氟喹诺酮C-3甲醛缩异烟肼类衍生物的设计、合成及生物活性研究
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摘要
从20世纪80年代中期开始，随着耐药结核病发病率的不断上升以及结核病与AIDS病的相互结合，结核病疫情再度上升，成为人类健康的重大威胁。遗憾的是，抗结核病药物的开发难度大，现有的治疗方案不够理想，以及耐药菌株的不断出现，自利福平问世至今的30年还没有一个新型化合物用于抗结核治疗，因此，开发新的或作用于新靶点的抗结核药物势在必行。氟喹诺酮类药物是一类作用于细菌DNA促旋酶（Gry）和拓扑异构酶IV（Top IV）合成抗菌药，对结核杆菌有着良好的抑制和杀灭作用，同时，由于具有该类药物与现有抗结核药物不交叉耐药，不抑制其他药物的活性，不良反应少，可口服等优点，某些品种（如环丙沙星、加替沙星、氧氟沙星等）已被作为二线抗结核药物，用于治疗多耐药结核病（MDR-TB）以及对不能耐受一线抗结核药物的患者的治疗。但是由于氟喹诺酮类（FQs）药物影响动物的软骨发育，有光毒性，而且对结核病的疗效也不及异烟肼（INH）、利福平（RFP）等经典的一线抗结核药物，因此该类药物对结核病的治疗存在着一定的缺陷。异烟肼类似物（异烟腙等）对结核分支杆菌具有极强的杀伤作用的一种抗结核药物，它们的不良反应低于异烟肼。鉴于此，依据栾药设计理论，我们将氟喹诺酮类（FQs）药物的C-3羧基转换为甲酰基，再与异烟肼缩合得到一类新的异烟腙类衍生物，有望实现氟喹诺酮与异烟肼两类抗结核病药物互补性，降低二者的毒副作用，降低结核杆菌对双效作用抗菌剂的耐药性产生机率，有望开发出一类新的抗结核杆菌药物。
1.目标化合物的设计与合成
以氟喹诺酮类抗菌剂及其类似物为起始原料，利用生物电子等排、药效活性基团拼合等药物设计原理，经脱羧、甲酰化、氧化、缩合等一系列反应制得C-3甲酰基氟喹诺酮缩异烟肼类目标化合物，其结构经1H-NMR、MS、IR等光谱数据进行表征。
2.生物活性研究
2.1体外抗结核活性评价
采用二倍稀释法测试目标化合物对分支杆菌标准株H37Ra，H37Rv的体外最小抑菌浓度（MIC）。结果表明，C-3甲酰基氟喹诺酮缩异烟肼类衍生物对结核分支杆菌具有较强的抑制作用（部分化合物MIC<0.195μg），活性接近异烟肼，比氟喹诺酮类抗菌剂更强的体外抗结核活性。
2.2细胞毒性实验
采用MTT法评价了目标化合物对VERO细胞的生长活性抑制。结果表明，除目标化合物B1、B3外，其它受试化合物体外对VERO细胞均表现出较低的抑制作用，没有明显的细胞毒性，化合物B2、B4、B5、B6、B7、B8、B9、B10的对VERO细胞的细胞毒性（IC50>100μmol）低于氧氟沙星。
3.结论
合成了10个目标化合物，其结构经光谱数据得到确证。体外抑菌实验表明，10个化合物对结核分枝杆菌H37Ra，H37Rv具有良好的抑制作用。体外细胞毒性实验表明，氟喹诺酮C-3甲醛缩异烟肼类衍生，大多无明显的细胞毒性。实验结果表明，C-3甲酰基氟喹诺酮缩异烟肼类衍生物具有良好的开发前景，值得进一步研究。
Since the mid-1980s, with the on-going rising incidence of drug-resistant tuberculosis and the increasein AIDS associated infections, the prevalence of tuberculosis (TB) has been increasing, and thattuberculosis becomes a leading infectious cause of death worldwide. Unfortunately, because of thehigh-difficulty of developing anti-tuberculosis drugs, the current anti-TB treatment program is far fromsatisfaction, as well as the emergency of drug-resistant strains, especially, multi-drug resistant strains, thereis not a new anti-tuberculosis drug since the advent of rifampicin during the past30years. Therefore, thereis an urgent need to develop new drugs or new target for anti-TB drugs. Fluoroquinolones is a kind ofsynthetic antibiotics which have a good inhibitory against Mycobacterium tuberculosis, their mainbiological targets are the DNA gyrase (Gyr) and topoisomerase IV (Top4). At present, There are no reportsof cross-resistance with other classes of anti-tuberculosis drugs. Fluoroquinolones can be administeredorally with good absorption and favorable pharmacokinetics, as well as low incidence of severity ofadverse effects. With above advantages, some species (Ciprofloxacin, Gatifloxacin, Ofloxacin, etc.) havebeen used as second-line anti-tuberculosis drugs in combination with other anti-tuberculosis drugs for thetreatment of multiple drug-resistant TB (MDR-TB), and the intolerable patients to the first-lineanti-tuberculosis drugs. Isoniazid derivatives (isonicotinoylhydrazone analogs) were reported to exhibit thesame levels of the in vitro anti-MTB activity as that of Isoniazid. However, these Isoniazid analogs areappreciably improved in pharmacological attributes, in terms of adverse effects or pharmacokinetics.Consequently, we alternate the C-3carboxyl of fluoroquinolones with formyl, and then condensed withisoniazid, in this way, it is expected to get new anti-tuberculosis drugs with a complementarity betweenfluoroquinolones and Isoniazid, and lower toxicity, as well as low incidence of cross-resistance.
1. Design and synthesis of target compounds
In this paper,10new compounds have been designed and synthesized with fluoroquinolones and itsderivatives in the principles of bioisosterism and combination of activity group. Through a series ofreactions, the C-3carboxyl of fluoroquinolones was substituted by Isonicotinoyl hydrazone, and thecorrespondingly target compounds were obtained. The structures of new compounds synthesized had beencharacterized by MS、1H-NMR and IR.
2. Evaluation of biological activity
2.1Evaluation of anti-tuberculosis activity in vitro
MIC of target compounds was determined against M. tuberculosis H37Rv strain and H37Ra strain byusing broth dilution assay method. All the tested compounds exhibited good activity against both of the twoM. tuberculosis strains which showed the similar levels of the in vitro anti-MTB activity as that ofIsoniazid.
2.2Cytotoxicity for VERO cells in vitro
Cell cytotoxicity of isonicotinoylhydrazones was tested by MTT assay respectively towards VEROcells. The result shows that most of the compounds were with wealy cytoxcicity which are better thanofloxacin.
3. Conclusion
10target compounds were synthesized and their structures confirmed by spectral data, the result ofanti-tuberculosis activity in vitro shows that: all the tested compounds exhibited good activity, the MIC ofthem are next to the level of Isoniazid; The cytotoxicity result showed that most of the compounds werewith wealy cytoxcicity which were better than ofloxacin. Therefore, the substatution of quinolone C-3carboxylic with isonicotinoylhydrazone is worthy to be developed into anti-tuberculosis agents.
1.目标化合物的设计与合成
以氟喹诺酮类抗菌剂及其类似物为起始原料，利用生物电子等排、药效活性基团拼合等药物设计原理，经脱羧、甲酰化、氧化、缩合等一系列反应制得C-3甲酰基氟喹诺酮缩异烟肼类目标化合物，其结构经1H-NMR、MS、IR等光谱数据进行表征。
2.生物活性研究
2.1体外抗结核活性评价
采用二倍稀释法测试目标化合物对分支杆菌标准株H37Ra，H37Rv的体外最小抑菌浓度（MIC）。结果表明，C-3甲酰基氟喹诺酮缩异烟肼类衍生物对结核分支杆菌具有较强的抑制作用（部分化合物MIC<0.195μg），活性接近异烟肼，比氟喹诺酮类抗菌剂更强的体外抗结核活性。
2.2细胞毒性实验
采用MTT法评价了目标化合物对VERO细胞的生长活性抑制。结果表明，除目标化合物B1、B3外，其它受试化合物体外对VERO细胞均表现出较低的抑制作用，没有明显的细胞毒性，化合物B2、B4、B5、B6、B7、B8、B9、B10的对VERO细胞的细胞毒性（IC50>100μmol）低于氧氟沙星。
3.结论
合成了10个目标化合物，其结构经光谱数据得到确证。体外抑菌实验表明，10个化合物对结核分枝杆菌H37Ra，H37Rv具有良好的抑制作用。体外细胞毒性实验表明，氟喹诺酮C-3甲醛缩异烟肼类衍生，大多无明显的细胞毒性。实验结果表明，C-3甲酰基氟喹诺酮缩异烟肼类衍生物具有良好的开发前景，值得进一步研究。
Since the mid-1980s, with the on-going rising incidence of drug-resistant tuberculosis and the increasein AIDS associated infections, the prevalence of tuberculosis (TB) has been increasing, and thattuberculosis becomes a leading infectious cause of death worldwide. Unfortunately, because of thehigh-difficulty of developing anti-tuberculosis drugs, the current anti-TB treatment program is far fromsatisfaction, as well as the emergency of drug-resistant strains, especially, multi-drug resistant strains, thereis not a new anti-tuberculosis drug since the advent of rifampicin during the past30years. Therefore, thereis an urgent need to develop new drugs or new target for anti-TB drugs. Fluoroquinolones is a kind ofsynthetic antibiotics which have a good inhibitory against Mycobacterium tuberculosis, their mainbiological targets are the DNA gyrase (Gyr) and topoisomerase IV (Top4). At present, There are no reportsof cross-resistance with other classes of anti-tuberculosis drugs. Fluoroquinolones can be administeredorally with good absorption and favorable pharmacokinetics, as well as low incidence of severity ofadverse effects. With above advantages, some species (Ciprofloxacin, Gatifloxacin, Ofloxacin, etc.) havebeen used as second-line anti-tuberculosis drugs in combination with other anti-tuberculosis drugs for thetreatment of multiple drug-resistant TB (MDR-TB), and the intolerable patients to the first-lineanti-tuberculosis drugs. Isoniazid derivatives (isonicotinoylhydrazone analogs) were reported to exhibit thesame levels of the in vitro anti-MTB activity as that of Isoniazid. However, these Isoniazid analogs areappreciably improved in pharmacological attributes, in terms of adverse effects or pharmacokinetics.Consequently, we alternate the C-3carboxyl of fluoroquinolones with formyl, and then condensed withisoniazid, in this way, it is expected to get new anti-tuberculosis drugs with a complementarity betweenfluoroquinolones and Isoniazid, and lower toxicity, as well as low incidence of cross-resistance.
1. Design and synthesis of target compounds
In this paper,10new compounds have been designed and synthesized with fluoroquinolones and itsderivatives in the principles of bioisosterism and combination of activity group. Through a series ofreactions, the C-3carboxyl of fluoroquinolones was substituted by Isonicotinoyl hydrazone, and thecorrespondingly target compounds were obtained. The structures of new compounds synthesized had beencharacterized by MS、1H-NMR and IR.
2. Evaluation of biological activity
2.1Evaluation of anti-tuberculosis activity in vitro
MIC of target compounds was determined against M. tuberculosis H37Rv strain and H37Ra strain byusing broth dilution assay method. All the tested compounds exhibited good activity against both of the twoM. tuberculosis strains which showed the similar levels of the in vitro anti-MTB activity as that ofIsoniazid.
2.2Cytotoxicity for VERO cells in vitro
Cell cytotoxicity of isonicotinoylhydrazones was tested by MTT assay respectively towards VEROcells. The result shows that most of the compounds were with wealy cytoxcicity which are better thanofloxacin.
3. Conclusion
10target compounds were synthesized and their structures confirmed by spectral data, the result ofanti-tuberculosis activity in vitro shows that: all the tested compounds exhibited good activity, the MIC ofthem are next to the level of Isoniazid; The cytotoxicity result showed that most of the compounds werewith wealy cytoxcicity which were better than ofloxacin. Therefore, the substatution of quinolone C-3carboxylic with isonicotinoylhydrazone is worthy to be developed into anti-tuberculosis agents.
引文
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[2]郝阳.我国结核病防治概况与今后工作设想[J].中华结核和呼吸杂志,2004,27(7):433-43
[3] Lonroth K, Kenneth GC, Jeremiah MC, et al. Tuberculosis control and elimination2010-50: cure, care,and social development[J]. Lancet,2010,375(9728):1814-29.
[4]袁群英.抗结核病药物治疗的研究进展[J].临床肺科杂志,2010,15(5):701-703.
[5] Blanc DC, Nunn P, Duncan K. Incentives and disincentives for new anti-tuberculous drugdevelopment. Situational analysis[J]. World Health Organization2000,2000(1985):1-59.
[6] Neel RG, Paul N, Keertan D, et al.Multidrug-resistant and extensively drug-resistant tuberculosis: athreat to global control of tuberculosis[J]. The Lancet,2010,375(9728):1830–1843.
[7] Cole ST, Broseh R, Parhill J, et al. Deciphering the biology of Mycobacterium tuberculosis from theeomplete genome sequenee[J].Nature,1998,393:537.
[8]陈冷.喹诺酮类化合物的合成及其抗结核活性研究[D].沈阳药科大学,2006.
[9] Drlick, Xu C, Wang JY, et al. Fluoroquinolone action in mycobacteria: similarity with effects inescherichia coli and detection by cell lysate viscosity[J]. Antimicrob Agents Chemother,1996,40(7):1594-1599.
[10]刘明亮,冯连顺,柴芸等.氟喹诺酮类抗菌药物抗结核作用研究进展[J].中国新药杂志,2010,19(3):190-198.
[11]张沂,段蕴铀,张沂杨等.喹诺酮类药物抗结核治疗的研究进展[J].中国抗生素志,2001,26(2):234.
[12] Ginsburg AS, Grosset JH, Bishai WR, et al. Fluoroquinolones, tuberculosis,and resistance [J]. LancetInfect Dis,2003,3(7):432-42.
[13] Jacobs MR. Fluoroquinolones as chemotherapeutics against mycobacterial infections[J]. Curr PharmDes,2004,10(7):3213-20.
[14] Bryskier A, Lowther J. Fluoroquinolones and tuberculosis[J]. Expert Opin Investig Drugs,2002,11(2):233-58.
[15] Ginsburg AS, Hooper N, Parrish N, et al. Fluoroquinolone resistance in patients with newly diagnosedtuberculosis[J]. Clinical Infectious Diseases,2003,37(11):1448-52.
[16] Alvirez-Freites EJ, Carter JM, Cynamon MH. In vitro and in vivo activities of gatifloxacin againstMycobaeterium tuberculosis[J]. Antimicrob Agents Chemother,2002,46(37):1022.
[17] Miyazaki E, Miyazaki M, Chen J M, et al. Moxifloxacin (Bay1228039), a new8-methoxyquinolone,is active in a mouse model of tubercilosis[J]. Antimicrob Agents Chemother,1999,3(26):85.
[18] Takiff H, Guerrero, E. Current prospects for the fluoroquinolones as first-line tuberculosis therapy[J].Antimicrob Agents Chemother,2011,55(12):5421-5429
[19] Suriyati M, Pazirah I, Sadiun A. Susceptibility of mycobacterium tuberculosis to isoniazid and itsderiveative,1-isonicotinyl-2-nonanoyl hydrazine:investigation at cellular level [J].Tuberculosis,2004,84(1),56-62.
[20] Cocco MT, Warrener P, Tomishige T, et al. Synthesis and antimycobacterial activity of some isonico-tinoylhydrazones [J]. European Journal of Medicinal Chemistry,1999,34(12):1071-76.
[21]陈爱国,张天民. KRM-1648研7年概况[J].冶金防痨,1996,6(4):347.
[22] Brown M,Miller R.F.AIDS和肺[J].国际内科双语杂志,2002,2(4):106.
[23]贺芝红.利福霉素类药物国内外研究情况综述[J].中国药业,1999,8(9):571.
[24]宋毅.抗结核药物的研究进展及前景展望[J].中国医院药学杂志,2009,29(19):1660.
[25]王艳红.抗结核药物的发展及应用[J].首都医药药物研究,2006,11(1):47.
[26]张惠燕.抗结核药物的研究现状及新进展[J].中华临床感染病杂志,2010,3(1):62.
[27]郑虎.药物化学[M].人民卫生出版社,2007:311.
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