含亚胺与含硫醚的3-取代喹唑啉酮类衍生物的合成及生物活性研究
摘要
喹唑啉酮类化合物及其衍生物因其结构的多变性和其高效广谱的生物活性,在医药和农药领域有着广泛的应用。为了创制高活性的抗菌、抗病毒药物,本文采用活性基团拼接法,设计合成了三类共34个喹唑啉酮类化合物,其中6-氯-2-甲基-3-(芳亚甲氨基)-4(3H)-喹唑啉酮类化合物16个(编号:Ⅰ_(1～16));6,8-二氯-2-甲基-3-(芳亚甲氨基)-4(3H)-喹唑啉酮类化合物8个(编号:Ⅱ_(1～8));3-(2-氯乙基)-4(3H)喹唑啉酮硫醚类化合物10个(编号:Ⅲ_(1～10))。所有目标化合物结构经IR、~1H NMR、~(13)C NMR和元素分析确证。
对目标化合物及其中间体的合成条件进行优化。第一类化合物的合成:以邻氨基苯甲酸为原料,通过酰化、氯化、环化、胺化得到6-氯-2-甲基-3-(芳亚甲氨基)-4(3H)-喹唑啉酮的化合物(化合物编号:Ⅰ),同时对重要中间体邻乙酰氨基苯甲酸的合成条件进行优化,提高了反应收率,缩短了反应时间。第二类化合物的合成:经过氯化、环化、胺化得到6,8-二氯-2-甲基-3-(芳亚甲氨基)-4(3H)-喹唑啉酮的化合物(化合物编号:Ⅱ)。在第三类化合物的合成中,经过环化、取代采用以DMF为溶剂在体系温度为120℃条件下得到目标化合物(化合物编号:Ⅲ)。
采用半叶枯斑法,对目标化合物进行了抗TMV病毒活性筛选。目标化合物在500 mg·L~(-1)浓度下,部分化合物对TMV具有一定的活体治疗活性,其中化合物I_2,I_(13)的抑制率分别为44.6%、45.3%,与对照药剂宁南霉素(54.8%)抑制活性相当。
4(3H)-Quinazolinones and their derivatives are important class of heterocyclic compounds. They occupy important position in medicinal and pesticide chemistry with wide range of bioactivities.In order to create novel and highly active antifungal and antiviral agents,three new series of quinazolinone derivatives were designed and synthesized which included nineteen new 6-chloro-2-methyl-3-(arylideneamino)-4(3H)-quinazolinone derivatives(Ⅰ_(1～16)),eight 6,8-dichloro-2-methyl-3-(arylideneamino)-4(3H)-quinazolinone derivatives(Ⅱ_(1～8)) and ten 3-(2-(1,3,4-oxadiazol-2-ylthio) ethyl)quinazolin-4(3H)-one derivatives(Ⅲ_(1～10)).The structures of the new compounds were verified by IR,~1H NMR,~(13)C NMR and elemental analyses.
The synthetic conditions for the intermediates and target compounds were optimized. 6-chloro-2-methyl-3-(arylideneamino)-4(3H)-quinazolinone derivatives(Compounds Number:Ⅰ) were synthesized from the starting material anthranilic acid in multistep reaction involving acylation,chlorination,cyclization,and ammoniation.At the same time,the synthetic conditions for the intermediates acetanthranilic acid were optimized.The suitable condition improved the yield and shortened the reaction time.The second series of compounds(Compounds Number:Ⅱ) were also synthesized from the starting material anthranilic acid in various steps involving chlorination,cyclization,and ammoniation.Finally,the last series of compounds(Compounds Number:Ⅲ) could be obtained from anthranilic acid through cyclization and nucleophilic substitution in DMF at 120℃.
Half-leaf method was used to determine curative effects of the 24 title compounds in vivo. At 500 mg/L,the title compoundsⅠ_2 andⅠ_(13) revealed effects against TMV at 44.6%and 45.3% respectively.The results showed that they had moderate antiviral activities in vivo,equivalent to Ningnanmycin(54.8%) against TMV at 500 mg/L.
对目标化合物及其中间体的合成条件进行优化。第一类化合物的合成:以邻氨基苯甲酸为原料,通过酰化、氯化、环化、胺化得到6-氯-2-甲基-3-(芳亚甲氨基)-4(3H)-喹唑啉酮的化合物(化合物编号:Ⅰ),同时对重要中间体邻乙酰氨基苯甲酸的合成条件进行优化,提高了反应收率,缩短了反应时间。第二类化合物的合成:经过氯化、环化、胺化得到6,8-二氯-2-甲基-3-(芳亚甲氨基)-4(3H)-喹唑啉酮的化合物(化合物编号:Ⅱ)。在第三类化合物的合成中,经过环化、取代采用以DMF为溶剂在体系温度为120℃条件下得到目标化合物(化合物编号:Ⅲ)。
采用半叶枯斑法,对目标化合物进行了抗TMV病毒活性筛选。目标化合物在500 mg·L~(-1)浓度下,部分化合物对TMV具有一定的活体治疗活性,其中化合物I_2,I_(13)的抑制率分别为44.6%、45.3%,与对照药剂宁南霉素(54.8%)抑制活性相当。
4(3H)-Quinazolinones and their derivatives are important class of heterocyclic compounds. They occupy important position in medicinal and pesticide chemistry with wide range of bioactivities.In order to create novel and highly active antifungal and antiviral agents,three new series of quinazolinone derivatives were designed and synthesized which included nineteen new 6-chloro-2-methyl-3-(arylideneamino)-4(3H)-quinazolinone derivatives(Ⅰ_(1～16)),eight 6,8-dichloro-2-methyl-3-(arylideneamino)-4(3H)-quinazolinone derivatives(Ⅱ_(1～8)) and ten 3-(2-(1,3,4-oxadiazol-2-ylthio) ethyl)quinazolin-4(3H)-one derivatives(Ⅲ_(1～10)).The structures of the new compounds were verified by IR,~1H NMR,~(13)C NMR and elemental analyses.
The synthetic conditions for the intermediates and target compounds were optimized. 6-chloro-2-methyl-3-(arylideneamino)-4(3H)-quinazolinone derivatives(Compounds Number:Ⅰ) were synthesized from the starting material anthranilic acid in multistep reaction involving acylation,chlorination,cyclization,and ammoniation.At the same time,the synthetic conditions for the intermediates acetanthranilic acid were optimized.The suitable condition improved the yield and shortened the reaction time.The second series of compounds(Compounds Number:Ⅱ) were also synthesized from the starting material anthranilic acid in various steps involving chlorination,cyclization,and ammoniation.Finally,the last series of compounds(Compounds Number:Ⅲ) could be obtained from anthranilic acid through cyclization and nucleophilic substitution in DMF at 120℃.
Half-leaf method was used to determine curative effects of the 24 title compounds in vivo. At 500 mg/L,the title compoundsⅠ_2 andⅠ_(13) revealed effects against TMV at 44.6%and 45.3% respectively.The results showed that they had moderate antiviral activities in vivo,equivalent to Ningnanmycin(54.8%) against TMV at 500 mg/L.
引文
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[2]史隋孝,张满让,张新民.烟草花叶病防治药剂筛选试验[J].西北农业学报,1998,8(4):13-16.
[3]刘刚.新型喹唑啉类衍生物的合成及生物活性研究.博士研究生学位论文.贵州大学,贵阳,2006,06.
[4]刘昕,黄润秋,李慧英,杨昭.O-(4-喹唑啉)羟肟酸硫代酯(酰胺)类化合物的合成及生物活性[J].应用化学,1999,16(2):23-26.
[5]余红霞,郭峰,徐雄立.乙苯甲喹唑啉酮盐酸合成方法的改进[J].武汉化工学院学报,2002,24(4):13-14.
[6]黄君珉,陈茹玉.α-硫羰基膦酸衍生化喹唑啉酮含磷类似物的研究[J].高等学校化学学报,2000,21(10):1510-1514.
[7]段行信.实用精细有机合成手册[M].化学工业出版社,北京,2000,230-231.
[8]高兴文 蔡学建 严凯 高丽丽 王和英 陈卓 宋宝安.4(3H)-喹唑啉酮类Schiff碱合成与的合成与抗烟草花叶病毒活性[J].有机化学,2008,28(10):1785-1791.
[9]樊能廷.有机合成单元过程实验.北京理工大学教材科,1988.53.
[10]Abdel-Jalil,R.J.;Volter,W.;Saeed,M.A novel method for the synthesis of 4(3H)-quinazolinones[J].Tetrahedron Lett.,2004,45:3475-3476.
[11]Alagarsamy,V.;Muthukumar,V.;Pavalarni,N.;Vasathanathan P.;Revathi R.Synthesis,Analgesic and Anti-inflammatory Activities of Some Novel 2,3-Disubstituted Quinazolin-4(3H)-ones[J].Biol.Pharm.Bull,2003.26(4),557-559.
[12]Al-Rashood,S.T.;Aboldahab,Ihsan A.;Nagi,M.N.;Abouzeid,L.A.;Abdel-Aziz,A.A.M.;Abdel-hamide,S.G.;Youssef,K.M.;Al-Obaid,A.M.;El-Subbagh,H.I.Synthesis,dihydrofolate reductase inhibition,antitumor testing,and molecular modeling study of some new 4(3H)-quinazolinone analogs[J].Bioorg.Med.Chem.,2006,14(24),8608-8621.
[13]Bogert,M.T.;Gortner,R.A.Researches on Quinazolines.Twenty-second Paper.On 2-Methyl-3-amino-4-quinazolone and Certain of Its Derivatives[J].J.Am.Chem.Soc.,1909,31,943-947.
[14]Bueyuktimkin,S.Quinazolinones,III.Preparation,pharmacology and structure-activity relations of 2-methyl-3-(4-oxo-3-phenylthiazolidin-2-ylidenamino)-4(3H)-quinazolinone derivatives[J].Arch.Pharm.(Weinheim,Germany),1985,318(6),496-501.
[15]Croce,P.D.;Ferracioli,R.Synthesis of 2-substituted quinazolinone[J].Heterocycles,1997,45:1309-1315.
[16]Chandrika,P.M.;Yakaiah,T.;Rao,A.R.R.;Narsaiah,B.;Reddy,N.C.;Sridhar,V.;Rao,J.Synthesis of novel 4,6-disubstituted quinazoline derivatives,their anti-inflammatory and anti-cancer activity(cytotoxic) against U937 leukemia cell lines[J].Eur.J.Med.Chem..2008,43(4):846-852.
[17]Corbett,J.W.;Pan,S.L.;Markwalder,J.A.;Cordova,B.C.;Klabe,R.M.;Garber,S.;Rodgers,J.D.;Erickson-Viitanen,S.K.3,3a-Dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones are Potent Non-Nucleoside Reverse Transcriptase Inhibitors[J].Bioorg.Med.Chem.Lett.,2001,11:211-214.
[18]Dai,X.-D.;Virgil,S.Synthesis of 2-heterosubstituted quinazolinone atropisomeric phosphine ligands by direct lithiation of a 2-unsubstituted quinazolinones system[J].Tetrahe dron:Asymmetry.,1999,10:25-29.
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