CN113512046B - C-7位卤代酰基头孢化合物、制备方法和应用 - Google Patents
C-7位卤代酰基头孢化合物、制备方法和应用 Download PDFInfo
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- CN113512046B CN113512046B CN202110349910.0A CN202110349910A CN113512046B CN 113512046 B CN113512046 B CN 113512046B CN 202110349910 A CN202110349910 A CN 202110349910A CN 113512046 B CN113512046 B CN 113512046B
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- halogenated acyl
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- cephalosporin
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- 229930186147 Cephalosporin Natural products 0.000 title claims abstract description 47
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- 241000191967 Staphylococcus aureus Species 0.000 claims description 6
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- 150000003839 salts Chemical class 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 abstract description 45
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- 229910052794 bromium Chemical group 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
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- 229960005446 cefpiramide Drugs 0.000 description 1
- PWAUCHMQEXVFJR-PMAPCBKXSA-N cefpiramide Chemical compound C1=NC(C)=CC(O)=C1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 PWAUCHMQEXVFJR-PMAPCBKXSA-N 0.000 description 1
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- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
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- 231100001095 no nephrotoxicity Toxicity 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/57—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with a further substituent in position 7, e.g. cephamycines
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- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
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Abstract
本发明公开了C‑7位卤代酰基头孢化合物、制备方法和应用，属于药物合成技术领域。C‑7位卤代酰基头孢化合物结构式如下。实验表明，合成的大多数C‑7位卤代酰基头孢化合物具有抗人致病菌活性，其中7个化合物对于所测试的8株人致病菌活性强于或相当于测试的上市头孢药物，TM1f显示了最强最广的抑菌活性；此外，TM1s对柑橘褐斑病菌Al.6的抑菌活性与阳性农药咪鲜胺相当，且强于同类药物头孢噻吩。所得高活性分子对人致病菌和柑橘真菌病菌具有非常好的应用前景。
Description
技术领域
本发明涉及药物合成技术领域，具体涉及C-7位卤代酰基头孢化合物、制备方法和应用。
背景技术
感染是指微生物在宿主体内生活时与宿主相互作用并导致不同程度的病理变化的过程。感染无处不在，导致人类很多烦恼、伤害甚至死亡。目前解决感染的医疗方法，主要采用化学治疗。化学治疗药物种类繁多，诸如抗生素类药物、抗细菌类药物、抗真菌类药物、抗结核类药物、抗病毒类药物等。这些药物，适用于一种或多种感染，能够解决感染性疾病的传播，有效保护人类健康。
头孢菌素是临床治疗感染的重要药物。头孢药物在临床中大致分为五代：以头孢拉定、头孢唑林、头孢氨苄为代表的第一代头孢药物对革兰阳性菌作用性强，对革兰阴性菌作用较弱；以头孢呋辛、头孢克洛、头孢替胺为代表的第二代头孢药物在保持对革兰阳性菌作用强的基础上，增强了对革兰阴性菌的抗菌活性；以头孢他啶、头孢曲松、头孢哌酮为代表的第三代头孢药物以及以头孢吡肟、头孢唑南、头孢匹罗为代表的第四代头孢药物对革兰阳性菌、革兰阴性菌以及厌氧菌均有广谱的抗菌活性，且第四代头孢药物抗革兰阳性菌活性强于第三代、对肾脏无毒性；第五代头孢药物包括头孢洛林酯、头孢托罗、头孢吡普，此类抗菌药物为超广谱，无肾毒性。分析头孢类上市药物分子的结构发现，头孢药物分子由头孢母核、C-7位氨基修饰基团、C-3位取代基(或无取代基)三部分组成；头孢母核，常见的有7-ACA,7-ACCA,7-ANCA,7-MAC,7-MCA(7-MAC脱除二苯甲基者)(结构式如下)；头孢C-7位氨基修饰基团，可以是简单的噻吩乙酰基、L-苯甘氨酰基、半胱氨酰基、氰甲基巯基乙酰基、氨基噻唑乙酰基等，也可以是很复杂的结构片段2-呋喃基-(Z)-2-甲氧基亚胺基乙酰基、2-(4-氨基)噻唑-(Z)-2-甲氧基亚胺基乙酰基等。C-3位修饰基团，较常见的有乙酰氧甲基、氯原子、甲巯基四氮唑甲基。第一代头孢到第五代头孢的主要差别是C-7位氨基侧链以及C-3位基团的不同。因此，头孢类分子的可衍生范围很广，对应新分子及其活性值得期待。
人类被感染，许多是被人致病性微生物攻击所致。医治感染疾病，最好最简单的措施是药物对症治疗。寻找针对不同致病菌株的药物，是药物研究的长期课题，人类迫切需要更有效、负担得起且无毒的新药物。
柑橘在全世界范围内具有长期的选育和栽培历史，近百年来随着全球柑橘种质和苗木的频繁交流，共同促进了柑橘真菌性病害的起源和扩散。柑橘褐斑病和柑橘炭疽病对柑橘生长危害较严重，每年必需做4～8次药剂防控，而长期使用化学杀菌剂会导致病原菌产生抗药性，并且大量喷洒杀菌剂也会造成环境污染。因此，生产上亟需低毒或无害且高效抑制柑橘真菌性病害的新药物。
柑橘溃疡病分布广泛，可危害几十种芸香科植物，是影响世界柑橘生产的重大检疫性病害。柑橘溃疡病菌系分化复杂、发病率高、传播快、寄主范围广，防治柑橘溃疡病一直是一个世界性难题，目前尚无一种方法可以根治；近年农用链霉素的使用被禁止，对溃疡病菌有效的控制药剂严重缺乏，开发新型抗柑橘溃疡病药物迫在眉睫。
发明内容
有鉴于此，本发明的目的在于提供C-7位卤代酰基头孢化合物、制备方法和应用。
经研究，本发明提供以下技术方案：
1、C-7位卤代酰基头孢化合物，具有以下结构式：
式中，Y为氯或溴；R1为H、Cl、OAc或
R2为H或OCH3；R3为H或CHPh2；n为1、2或3。
2、本发明还提供如下结构的化合物，或它们的药学可接受盐：
3、如上所述C-7位卤代酰基头孢化合物的制备方法，包括以下步骤：
将头孢母核7-MAC与卤代酰氯反应，制得C-7位卤代酰基化的目标分子TM1a～TM1e；
将TM1a～TM1e脱除二苯甲基Ph2CH，制得C-7位卤代酰基化的目标分子TM1f～TM1j；
将统称为7-AXCA的三种头孢母核与卤代酰氯反应，制得C-7位卤代酰基化的目标分子TM1k～TM1y；
式中，Y、R1以及n的定义均与所述的C-7位卤代酰基头孢化合物结构式中Y、R1以及n的定义相同。
优选的，所述C-7位卤代酰基头孢化合物的制备方法，包括以下步骤：
A、在碱作用下，头孢母核7-MAC与卤代酰氯于有机溶剂中低温反应，制得TM1a～TM1e；所述有机溶剂为二氯甲烷、氯仿、乙腈、四氢呋喃或N,N-二甲基甲酰胺；所述碱为三乙胺、吡啶、4-二甲氨基吡啶、碳酸钠、碳酸钾或碳酸氢钠；所述温度为-40℃～4℃。
B、将TM1a～TM1e在阳离子捕获剂存在下，在有机溶剂中与脱二苯甲基酸性试剂反应，控温搅拌，溶剂析出，制得TM1f～TM1j。所述有机溶剂为二氯甲烷、氯仿、丙酮、乙酸乙酯、四氢呋喃或乙醚；所述脱二苯甲基酸性试剂为三氯化铝、氯化锌、溴化铜、浓盐酸、浓氢溴酸或三氟醋酸；所述阳离子捕获剂为苯酚、间苯二酚、苯甲醚或2-巯基乙醇；所述温度为-20℃～40℃；所述析出溶剂为乙醚、甲基叔丁基醚、石油醚、乙酸乙酯、正己烷或环己烷。
C、在碱作用下，头孢母核7-AXCA与卤代酰氯在有机溶剂和水中反应，制得TM1k～TM1y；所述有机溶剂为二氯甲烷、氯仿、丙酮、乙腈、四氢呋喃或N,N-二甲基甲酰胺；所述碱为甲醇钠、氢氧化钠、碳酸钠、碳酸钾、碳酸氢钠、三乙胺或吡啶。
更优选的，所述步骤A中，有机溶剂为二氯甲烷；所述碱为吡啶；所述温度为-25℃。
更优选的，所述步骤B中，有机溶剂为二氯甲烷；所述脱二苯甲基酸性试剂为三氟醋酸；所述阳离子捕获剂为苯甲醚；所述温度为-4℃～19℃；所述析出溶剂为乙醚和石油醚。
更优选的，所述步骤C中，有机溶剂为丙酮和水；所述碱为碳酸氢钠。
4、本发明还提供一种药物制剂，包括所述C-7位卤代酰基头孢化合物或其药学可接受盐，以及药学可接受的载体和/或助剂。
5、本发明还提供一种复方药物，包括所述C-7位卤代酰基头孢化合物或其药学可接受盐及其他活性成分。
6、本发明还提供上述化合物或它们的药学可接受盐在制备防治人致病菌药物中的应用。所述人致病菌优选金黄色葡萄球菌、藤黄微球菌、枯草芽孢杆菌、大肠杆菌和铜绿假单胞菌。
7、本发明还提供上述化合物或它们的药学可接受盐在制备防治柑橘溃疡病或柑橘褐斑病的药物中的应用。所述柑橘相关病害优选柑橘褐斑病。
本发明的有益效果在于：
1)本发明提供的C-7位卤代酰基头孢化合物，是以4种头孢母核7-MAC、7-ACA、7-ACCA及7-ANCA(后3者统称为7-AXCA)为起始原料，对其C-7位氨基进行卤代酰基化修饰，获得TM1a～TM1e和TM1k～TM1y；TM1a～TM1e在酸性试剂作用下脱去二苯甲基，进一步获得TM1f～TM1j。本发明构建了一类结构简单的C-7位卤代酰基头孢化合物，产物的化学结构经1HNMR确认。
2)本发明提供的C-7位卤代酰基头孢化合物，进行了体外抗人致病菌活性测定，发现所有目标化合物(即卤代酰基产物)的活性都强于或相当于母核分子、强于或相当于或弱于头孢上市药物；TM1f对所测试菌株的抑制活性整体最好；所有目标化合物对藤黄微球菌株的抑制活性整体最强。其中，对金黄色葡萄球菌ATCC25129、ATCC14125，TM1f的抑菌活性强于所测试3种头孢药物；对大肠杆菌，25个头孢卤代酰基产物中有11个化合物的活性强于或相当于上市药物头孢噻吩，TM1f及TM1g与上市药物头孢西丁钠、头孢唑肟钠抑制活性相当，是头孢噻吩的8倍；对藤黄微球菌，所合成的25个卤代酰基产物均显示优秀的抑制活性，其中有16个化合物与头孢噻吩、头孢西丁钠、头孢唑肟钠活性相当，整体活性很好；对沙门氏菌，TM1k/TM1n的抑制活性为上市药物头孢噻吩的2倍或相当；对铜绿假单胞菌，TM1f抑制活性为头孢西丁钠的4倍、头孢噻吩的8倍、头孢唑肟钠的16倍；对枯草芽孢杆菌，TM1a、TM1k的抑制活性分别为头孢噻吩的4倍和8倍。证明C-7位卤代酰基头孢化合物在抗细菌领域具有很好的应用前景。
3)本发明提供的C-7位卤代酰基头孢化合物，体外抗柑橘病菌活性测定结果表明，4μg/mL浓度的TM1s对褐斑病菌Al.6的抑制率高达90％,与阳性对照咪鲜胺相当，强于同类药物头孢噻吩，值得进一步开发；在浓度为2μg/mL、1μg/mL下，7-MCA卤代酰基产物TM1f～TM1j抑菌活性最好(抑制率分别为66％～71％，54～70％)，强于同等浓度下的7-MAC卤代酰基产物TM1a～TM1e(17～70％，-7～45％)，也远强于头孢噻吩(12％,7％)。本研究首次发现，某些头孢母核的卤代酰基衍生物具有抑制柑橘溃疡病菌活性、对柑橘病原真菌具有强烈抑制活性，证明了C-7位卤代酰基头孢化合物在抗柑橘病菌领域具有非常好的应用前景。
具体实施方式
下面结合实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明合成涉及的主要试剂和仪器有：7-MAC、7-ACA、7-ACCA及7-ANCA(重庆天地药业有限责任公司赠送,AR)；氯乙酰氯、3-氯丙酰氯、4-氯丁酰氯和4-溴丁酰氯(上海达瑞精细化工有限公司,AR)；碳酸氢钠、吡啶(重庆市钛新化工有限公司,AR)；其余试剂均为市售化学纯或分析纯产品,未经纯化直接使用。磁力搅拌低温恒温水槽(PSL-1810，上海爱朗仪器有限公司)；熔点测定仪(X-6,北京福凯仪器有限公司)；自动旋光仪(WZZ-2S,上海精密科学仪器有限公司)；核磁共振仪(AV-600,Bruker,USA；TMS为内标)。
实施例1TM1a合成条件探索
首先进行碱种类的选择。取7-MAC 2mmol于50mL圆底烧瓶,加8mL二氯甲烷(DCM)溶解，均分为8份，置于8个25mL圆底烧瓶。冰浴搅拌,向每个圆底烧瓶加不同碱,10min后滴加2-氯乙酰氯，TLC跟踪监测，实验结果见表1.
表1碱的种类对TM1a合成的影响
其中，Et3N为三乙胺，Py为吡啶，DMAP为4-二甲氨基吡啶，DBU为1,8-二氮双环[5.4.0]十一碳-7-烯
TLC检测发现,使用有机碱吡啶时反应最好。随后进行吡啶用量的探索。
表2吡啶用量对TM1a合成的影响
如上法炮制，TLC检测发现，7-MAC/Py＝1:1.5摩尔比时反应最好。
表3酰氯用量对TM1a合成的影响
TLC监测平行实验发现，7-MAC与2-氯乙酰氯的摩尔比为1:1.5或1:2，都能在2h反应完全，最终选取1:1.5作为合成的投料比。
表4温度对TM1a合成的影响
选用前面探索出的反应条件，采用平行实验，于低温反应器(-25℃)、冰浴(4℃)中搅拌反应，TLC检测发现，氯乙酰化都能在2h完成反应。1HNMR表征显示，4℃进行的反应其部分产物双键移位，成为2-位双键(Δ2)及3-位双键(Δ3)异构体的混合物且分离困难，而-25℃条件下的反应产物双键未移位。因此，反应温度应控制为-25℃。
至此，TM1a合成的优化的反应条件为：7-MAC与氯乙酰氯及吡啶的投料比为1:1.5:1.5，在-25℃的DCM溶液中快速搅拌反应。采用此优化条件，实现了目标分子TM1a～TM1e的有效合成(见表5)，收率高于85％。
实施例2TM1a～TM1e合成
100mL圆底烧瓶中加入7-MAC 5mmol、DCM 4mL，搅拌，溶解完全后，置于低温反应器中，控温(-25℃)搅拌，溶解均匀后加入吡啶(Py)7.5mmol,搅拌20min,滴加酰氯7.5mmol的DCM 1mL溶液，滴加速度约为1d/4s。滴毕，-25℃下持续搅拌反应，薄层层析(TLC)监测反应进程。反应结束，加入冰冷的饱和食盐水20mL和DCM 20mL,快速搅拌，0.5NHCl溶液调节pH＝2-3。移至分液漏斗，分液，DCM萃取(20mL×1)水相,合并有机相，饱和食盐水洗涤(20mL×2),收集有机相，无水Na2SO4干燥，旋蒸，真空干燥，得到目标分子TM1a～TM1e。
表5TM1a～TM1e合成实验结果
所合成分子的表征数据如下：
TM1a:淡黄色固体,m.p.:96-97℃,
(c＝1mg/mL,DMSO-CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 9.68(s,1H),7.54(d,J＝7.5Hz,2H),7.46(d,J＝7.5Hz,2H),7.36(t,J＝7.5Hz,2H),7.33(t,J＝7.5Hz,2H),7.29(dd,J＝13.5,7.3Hz,2H),6.89(s,1H),5.22(s,1H),4.39(d,J＝13.3Hz,1H),4.22(d,J＝3.8Hz,2H),4.18(d,J＝13.4Hz,1H),3.88(s,3H),3.76(d,J＝17.9Hz,1H),3.57(d,J＝17.8Hz,1H),3.44(s,3H).
TM1b:淡黄色固体,m.p.:96-97℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 9.42(s,1H),7.54(d,J＝7.5Hz,2H),7.46(d,J＝7.6Hz,2H),7.36(t,J＝7.5Hz,2H),7.33(t,J＝7.5Hz,2H),7.29(dd,J＝14.1,7.2Hz,2H),6.88(s,1H),5.18(s,1H),4.37(d,J＝13.3Hz,1H),4.16(d,J＝13.3Hz,1H),3.87(s,3H),3.79(t,J＝6.2Hz,2H),3.75(d,J＝18.1Hz,1H),3.55(d,J＝17.9Hz,1H),3.42(s,3H),2.76(tt,J＝12.3,8.0Hz,2H).
TM1c:黄色油状物,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH9.33(s,1H),7.54(d,J＝7.4Hz,2H),7.45(d,J＝7.5Hz,2H),7.36(t,J＝7.6Hz,2H),7.32(t,J＝7.5Hz,2H),7.29(dd,J＝14.2,7.3Hz,2H),6.87(s,1H),5.16(s,1H),4.37(d,J＝13.3Hz,1H),4.16(d,J＝13.3Hz,1H),3.88(s,3H),3.74(d,J＝17.9Hz,1H),3.65(t,J＝6.5Hz,2H),3.55(d,J＝17.9Hz,1H),3.41(s,3H),2.44–2.40(m,2H),1.98–1.93(m,2H).
TM1d:黄色油状物,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH9.41(s,1H),7.54(d,J＝7.5Hz,2H),7.46(d,J＝7.6Hz,2H),7.36(t,J＝7.5Hz,2H),7.33(t,J＝7.5Hz,2H),7.29(dd,J＝14.1,7.2Hz,2H),6.88(s,1H),,5.17(s,1H),4.37(d,J＝13.3Hz,1H),4.16(d,J＝13.3Hz,1H),3.87(s,3H),3.75(d,J＝18.0Hz,1H),3.64(t,J＝6.3Hz,2H),3.55(d,J＝17.9Hz,1H),3.43(d,J＝5.0Hz,3H),2.90(m,J＝16.4,7.8Hz,2H).
TM1e:黄色油状物,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH9.35(s,1H),7.55(d,J＝7.4Hz,2H),7.47(d,J＝7.6Hz,2H),7.37(t,J＝7.5Hz,2H),7.33(t,J＝7.5Hz,2H),7.31–7.27(m,2H),6.89(s,1H),5.17(s,1H),4.39(d,J＝13.3Hz,1H),4.17(d,J＝13.4Hz,1H),3.87(d,J＝14.8Hz,4H),3.76(d,J＝17.9Hz,1H),3.56(dd,J＝12.3,5.3Hz,2H),3.46(s,3H),2.45–2.40(m,2H),2.05(td,J＝13.5,6.9Hz,2H).
实施例3TM1f～TM1j合成的操作示例
100mL圆底烧瓶中加入TM1a～TM1e 2.0mmol、DCM 1.0mL，搅拌溶解，加入苯甲醚2.0mmol，冰盐浴，搅拌，滴加三氟醋酸(TFA)1.0mL。滴毕，移至室温搅拌，TLC监测反应进程。反应结束，慢加乙醚5mL、石油醚20mL，搅拌，冷冻，析出固体后，抽滤，石油醚洗涤，得固体粉末,真空干燥，得到目标分子TM1f～TM1j.
表6TM1f～TM1j的合成实验结果
TM1f～TM1j表征数据如下：
TM1f:淡黄色固体,m.p.:131-132℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 9.61(s,1H),5.14(s,1H),4.36(d,J＝13.4Hz,1H),4.23(d,J＝8.8Hz,1H),4.19(t,J＝10.7Hz,2H),3.94(s,3H),3.73(d,J＝17.5Hz,1H),3.49(d,J＝17.9Hz,1H),3.40(s,3H).TM1g:淡黄色固体,m.p.:100-101℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 9.36(s,1H),5.10(s,1H),4.35(d,J＝13.4Hz,1H),4.20(d,J＝13.4Hz,1H),3.94(s,3H),3.78(t,J＝6.2Hz,2H),3.73(d,J＝18.2Hz,2H),3.48(d,J＝17.9Hz,1H),3.39(s,3H),2.82–2.70(m,2H).
TM1h:淡黄色固体,m.p.:100-102℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 9.28(s,1H),5.09(s,1H),4.36(d,J＝13.4Hz,1H),4.19(d,J＝13.4Hz,1H),3.94(s,3H),3.72(d,J＝17.8Hz,1H),3.65(t,J＝6.0Hz,2H),3.48(d,J＝17.9Hz,1H),3.37(s,3H),2.39(dd,J＝16.0,8.8Hz,2H),1.95(dt,J＝13.6,6.7Hz,2H).
TM1i:淡黄色固体,m.p.:110-114℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 9.36(s,1H),5.10(s,1H),4.35(d,J＝13.5Hz,1H),4.20(d,J＝13.4Hz,1H),3.94(s,3H),3.75–3.69(m,2H),3.63(t,J＝6.2Hz,2H),3.48(d,J＝17.9Hz,2H),3.39(s,3H),2.95–2.84(m,2H).
TM1j:淡黄色固体,m.p.:106-109℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 9.29(s,1H),5.09(s,1H),4.36(d,J＝13.4Hz,1H),4.19(d,J＝13.4Hz,1H),3.94(s,3H),3.73(dd,J＝14.5,7.5Hz,1H),3.54(t,J＝6.1Hz,2H),3.48(d,J＝17.9Hz,1H),3.37(s,3H),2.41(dd,J＝16.6,7.4Hz,2H),2.04(td,J＝13.6,6.9Hz,2H).
实施例4TM1k～TM1y合成的操作示例
于100mL反应瓶中依次加入7-AXCA(5mmol)、丙酮5mL和水1mL，室温搅拌，加入碳酸氢钠(1.26g,1.5mmol)，冰盐浴，滴加酰氯(1.0mmol)，搅拌。TLC监测反应进程。反应完全后，加入冰冷2NHCl调节pH＝7，旋除溶剂丙酮，冷冻析出固体，加入冰冷2NHCl调节pH＝3,大量固体析出。抽滤，干燥，得固体TM1k～TM1y。实验结果见表7。
表7TM1k～TM1y合成实验结果
TM1k～TM1y表征数据如下：
TM1k:白色固体,m.p.:182-185℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 8.93(d,J＝8.0Hz,1H),5.68(dd,J＝8.0,5.0Hz,1H),5.10(d,J＝5.0Hz,1H),5.00(d,J＝12.8Hz,1H),4.69(d,J＝12.8Hz,2H),4.17(s,2H),3.55–3.47(m,2H),2.03(s,3H).TM1l:白色固体,m.p.:164-165℃,
(c＝1mg/mL,CH2Cl2).1HNMR(600MHz,DMSO-d6)δH 13.53(s,1H),9.01(d,J＝8.2Hz,1H),5.77–5.71(m,1H),5.11(d,J＝4.4Hz,1H),5.01(d,J＝12.8Hz,1H),4.69(d,J＝12.8Hz,1H),3.79(t,J＝6.0Hz,2H),3.63(d,J＝18.1Hz,1H),3.49(d,J＝18.1Hz,1H),2.70(s,2H),2.03(s,3H).
TM1m:白色固体,m.p.:189-192℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 8.93(d,J＝8.0Hz,1H),5.69–5.66(m,1H),5.09(d,J＝4.7Hz,1H),5.00(d,J＝12.6Hz,1H),4.69(d,J＝12.6Hz,1H),3.64(s,2H),3.62(d,J＝8.6Hz,1H),3.49(d,J＝18.2Hz,1H),2.35(t,J＝7.3Hz,2H),2.03(s,3H),1.95(dd,J＝8.3,5.2Hz,2H).
TM1n:白色固体,m.p.:153-156℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 13.56(s,1H),9.00(d,J＝8.3Hz,1H),5.73(dd,J＝8.2,4.8Hz,1H),5.11(d,J＝4.8Hz,1H),5.01(d,J＝12.8Hz,1H),4.69(d,J＝12.8Hz,1H),3.65(dd,J＝8.4,3.6Hz,2H),3.62(d,J＝10.3Hz,1H),3.49(d,J＝18.1Hz,1H),2.84(dd,J＝12.8,6.4Hz,2H),2.03(s,3H).TM1o:白色固体,m.p.:176-178℃,
(c＝1mg/mL,CH2Cl2).1HNMR(600MHz,DMSO-d6)δH 8.93(d,J＝8.0Hz,1H),5.68(dd,J＝8.0,4.8Hz,1H),5.10(d,J＝4.8Hz,1H),5.00(d,J＝12.8Hz,1H),4.69(d,J＝12.8Hz,1H),3.66–3.61(m,2H),3.55–3.47(m,2H),2.36(t,J＝7.0Hz,2H),2.25–2.13(m,1H),2.04(d,J＝7.3Hz,3H),1.98–1.91(m,1H).
TM1p:淡黄色固体,m.p.:235-238℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 13.95(s,1H),9.10(s,1H),5.75(dd,J＝8.1,4.8Hz,1H),5.19(d,J＝4.8Hz,1H),4.17(s,2H),3.97(d,J＝18.0Hz,1H),3.63(d,J＝18.0Hz,1H).
TM1q:淡黄色固体,m.p.:236-237℃,
(c＝1mg/mL,CH2Cl2).1HNMR(600MHz,DMSO-d6)δH 8.95(d,J＝8.3Hz,1H),5.72(dd,J＝8.3,4.9Hz,1H),5.19(d,J＝4.9Hz,1H),3.97(d,J＝18.0Hz,1H),3.82(ddd,J＝57.5,16.8,6.0Hz,2H),3.68(d,J＝18.0Hz,1H),2.72(t,J＝6.0Hz,2H).
TM1r:淡黄色固体,m.p.:237-241℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 8.90(d,J＝8.0Hz,1H),5.68(dd,J＝8.0,4.9Hz,1H),5.18(d,J＝4.9Hz,1H),3.99–3.95(m,1H),3.69–3.64(m,1H),3.09–3.05(m,2H),2.63(t,J＝7.2Hz,7H),1.67–1.61(m,2H).
TM1s:淡黄色固体,m.p.:144-148℃,
(c＝1mg/mL,CH2Cl2).1HNMR(600MHz,DMSO-d6)δH 9.15(d,J＝8.2Hz,1H),6.35(dd,J＝17.1,8.2Hz,1H),5.79(dd,J＝8.2,4.9Hz,1H),5.23(d,J＝4.8Hz,1H),5.20(d,J＝4.8Hz,1H),4.00(d,J＝9.3Hz,1H),3.72–3.70(m,1H),2.84(dt,J＝13.0,6.6Hz,2H).
TM1t:淡黄色固体,m.p.:172-176℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 13.45(s,1H),8.82(d,J＝8.2Hz,1H),5.68(dd,J＝8.2,4.8Hz,1H),5.09(d,J＝4.8Hz,1H),3.62(d,J＝18.1Hz,1H),3.46(d,J＝18.1Hz,1H),3.08(dd,J＝13.2,7.0Hz,2H),2.63(t,J＝7.0Hz,3H),1.65(dt,J＝13.7,7.0Hz,2H).
TM1u:白色固体,m.p.:170-173℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 13.17(s,1H),9.24(d,J＝8.2Hz,1H),6.50(dd,J＝6.3,2.3Hz,1H),5.74(dd,J＝8.2,5.0Hz,1H),5.08(d,J＝5.0Hz,1H),4.17(s,2H),3.65(dd,J＝19.0,2.3Hz,1H),3.56(dd,J＝19.0,6.4Hz,1H).
TM1v:白色固体,m.p.:170-173℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 13.19(s,1H),9.00(d,J＝8.2Hz,1H),6.49(dd,J＝6.2,2.1Hz,1H),5.75(dd,J＝8.2,5.0Hz,1H),5.05(d,J＝5.0Hz,1H),3.79(t,J＝5.5Hz,2H),3.63(dd,J＝19.0,2.1Hz,1H),3.54(dd,J＝19.0,6.2Hz,1H),2.71(td,J＝6.0,3.0Hz,2H).
TM1w:白色固体,m.p.:149-153℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 8.89(d,J＝8.2Hz,1H),6.35(dd,J＝6.1,2.0Hz,1H),5.66(dd,J＝8.2,4.9Hz,1H),5.00(d,J＝4.9Hz,1H),3.65–3.62(m,2H),3.59(dd,J＝18.8,2.2Hz,1H),3.49(dd,J＝18.8,6.3Hz,1H),2.36(dd,J＝10.8,3.9Hz,2H),1.97–1.92(m,2H).
TM1x:白色固体,m.p.:151-152℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 13.04(s,1H),8.98(d,J＝8.2Hz,1H),6.49(dd,J＝6.3,2.3Hz,1H),5.75(dd,J＝8.2,5.0Hz,1H),5.05(d,J＝5.0Hz,1H),3.65(dd,J＝6.0,2.2Hz,2H),3.62(dd,J＝12.6,2.5Hz,1H),3.54(dd,J＝19.0,6.3Hz,1H),2.89–2.78(m,2H).
TM1y:白色固体,m.p.:152-154℃,
(c＝1mg/mL,CH2Cl2).1H NMR(600MHz,DMSO-d6)δH 12.84(s,1H),8.81(d,J＝8.2Hz,1H),6.48(dd,J＝6.2,2.2Hz,1H),5.71(dd,J＝8.2,4.9Hz,1H),5.04(d,J＝4.9Hz,1H),3.62(dd,J＝18.9,2.1Hz,1H),3.52(dd,J＝19.0,6.4Hz,1H),3.07(m,2H),2.63(m,2H),1.68–1.61(m,2H).
实施例5抗人致病菌活性测试
5.1试验菌株
革兰阳性菌：金黄色葡萄球菌(Staphyloccocus aureus ATCC 25129)、金黄色葡萄球菌(Staphyloccocus aureusATCC 14125)、藤黄微球菌(Micrococcus luteus)、枯草芽孢杆菌(Bacillus subtilis)。革兰阴性菌：大肠杆菌(Escherichia coliATCC 25922)、鲍曼不动杆菌(Acinetobacter baumannii ATCC 19606)、沙门氏菌(SalmonellaEnteritidis ATCC 13076)、铜绿假单胞菌(Pseudomonas aeruginosaATCC 27853)。
5.2培养基与试剂
普通液体培养基：牛肉膏0.3％、蛋白胨1％、氯化钠0.5％、去离子水。调节pH至7.0～7.2，分装于500mL锥形瓶，121℃下30分钟高压蒸汽灭菌备用；
试剂：蒸馏水、0.9％生理盐水，配好后在121℃下30分钟高压蒸汽灭菌备用。二甲基亚砜(DMSO,AR)、吐温-80(重庆市钛新化工有限公司,AR)。
5.3仪器
电子天平(FA1104型,上海舜宇恒平科学仪器有限公司)，超净工作台(SW-CJ-1FD型单人单面净化工作台,苏州净化设备有限公司)，恒温振荡器(ZD-85型,常州澳华仪器有限公司)，数显恒温水浴锅(北京市长风仪器有限公司)，自动蒸汽灭菌锅(日本东京APL公司产品)，移液枪(Finnpipette)，超声仪器(KQ3200,昆山市超声仪器有限公司)。
5.4最小抑菌浓度(MIC)测定
(1)样品溶液的制备：于每只2mLPE管中加入在干燥室内精确称取的TM1a～TM1y样品3.2mg，用移液枪加入DMSO 1mL，配制成3.2mg/mL的澄清透明溶液，封口膜封口，冰柜避光保存。部分难溶的化合物使用DMSO/吐温-80＝200/1(v/v)溶解。
(2)待测液的配制：吸取320μL样品溶液，用培养基稀释至1mL，得到浓度为1024μg/mL的待测液。
(3)菌悬液的制备：接种保存的菌株于普通液体培养基中，置于37℃恒温摇床活化培养24小时，然后用培养基稀释成105CFU/mL的菌悬液备用。
(4)加样操作：无菌条件下操作。在96孔板每个孔加入培养基50μL；在第一排的第一孔、第二孔加入待测液50μL，经过此二倍稀释后，浓度变为512μg/mL，接着用移液枪充分吹打至少4次以上，使待测物与培养基充分混匀，然后吸取50μL加入第二排对应孔，再充分吹打使之与培养基充分混匀；照此重复直至第八排，第八排每孔吸取50μL弃去；此时每列待测物浓度从高至低依次为512,256,128,64,32,16,8,4μg/mL；随后每孔中加入稀释好的菌液50μL，此时每孔待测物浓度即为最终待测物浓度，从高至低依次为256,128,64,32,16,8,4,2μg/mL。96孔板的其他列也如此操作。每一块板的最后两列作为对照，都不含待测物，一列作为细菌生长对照加入菌液，另一列作为阴性对照不加菌液。每块板测试5个化合物。
(5)培养与结果判定：将接种好的96孔板放入37℃恒温培养箱培养16-20h。培养完成后，将96孔板从恒温箱中取出，观察和记录孔内细菌生长情况。在判定结果之前，要确定空白无药对照孔的细菌正常生长、阴性对照孔无细菌生长时结果才有意义。将肉眼观察没有细菌生长的孔中的待测物浓度作为该待测物对该细菌的MIC。如果出现跳孔现象或两孔结果不一，则需重复试验进行验证。
测试结果见表8。
表8目标化合物TM1对人致病菌抑制活性测试结果(MIC值,μg/mL)
所有目标化合物(即卤代酰基产物)的活性都强于或相当于母核分子、强于或相当于或弱于头孢上市药物；TM1f对所测试菌株的抑制活性整体最好；所有目标化合物对藤黄微球菌株的抑制活性整体最强。
对大肠杆菌，卤代酰基产物的整体活性是TM1f～TM1j>TM1k～TM1o>TM1a～TM1e>TM1u～TM1y>TM1p～TM1t；从头孢母核考虑，活性强度为7-MCA>7-ACA>7-MAC>7-ANCA>7-ACCA。7-MAC卤代酰基产物TM1a～TM1e的活性弱于脱除二苯甲基后的产物TM1f～TM1fj(7-MCA型),说明C-4位羧基型分子的抗菌活性明显强于对应酯型分子。25个头孢卤代酰基产物中有11个化合物MIC＝2～16μg/mL，活性强于或相当于上市药物头孢噻吩(16μg/mL,MIC值,后同)；TM1f及TM1g与上市药物头孢西丁钠、头孢唑肟钠抑制活性(2μg/mL)相当，是头孢噻吩的8倍。
对沙门氏菌，上市药物头孢西丁钠及头孢唑肟钠、4个头孢母核以及绝大多数卤代酰基产物均未显示出明显抑制活性(≥256μg/mL)，但是7-ACA卤代酰基产物TM1k/TM1n的抑制活性(32/64μg/mL)为上市药物头孢噻吩(64μg/mL)的2倍或相当。
对鲍曼不动杆菌，头孢母核、头孢西丁钠及所合成卤代酰基产物未显示出明显抑制活性(≥256μg/mL)，然而TM1k与头孢噻吩、头孢唑肟钠相当(128μg/mL)。
对铜绿假单胞菌，虽然头孢母核7-ANCA、7-ACCA、7-MAC的酰基衍生物活性很差(MIC≥256μg/mL)，但7-MCA和7-ACA的卤代酰基产物显示明显的抑制活性(4～128μg/mL)，7-MCA卤代酰基产物TM1f～TM1j抑制活性为7-MAC卤代酰基产物TM1a～TM1e的4-8倍；特别地，TM1f抑制活性(4μg/mL)为头孢西丁钠(16μg/mL)的4倍、头孢噻吩(32μg/mL)的8倍、头孢唑肟钠(64μg/mL)的16倍，值得进一步研究。
对藤黄微球菌，所合成的25个卤代酰基产物均显示优秀的抑制活性，其中有16个化合物MIC值为2μg/mL,与头孢噻吩、头孢西丁钠、头孢唑肟钠(2μg/mL)相当，尤其是7-MCA衍生的TM1f～TM1j、7-ACA衍生的TM1k～TM1o，MIC值都为2μg/mL，整体活性很好。
对金黄色葡萄球菌ATCC25129、ATCC14125，7-MCA卤代酰基产物普遍具有抑菌活性(8～128μg/mL)，其中TM1f的抑菌活性强于所测试3种头孢药物；7-MAC及7-ACA卤代酰基产物中的TM1a及TM1k也具有较好抑菌活性(16～64μg/mL)。
对枯草芽孢杆菌，7-MCA卤代酰基产物TM1f～TM1j都有较好抑菌活性(8～32μg/mL)，7-MAC、7-ACA卤代酰基产物中连有氯乙酰基者(TM1a,TM1k)的抑制活性(16,8μg/mL)分别为头孢噻吩(64μg/mL)的4倍和8倍，且TM1a与头孢西丁钠(16μg/mL)抑制活性相当、TM1k抑制活性为头孢西丁钠的2倍。
实施例6抗毕赤酵母菌活性测试
采用NCCLS推荐的微量肉汤稀释法测定TM1a～TM1y抑制毕赤酵母菌的MIC值。
6.1试验菌株及材料
(1)试验菌株：毕赤酵母菌
(2)待测化合物：TM1a～TM1y，以及阳性对照药物氟康唑。
(3)培养基：选用沙氏培养基，由蛋白胨1％、葡萄糖4％、去离子水95％构成。按比例配制后，加热溶解为均相，分装于500mL锥形瓶，在121℃下高压蒸汽灭菌20分钟后备用。试剂：0.9％生理盐水、DMSO、吐温-80，均为市面常见分析纯药品。
(4)仪器：同5.3。
6.2最小抑菌浓度MIC的测定方法
(1)样品溶液的制备、待测液的配制，同5.4。
(2)菌悬液的制备：接种保存的菌株于沙氏琼脂液体培养基中，置于30℃恒温摇床活化培养24小时；用蒸馏水洗涤琼脂表面菌落，用沙氏培养基稀释成105CFU/mL的菌悬液备用。
(3)加样操作：同5.4的加样操作。
(4)培养：将接种好的96孔板放入30℃恒温培养箱培养48h，然后观察和记录24h及48h的结果。
(5)结果判定：同5.4的结果判定。测试结果见表9。
表9目标化合物TM1对毕赤酵母菌抑制活性测试结果(MIC值,μg/mL)
表9表明，4种头孢母核没有抑制活性，头孢噻吩也很差，但是TM1a(MIC＝32μg/mL)、TM1f(MIC＝64μg/mL)显示明显的抑制活性，分别为头孢噻吩的8倍及4倍。
实施例7抗柑橘病原真菌活性测试
7.1材料与试验菌株
(1)待测化合物TM1a～TM1y(1mg/mL)、阳性对照咪鲜胺(1mg/mL)、24孔板、PDA培养基、10mL离心管、5mL微量移液器、吸头。
(2)菌株：柑橘胶孢炭疽菌Co.3菌株(Colletotrichum gloeosporioides,Co.3)和柑橘褐斑病菌Al.6菌株(Alternaria alternate,Al.6)。
7.2测定方法
(1)待测化合物母液的配制：准确称取所需的各种待测化合物1.0mg，用适宜的溶剂1mL溶解，得到1.0mg/mL的化合物母液。
(2)化合物培养基配制：含2μg/mL化合物培养基配制：取10μL化合物母液与4990μL热PDA培养基在10mL离心管中充分混匀；含4μg/mL化合物培养基配制：取20μL化合物母液与4980μL热PDA培养基在10mL离心管中充分混匀。对照组：以不加化合物的PDA培养基和加入咪鲜胺的PDA培养基(2μg/mL和4μg/mL)作为阴性、阳性对照。
(3)接菌和培养：将配置好的化合物培养基倒入24孔板内，每株菌每种化合物每个浓度倒4个孔，并做好编号的标记。挑取28℃培养7d的菌株的菌丝，接种于每孔正中央。将24孔板放于28℃、光照16h的培养箱内培养48h。
(4)测量与计算：运用十字交叉法测量菌落直径，并按下述公式计算抑制率
抑制率％＝(CK菌落直径值-测量菌落直径值)×100％/CK菌落直径值。
相关结果见表10。
表10目标化合物TM1对柑橘病原真菌抑制活性测试结果
表11TM1s对柑橘褐斑病菌Al.6复筛结果
在浓度为2μg/mL、4μg/mL时，绝大多数所合成头孢卤代酰基产物对柑橘胶孢炭疽菌Co.3及柑橘褐斑病菌Al.6无抑制活性，但4μg/mL浓度的TM1s对褐斑病菌Al.6的抑制率高达90％,与阳性对照咪鲜胺相当，强于同类药物头孢噻吩，值得进一步开发。头孢卤代酰基产物对柑橘病原真菌具有强烈抑制活性，目前未见文献报道。
实施例8抗柑橘溃疡病菌测试
8.1材料与试验菌株
(1)培养基的配制：实验选用LB液体培养基。
菌悬液的制备：将柑橘溃疡病菌RL菌株(Xanthomonas campestrispv.Citri,RLstrain)在PDA培养基上活化，28℃培养3d以后，在超净工作台上用蓝枪头管口轻轻刮取少量菌落于无菌水中，于摇床上28℃，200r震荡培养2h制成菌悬液。
化合物TM1a～TM1y和阳性对照噻霉酮母液的配制：准确称取化合物，溶于无菌水或有机溶剂中配置成1mg/mL的母液备用。
(2)方法
实验在96孔板上进行，每个化合物设置4个浓度梯度，每个浓度5次重复，不同浓度对应设置不加菌悬液的对照CK1(以此排除化合物自身颜色影响)，并同时设置不加化合物只加菌的对照(CK)。每种化合物设置4个稀释浓度，分别为2μg/mL(即稀释500倍)、1μg/mL(即稀释1000倍)、0.5μg/mL(即稀释2000倍)、0.2μg/mL(即稀释5000倍)。即：取10μL化合物母液于990μL无菌水中作为样品溶液(10μg/mL，即稀释100倍)，然后采用倍比稀释法依次稀释样品溶液，实验组4个浓度梯度依次添加样品溶液40μL、20μL、10μL、4μL，然后用排枪每孔中加140μL LB液体培养基，每孔补足无菌水使每孔总溶液体积达到180μL。最后用排枪每孔加入20μL配置好的菌悬液，制成总体积200μL的混合菌液，使得各样品最终浓度分别为A(2μg/mL)、B(1μg/mL)、C(0.5μg/mL)、D(0.2μg/mL)。CK1中菌悬液体积用20μL LB培养基代替，CK中则利用灭菌水补足化合物体积。充分混匀后于28℃恒温培养箱中培养48h。
使用分光光度计测定OD600时的吸光值，并计算抑菌率。
抑菌率％＝CKOD600–(化合物OD600–该化合物CK1 OD600)/CKOD600X100
相关结果见表12。
表12目标化合物TM1a～TM1y对柑橘溃疡病菌抑制活性测试结果
表12结果显示，所合成的化合物抑制柑橘溃疡病菌活性随化合物浓度降低而减弱，具有较好的活性-剂量关系；在浓度为2μg/mL、1μg/mL下，7-MCA卤代酰基产物TM1f～TM1j抑菌活性最好(抑制率分别为66％～71％，54～70％)，强于同等浓度下的7-MAC卤代酰基产物TM1a～TM1e(17～70％，-7～45％)，也远强于头孢噻吩(12％,7％)；头孢母核对应卤代酰基产物的活性强弱顺序为7-MCA>7-MAC>7-ACA≈7-ACCA>7-ANCA。本研究首次报道，某些头孢母核的酰基衍生物具有抑制柑橘溃疡病菌活性。
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明的权利要求范围当中。
Claims (1)
1.C-7位卤代酰基头孢化合物或其药学可接受盐在制备防治人致病菌和/或柑橘溃疡病菌药物中的应用，所述人致病菌为金黄色葡萄球菌、枯草芽孢杆菌或铜绿假单胞菌，所述C-7位卤代酰基头孢化合物具有以下结构式之一：
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