硝基咪唑类抗结核药物结构修饰研究策略
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摘要
结核病现已成为全球第二大致死疾病,虽然目前结核病的发生率呈现缓慢下降趋势,但耐药结核及耐多药结核仍是严重威胁人类健康的疾病.近年来,以PA-824,OPC-67683为代表的硝基咪唑类药物对结核杆菌尤其是耐多药结核杆菌表现出良好的抗菌活性.研究者进行了大量硝基咪唑化合物的构效关系研究,期望通过结构修饰改善其溶解性及安全性.综述了近年来硝基咪唑类化合物在抗结核领域的研究进展.
Tuberculosis has become the second leading disease that causes death in the world. Although the incidence of tuberculosis is decreasing slowly,drug-resistant tuberculosis and multi-drugresistant tuberculosis are still the main threats. In recent years,the nitroimidazole drugs,such as PA-824 and OPC-67683,have shown good antimicrobial activity against Mycobacterium tuberculosis,especially against multidrug-resistant Mycobacterium tuberculosis. In the aim of improving the solubility and the safety of compounds,researchers have made extensive investigations into the structure-activity relationship of nitroimidazole compounds through structural modification. In this paper,the recent progress of nitroimidazole compounds that are used in anti-tuberculosis is reviewed.
Tuberculosis has become the second leading disease that causes death in the world. Although the incidence of tuberculosis is decreasing slowly,drug-resistant tuberculosis and multi-drugresistant tuberculosis are still the main threats. In recent years,the nitroimidazole drugs,such as PA-824 and OPC-67683,have shown good antimicrobial activity against Mycobacterium tuberculosis,especially against multidrug-resistant Mycobacterium tuberculosis. In the aim of improving the solubility and the safety of compounds,researchers have made extensive investigations into the structure-activity relationship of nitroimidazole compounds through structural modification. In this paper,the recent progress of nitroimidazole compounds that are used in anti-tuberculosis is reviewed.
引文
[1]World Health Organization. Global tuberculosis report[R/OL].(2016-06-27)[2017-08-01]. http://apps. who. int/iris/bitstream/10665/250441/1/9789241565394-eng. pdf? ua=1.
[2]World Health Organization. Global tuberculosis report 2014[R/OL].(2014-10-22)[2016-03-20]. http://reliefweb. int/report/world/global-tuberculosis-report-2014.
[3]Singh R,Manjunatha U,Boshoff H I,et al. PA-824 kills nonreplicating mycobacterium tuberculosis by intracellular NO release[J]. Science,2008,322(5906):1392-1395.
[4]William R B,Cai S P,Eric L K. Nitroimidazole antibacterial compounds and methods of use thereof:EP0866793[P]. 2004-10-27.
[5]Meera G,Tathagata M,Cythia S D,et al. Substrate specify of the deazaflayin-dependent nitroreductase from mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles[J]. FEBS J,2011,279(1):113-125.
[6]Stover CK,Warrener P,Vandevanter DR,et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis[J]. Nature,2000,405(6789):962-966.
[7]Gler MT,Skripconoka V,Sanchez-Garavito E,et al. Delamanid for multidrug-resistant pulmonary tuberculosis[J]. N Engl Med,2012,366(23):2151-2160.
[8]Matsumoto M,Hashizume H,Tomishige T,et al. OPC-67683,a nitrodihydroimidazooxazole a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice[J]. PLo S Med,2006,3(11):2131-2144.
[9]Upton AM. TBA-354:A next generation nitroimidazole for treatment of drug sensitive and drug-resistant tuberculosis[C]//52nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco,CA,USA:Medscape,2012.
[10]Kim P,Zhang L,Manjunatha V H,et al. Structure-activity relationships of antitubercular with aerobic and anaerobic activities of 4-and 5-Nitroimidazoles[J]. J Med Chem,2009,52(5):1317-1328.
[11]Bollo S,Nunez-vergara L J,Kang S H,et al. The effect of 5-substitution on the electrochemical behaviorandantitubercularativity of PA-824[J]. Bioorg Med Chem Lett,2011,21(2):812-817.
[12]Kim P,Kang S H,Boshoff H I,et al. Structure activity relationships of antitubercular nitroimidazoles 2 determinants of aerobic activity and quantitative structure-activity relationships[J]. J Med Chem,2009,52(5):1329-1344.
[13]Maria V P,William D B,Howard S R,et al. The antitubercular activity of various nitro(triazole/imidazole)-base dcompounds[J]. Bioorg Med Chem Lett,2017,25(21):6039-6048.
[14]Li X J,Manjunatha V H,Goodwin M B,et al. Synthesis and antitubercular activity of 7-(R)and 7-(S)-methyl-2-nitro-6-(S)(4-(trifluoromet)bezyloxy)-6,7-dihydro-5H-imidazo[2,1-b],3]oxazines,analogues of PA-824[J]. Bioorg Med Chem Lett,2008,18(7):2256-2262.
[15]Palmar B D,Thompson A M,Sutherland H S,et al. Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug(6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine(PA-824)[J]. J Med Chem,2010,53(1):282-294.
[16]Ray S,Roy P P. A QSAR Study of biphenyl analogues of 2-nitroimidazo-[2,1-b][1,3]-oxazines as Antitubercular agents using genetic function approximation[J]. Med Chem,2012,8(4):717-726.
[17]Kang Y G,Park C Y,Shin H,et al. Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs[J]. Bioorg Med Chem Lett,2015,25(17):3650-3653.
[18]Kmentova I,Sutherland H S,Palmer B D,et al. Synthesis and structure activity relationships of aza and diazabiphenyl analogues of the antitubercular drug-6-l[4-(trifluorometho)benzy I]oxy)-6,7-dihydro-5H-imidazo[2,1-b][1. 3]oxazin(PA-824)[J]. J Med Chem,2010,53(23):8421-8439.
[19]Thompson A M,Sutherland H S,Palmer B D,et al. Synthesis and structure activity relationships of varied ether linker analogues of the antitubercular drug(6S)-2-Nitro-6-[[4-(trifluoromethoxy)benzyl]oxy-6,7-dihydro-5H-imidazo-[2,1-b][1,3]oxazine(PA-824)[J]. J Med Chem,2015,58(7):3036-3059.
[20]Blaser A,Plamer B D,Sutherland H S,et al. Structure activity relationships for amide-Carbamateand urea-linked analogues of the tuberculosis drug(6S)-2-Ntro-6-[4-(rifluorometoxy)benzyoxy6,-diydr-imidazo[2,1-b][1,3]oxazine(PA-824)[J]. J Med Chem,2012,55(1):312-326.
[21]Cherian J,Choi I,Nayyar A,et al. Structure activity relationships of antitubercular nitroimidazoles. 3. Exploration of the linker and lipophilic tail of((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][13oxazin-6-yl)-(4-trifluoromethoxybenzyl)amine(6-amino PA-824)[J]. J Med Chem,2011,54(16):5639-5659.
[2]World Health Organization. Global tuberculosis report 2014[R/OL].(2014-10-22)[2016-03-20]. http://reliefweb. int/report/world/global-tuberculosis-report-2014.
[3]Singh R,Manjunatha U,Boshoff H I,et al. PA-824 kills nonreplicating mycobacterium tuberculosis by intracellular NO release[J]. Science,2008,322(5906):1392-1395.
[4]William R B,Cai S P,Eric L K. Nitroimidazole antibacterial compounds and methods of use thereof:EP0866793[P]. 2004-10-27.
[5]Meera G,Tathagata M,Cythia S D,et al. Substrate specify of the deazaflayin-dependent nitroreductase from mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles[J]. FEBS J,2011,279(1):113-125.
[6]Stover CK,Warrener P,Vandevanter DR,et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis[J]. Nature,2000,405(6789):962-966.
[7]Gler MT,Skripconoka V,Sanchez-Garavito E,et al. Delamanid for multidrug-resistant pulmonary tuberculosis[J]. N Engl Med,2012,366(23):2151-2160.
[8]Matsumoto M,Hashizume H,Tomishige T,et al. OPC-67683,a nitrodihydroimidazooxazole a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice[J]. PLo S Med,2006,3(11):2131-2144.
[9]Upton AM. TBA-354:A next generation nitroimidazole for treatment of drug sensitive and drug-resistant tuberculosis[C]//52nd Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco,CA,USA:Medscape,2012.
[10]Kim P,Zhang L,Manjunatha V H,et al. Structure-activity relationships of antitubercular with aerobic and anaerobic activities of 4-and 5-Nitroimidazoles[J]. J Med Chem,2009,52(5):1317-1328.
[11]Bollo S,Nunez-vergara L J,Kang S H,et al. The effect of 5-substitution on the electrochemical behaviorandantitubercularativity of PA-824[J]. Bioorg Med Chem Lett,2011,21(2):812-817.
[12]Kim P,Kang S H,Boshoff H I,et al. Structure activity relationships of antitubercular nitroimidazoles 2 determinants of aerobic activity and quantitative structure-activity relationships[J]. J Med Chem,2009,52(5):1329-1344.
[13]Maria V P,William D B,Howard S R,et al. The antitubercular activity of various nitro(triazole/imidazole)-base dcompounds[J]. Bioorg Med Chem Lett,2017,25(21):6039-6048.
[14]Li X J,Manjunatha V H,Goodwin M B,et al. Synthesis and antitubercular activity of 7-(R)and 7-(S)-methyl-2-nitro-6-(S)(4-(trifluoromet)bezyloxy)-6,7-dihydro-5H-imidazo[2,1-b],3]oxazines,analogues of PA-824[J]. Bioorg Med Chem Lett,2008,18(7):2256-2262.
[15]Palmar B D,Thompson A M,Sutherland H S,et al. Synthesis and structure-activity studies of biphenyl analogues of the tuberculosis drug(6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine(PA-824)[J]. J Med Chem,2010,53(1):282-294.
[16]Ray S,Roy P P. A QSAR Study of biphenyl analogues of 2-nitroimidazo-[2,1-b][1,3]-oxazines as Antitubercular agents using genetic function approximation[J]. Med Chem,2012,8(4):717-726.
[17]Kang Y G,Park C Y,Shin H,et al. Synthesis and anti-tubercular activity of 2-nitroimidazooxazines with modification at the C-7 position as PA-824 analogs[J]. Bioorg Med Chem Lett,2015,25(17):3650-3653.
[18]Kmentova I,Sutherland H S,Palmer B D,et al. Synthesis and structure activity relationships of aza and diazabiphenyl analogues of the antitubercular drug-6-l[4-(trifluorometho)benzy I]oxy)-6,7-dihydro-5H-imidazo[2,1-b][1. 3]oxazin(PA-824)[J]. J Med Chem,2010,53(23):8421-8439.
[19]Thompson A M,Sutherland H S,Palmer B D,et al. Synthesis and structure activity relationships of varied ether linker analogues of the antitubercular drug(6S)-2-Nitro-6-[[4-(trifluoromethoxy)benzyl]oxy-6,7-dihydro-5H-imidazo-[2,1-b][1,3]oxazine(PA-824)[J]. J Med Chem,2015,58(7):3036-3059.
[20]Blaser A,Plamer B D,Sutherland H S,et al. Structure activity relationships for amide-Carbamateand urea-linked analogues of the tuberculosis drug(6S)-2-Ntro-6-[4-(rifluorometoxy)benzyoxy6,-diydr-imidazo[2,1-b][1,3]oxazine(PA-824)[J]. J Med Chem,2012,55(1):312-326.
[21]Cherian J,Choi I,Nayyar A,et al. Structure activity relationships of antitubercular nitroimidazoles. 3. Exploration of the linker and lipophilic tail of((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][13oxazin-6-yl)-(4-trifluoromethoxybenzyl)amine(6-amino PA-824)[J]. J Med Chem,2011,54(16):5639-5659.