and erythromycin B, Experentia 27 (1971) 362.

    2. [2] K. Krowick, A. Zamojski, Chemical modification of erythromycin I. 8,9-anhydro-69-hemiketal of A, J. Antibiot. 26 (1973) 569-574.[2] K. Krowick, A. Zamojski, Chemical modification of erythromycin I. 8,9-anhydro-69-hemiketal of A, J. Antibiot. 26 (1973) 569-574.

    3. [3] R. Leclercq, Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications, Clin. Infect. Dis. 34 (2002) 482-492.[3] R. Leclercq, Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications, Clin. Infect. Dis. 34 (2002) 482-492.

    4. [4] J.C. Pechere, Macrolide resistance mechanisms in Gram-positive cocci, Int. J. Antimicrob. Agents 18 (2001) S25-S28.[4] J.C. Pechere, Macrolide resistance mechanisms in Gram-positive cocci, Int. J. Antimicrob. Agents 18 (2001) S25-S28.

    5. [5] T. Tanikawa, T. Asaka, M. Kashimura, et al., Synthesis and antibacterial activity of a novel series of acylides: 3-O-(3-pyridyl) acetylerythromycin A derivatives, J. Med. Chem. 46 (2003) 2706-2715.[5] T. Tanikawa, T. Asaka, M. Kashimura, et al., Synthesis and antibacterial activity of a novel series of acylides: 3-O-(3-pyridyl) acetylerythromycin A derivatives, J. Med. Chem. 46 (2003) 2706-2715.

    6. [6] T. Ly, S. Yat, M. Zhenkun, 6-O-alkyl-2-nor-2-substituted ketolide derivatives, U.S. Patent. 0103140 (2002).[6] T. Ly, S. Yat, M. Zhenkun, 6-O-alkyl-2-nor-2-substituted ketolide derivatives, U.S. Patent. 0103140 (2002).

    7. [7] A.K. Ghosh, K. Jae-Hun, An enantioselective synthesis of the C1 C9 segment of antitumor macrolide peloruside A, Tetrahedron Lett. 44 (2003) 3967-3969.[7] A.K. Ghosh, K. Jae-Hun, An enantioselective synthesis of the C1 C9 segment of antitumor macrolide peloruside A, Tetrahedron Lett. 44 (2003) 3967-3969.

    8. [8] Selected characteristic data for the compounds. 9: Yellow powder; mp 91-93℃, IR (KBr, cm-1): v 1706, 1729, 1748; 1H NMR (300 MHz, CDCl3): δ7.28-7.40 (m, 5H, Ph-H), 5.03 (dd, 1 H, J = 2.3 Hz and 9.2 Hz, H13), 4.69 (dd, 1 H, J = 2.3 Hz and 8.2 Hz, H2), 3.10 (s, 3H, C6-OCH3), 1.88 (s, 3H, C20-OCOCH3), 1.66 (s, 3H, C10-CH3); ESI-MS m/z (%): 772 (M+Na+). X-ray analysis: C39H59NO13, Mr = 749.90, crystal size 0.586 mm×0.173 mm×0.049 mm, orthorhombic in p21/n with a = 14.024(3), b = 28.998(6), c = 10.915(2)Å, a, b, g = 90°, V = 3185.0(9)Å3, Dcalu = 1.151 Mg/m3, and Z = 4, absorption coefficient 0.087 mm-1, computing structure solution SHELXL-97, theta range for data collection 1.61 to 25.508, limiting indices -16≤h≤10,-35≤k≤19,-13≤l≤12, reflection collected 23690, refinement method full-matrix least-squares, final R indices [I > 2 sigma (I)] R1 = 0.1016, wR2 = 0.2461, R indices (all data) R1 = 0.2601, wR2 = 0.3102, goodness-of-fit on F2 0.894, largest difference peak 0.360 eAÅ3, largest difference hole 0.236 eÅ3. 14a: White crystal; mp 127-129℃, IR (KBr, cmÅ-1): v 1165, 1706, 1741; 1H NMR (300 MHz, CDCl3): δ 7.09-7.28 (m, 5H, Ph-H), 5.01 (dd, 1 H, J = 2.4 Hz and 10.4 Hz, H13), 3.23 (s, 3H, C6-OCH3), 3.18 (m, 4H, 2 CH2 in piperazinyl), 2.65 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.39 (s, 6H, N(CH3)2), 1.64 (s, 3H, C10-OCH3); ESI-MS m/z (%): 803 (M+H+). 14b: White crystal; mp 117-119℃, IR (KBr, cm-1): v 1164, 1512, 1741; 1H NMR(300 MHz, CDCl3): δ 6.81-7.27 (m, 4H, Ph-H), 5.01 (dd, 1 H, J = 2.3 Hz and 10.3 Hz, H13), 3.76 (s, 3H, Ar-OCH3), 3.12 (s, 3H, C6-OCH3), 3.07 (m, 4H, 2 CH2 in piperazinyl), 2.68 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.46 (s, 6H, N(CH3)2), 1.62 (s, 3H, C10-CH3); ESI-MS m/z (%): 833 (M+H+). 14c: White crystal; mp 105-106℃, IR (KBr, cm-1): y 1164, 1741; 1H NMR (300 MHz, CDCl3): δ 6.81-7.27 (m, 4H, Ph-H), 5.01 (dd, 1 H, J = 2.7 Hz and 10.5 Hz, H13), 3.22 (s, 3H, C6-OCH3), 3.15 (m, 4H, 2 CH2 in piperazinyl), 2.63 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.38 (s, 6H, N(CH3)2), 2.17 (s, 3H, Ar-CH3), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 817 (M+H+). 14d: White crystal; mp 112-113℃, IR (KBr, cm-1): v 1164, 1742; 1H NMR (300 MHz, CDCl3): δ 7.03-7.37 (m, 4H, Ph-H), 5.01 (dd, 1 H, J = 6.5 Hz and 14.0 Hz, H13), 3.24 (s, 3H, C6-OCH3), 3.11 (m, 4H, 2 CH2 in piperazinyl), 2.66 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.40 (s, 6H, N(CH3)2), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 871 (M+H+). 14e: White crystal; mp 114-116℃, IR (KBr, cm-1): v 1164, 1742; 1H NMR (300 MHz, CDCl3): δ 6.90-7.45 (m, 4H, Ph-H), 5.00 (dd, 1 H, J = 2.4 Hz and 10.3 Hz, H13), 3.23 (s, 3H, C6-OCH3), 3.14 (m, 4H, 2 CH2 in piperazinyl), 2.82 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.29 (s, 6H, N(CH3)2), 1.64 (s, 3H, C10-OCH3); ESI-MS m/z (%): 821 (M+H+). 14f: White crystal; mp 124-125℃, IR (KBr, cm-1): v 1163, 1742; 1H NMR (300 MHz, CDCl3): δ 6.95-7.18 (m, 4H, Ph-H), 5.00 (dd, 1 H, J = 2.2 Hz and 10.2 Hz, H13), 3.24 (s, 3H, C6-OCH3), 3.19 (m, 4H, 2 CH2 in piperazinyl), 2.83 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.29 (s, 9H, Ph-CH3 and N(CH3)2), 1.63 (s, 3H, C10-OCH3); ESI-MS m/z (%): 817 (M+H+). 14g: White crystal; mp 134-136℃, IR (KBr, cm-1): v 1164, 1741; 1H NMR (300 MHz, CDCl3): δ 6.87-7.02 (m, 4H, Ph-H), 5.00 (dd, 1 H, J = 2.7 Hz and 10.1 Hz, H13), 3.86 (s, 3H, Ph-OCH3), 3.23 (s, 3H, C6-OCH3), 3.15 (m, 4H, 2 CH2 in piperazinyl), 2.69 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.31 (s, 6H, N(CH3)2), 1.64 (s, 3H, C10-OCH3); ESI-MS m/z (%): 833 (M+H+). 14h: White crystal; mp 99-107℃, IR (KBr, cm-1): v 1165, 1741; 1H NMR (300 MHz, CDCl3): δ 8.18 (d, 1 H, Pyr-H6), 7.47 (t, 1 H, Pyr-H4), 6.63 (t, 2H, Pyr-H3, Pyr-H5), 5.00 (dd, 1 H, J = 3.7 Hz and 8.9 Hz, H13), 3.22 (s, 3H, C6-OCH3), 3.18 (m, 4H, 4H, 2 2 in piperazinyl), 2.61 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.41 (s, 6H, N(CH3)2), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 842 (M+H+). 14i: White crystal; mp 100-102℃, IR (KBr, cm-1): v 1164, 1742; 1H NMR (300 MHz, CDCl3): δ 6.90-6.99 (m, 3H, Ph-H), 5.00 (dd, 1 H, J = 2.7 Hz and 10.1 Hz, H13), 3.23 (s, 3H, C6-OCH3), 3.11 (m, 4H, 2 CH2 in piperazinyl), 2.66 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.26 (s, 6H, N(CH3)2), 2.25 (s, 3H, Ph-CH3), 2.22 (s, 3H, Ph-CH3), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 832 (M+H+). 14j: White crystal; mp 114-115℃, IR (KBr, cm-1): y 1165, 1741; 1H NMR (300 MHz, CDC13): δ 6.80-7.07 (m, 3H, Ph-H), 5.00 (dd, 1 H, J = 2.7 Hz and 10.1 Hz, H13), 3.22 (s, 3H, C6-OCH3), 3.14 (m, 4H, 2 CH2 in piperazinyl), 2.65 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.31 (s, 6H, N(CH3)2), 2.24 (s, 3H, Ph-CH3), 2.21 (s, 3H, Ph-CH3), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 832 (M+H+).[8] Selected characteristic data for the compounds. 9: Yellow powder; mp 91-93℃, IR (KBr, cm-1): v 1706, 1729, 1748; 1H NMR (300 MHz, CDCl3): δ7.28-7.40 (m, 5H, Ph-H), 5.03 (dd, 1 H, J = 2.3 Hz and 9.2 Hz, H13), 4.69 (dd, 1 H, J = 2.3 Hz and 8.2 Hz, H2), 3.10 (s, 3H, C6-OCH3), 1.88 (s, 3H, C20-OCOCH3), 1.66 (s, 3H, C10-CH3); ESI-MS m/z (%): 772 (M+Na+). X-ray analysis: C39H59NO13, Mr = 749.90, crystal size 0.586 mm×0.173 mm×0.049 mm, orthorhombic in p21/n with a = 14.024(3), b = 28.998(6), c = 10.915(2)Å, a, b, g = 90°, V = 3185.0(9)Å3, Dcalu = 1.151 Mg/m3, and Z = 4, absorption coefficient 0.087 mm-1, computing structure solution SHELXL-97, theta range for data collection 1.61 to 25.508, limiting indices -16≤h≤10,-35≤k≤19,-13≤l≤12, reflection collected 23690, refinement method full-matrix least-squares, final R indices [I > 2 sigma (I)] R1 = 0.1016, wR2 = 0.2461, R indices (all data) R1 = 0.2601, wR2 = 0.3102, goodness-of-fit on F2 0.894, largest difference peak 0.360 eAÅ3, largest difference hole 0.236 eÅ3. 14a: White crystal; mp 127-129℃, IR (KBr, cmÅ-1): v 1165, 1706, 1741; 1H NMR (300 MHz, CDCl3): δ 7.09-7.28 (m, 5H, Ph-H), 5.01 (dd, 1 H, J = 2.4 Hz and 10.4 Hz, H13), 3.23 (s, 3H, C6-OCH3), 3.18 (m, 4H, 2 CH2 in piperazinyl), 2.65 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.39 (s, 6H, N(CH3)2), 1.64 (s, 3H, C10-OCH3); ESI-MS m/z (%): 803 (M+H+). 14b: White crystal; mp 117-119℃, IR (KBr, cm-1): v 1164, 1512, 1741; 1H NMR(300 MHz, CDCl3): δ 6.81-7.27 (m, 4H, Ph-H), 5.01 (dd, 1 H, J = 2.3 Hz and 10.3 Hz, H13), 3.76 (s, 3H, Ar-OCH3), 3.12 (s, 3H, C6-OCH3), 3.07 (m, 4H, 2 CH2 in piperazinyl), 2.68 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.46 (s, 6H, N(CH3)2), 1.62 (s, 3H, C10-CH3); ESI-MS m/z (%): 833 (M+H+). 14c: White crystal; mp 105-106℃, IR (KBr, cm-1): y 1164, 1741; 1H NMR (300 MHz, CDCl3): δ 6.81-7.27 (m, 4H, Ph-H), 5.01 (dd, 1 H, J = 2.7 Hz and 10.5 Hz, H13), 3.22 (s, 3H, C6-OCH3), 3.15 (m, 4H, 2 CH2 in piperazinyl), 2.63 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.38 (s, 6H, N(CH3)2), 2.17 (s, 3H, Ar-CH3), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 817 (M+H+). 14d: White crystal; mp 112-113℃, IR (KBr, cm-1): v 1164, 1742; 1H NMR (300 MHz, CDCl3): δ 7.03-7.37 (m, 4H, Ph-H), 5.01 (dd, 1 H, J = 6.5 Hz and 14.0 Hz, H13), 3.24 (s, 3H, C6-OCH3), 3.11 (m, 4H, 2 CH2 in piperazinyl), 2.66 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.40 (s, 6H, N(CH3)2), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 871 (M+H+). 14e: White crystal; mp 114-116℃, IR (KBr, cm-1): v 1164, 1742; 1H NMR (300 MHz, CDCl3): δ 6.90-7.45 (m, 4H, Ph-H), 5.00 (dd, 1 H, J = 2.4 Hz and 10.3 Hz, H13), 3.23 (s, 3H, C6-OCH3), 3.14 (m, 4H, 2 CH2 in piperazinyl), 2.82 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.29 (s, 6H, N(CH3)2), 1.64 (s, 3H, C10-OCH3); ESI-MS m/z (%): 821 (M+H+). 14f: White crystal; mp 124-125℃, IR (KBr, cm-1): v 1163, 1742; 1H NMR (300 MHz, CDCl3): δ 6.95-7.18 (m, 4H, Ph-H), 5.00 (dd, 1 H, J = 2.2 Hz and 10.2 Hz, H13), 3.24 (s, 3H, C6-OCH3), 3.19 (m, 4H, 2 CH2 in piperazinyl), 2.83 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.29 (s, 9H, Ph-CH3 and N(CH3)2), 1.63 (s, 3H, C10-OCH3); ESI-MS m/z (%): 817 (M+H+). 14g: White crystal; mp 134-136℃, IR (KBr, cm-1): v 1164, 1741; 1H NMR (300 MHz, CDCl3): δ 6.87-7.02 (m, 4H, Ph-H), 5.00 (dd, 1 H, J = 2.7 Hz and 10.1 Hz, H13), 3.86 (s, 3H, Ph-OCH3), 3.23 (s, 3H, C6-OCH3), 3.15 (m, 4H, 2 CH2 in piperazinyl), 2.69 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.31 (s, 6H, N(CH3)2), 1.64 (s, 3H, C10-OCH3); ESI-MS m/z (%): 833 (M+H+). 14h: White crystal; mp 99-107℃, IR (KBr, cm-1): v 1165, 1741; 1H NMR (300 MHz, CDCl3): δ 8.18 (d, 1 H, Pyr-H6), 7.47 (t, 1 H, Pyr-H4), 6.63 (t, 2H, Pyr-H3, Pyr-H5), 5.00 (dd, 1 H, J = 3.7 Hz and 8.9 Hz, H13), 3.22 (s, 3H, C6-OCH3), 3.18 (m, 4H, 4H, 2 2 in piperazinyl), 2.61 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.41 (s, 6H, N(CH3)2), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 842 (M+H+). 14i: White crystal; mp 100-102℃, IR (KBr, cm-1): v 1164, 1742; 1H NMR (300 MHz, CDCl3): δ 6.90-6.99 (m, 3H, Ph-H), 5.00 (dd, 1 H, J = 2.7 Hz and 10.1 Hz, H13), 3.23 (s, 3H, C6-OCH3), 3.11 (m, 4H, 2 CH2 in piperazinyl), 2.66 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.26 (s, 6H, N(CH3)2), 2.25 (s, 3H, Ph-CH3), 2.22 (s, 3H, Ph-CH3), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 832 (M+H+). 14j: White crystal; mp 114-115℃, IR (KBr, cm-1): y 1165, 1741; 1H NMR (300 MHz, CDC13): δ 6.80-7.07 (m, 3H, Ph-H), 5.00 (dd, 1 H, J = 2.7 Hz and 10.1 Hz, H13), 3.22 (s, 3H, C6-OCH3), 3.14 (m, 4H, 2 CH2 in piperazinyl), 2.65 (m, 6H, 2 CH2 in piperazinyl and CH2N), 2.31 (s, 6H, N(CH3)2), 2.24 (s, 3H, Ph-CH3), 2.21 (s, 3H, Ph-CH3), 1.65 (s, 3H, C10-OCH3); ESI-MS m/z (%): 832 (M+H+).

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  • 发布日期:  2013-03-13
  • 收稿日期:  2013-01-21
  • 网络出版日期:  2013-02-04
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