四氢异喹啉衍生物的合成及体外抗多子小瓜虫活性的研究
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摘要
合成四氢异喹啉衍生物并进行杀多子小瓜虫(Ichthyophthirius multifiliis)药效评价。以1-甲基-1,2,3,4-四氢异喹啉为起始原料,在2位的胺基上引入与环己甲酰氯、苯甲酰氯、噻吩甲酰氯、乙酰氯以及氯乙酰氯等不同的酰基进而合成5种四氢异喹啉衍生物(化合物1~化合物5),研究其对小瓜虫掠食体和包囊的杀虫活性,并对杀虫活性物质进行安全性评价。结果显示,5种化合物均具有一定的杀虫活性,其中,化合物1 [(1-甲基-3,4-二氢异喹啉-2(1H)-基)-苯基-甲酮]的杀虫活性最强,其对多子小瓜虫掠食体4 h的100%杀灭浓度为24.0 mg/L,对包囊6 h的100%杀灭浓度为60.0 mg/L,对掠食体的半数致死浓度(LD_(50))为16.4mg/L。急性毒性实验结果显示,化合物1对翘嘴红鲌(Erythroculter ilishaeformi)的48 h LD_(50)为234.3 mg/L,其安全浓度为64.1 mg/L。研究表明,化合物1[(1-甲基-3,4-二氢异喹啉-2(1H)-基)-苯基-甲酮]是一种具有较好开发前景的杀小瓜虫药物。
To develop novel antiparasitic agents, five 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized. Cyclohexanecarboxylic acid chloride, benzoyl chloride, thiophene formyl chloride, acetylchloride, and chloroacetyl chloride were introduced into the 2-position of amido in the initial compound-1-methyl-1,2,3,4-tetrahydroisoquinoline. The chemical structures of all five synthesized compounds were identified by comparing spectral data(EI-MS, ~1H NMR, and ~(13) C NMR) with literature values, and their antiparasitic activity against Ichthyophthirius multifiliis theronts and encysted tomonts in vitro were also evaluated. Additionally, the acute toxicity of the five synthesized compounds against Erythroculter ilishaeformis was evaluated. The results indicated that all five synthesized compounds showed promising antiparasitic activity against I. multifiliis theronts and encysted tomonts; however, compound 1 [cyclohexyl-(1-methyl-3,4-dihydroiso-quinoline)-ketone] with the cyclohexanecarboxylic acid chloride group showed better antiparasitic activity than the other four compounds. The in vitro tests revealed that compound 1 could be 100% effective against theronts at a concentration of 24.0 mg/L. The median lethal dose(LD_(50)) of compound 1 against theronts at 4 h was 16.4 mg/L. All encysted tomonts were killed when the concentration of compound 1 was 60.0 mg/L. The LD_(50) of compound 1 for E. ilishaeformis was 234.3 mg/L with a safe concentration of 64.1 mg/L. This study firstly demonstrated that compound 1 has potent antiparasitic efficacy against I. multifiliis, and it could be a good candidate drug for chemotherapy and control of I. multifiliis infections.
To develop novel antiparasitic agents, five 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives were designed and synthesized. Cyclohexanecarboxylic acid chloride, benzoyl chloride, thiophene formyl chloride, acetylchloride, and chloroacetyl chloride were introduced into the 2-position of amido in the initial compound-1-methyl-1,2,3,4-tetrahydroisoquinoline. The chemical structures of all five synthesized compounds were identified by comparing spectral data(EI-MS, ~1H NMR, and ~(13) C NMR) with literature values, and their antiparasitic activity against Ichthyophthirius multifiliis theronts and encysted tomonts in vitro were also evaluated. Additionally, the acute toxicity of the five synthesized compounds against Erythroculter ilishaeformis was evaluated. The results indicated that all five synthesized compounds showed promising antiparasitic activity against I. multifiliis theronts and encysted tomonts; however, compound 1 [cyclohexyl-(1-methyl-3,4-dihydroiso-quinoline)-ketone] with the cyclohexanecarboxylic acid chloride group showed better antiparasitic activity than the other four compounds. The in vitro tests revealed that compound 1 could be 100% effective against theronts at a concentration of 24.0 mg/L. The median lethal dose(LD_(50)) of compound 1 against theronts at 4 h was 16.4 mg/L. All encysted tomonts were killed when the concentration of compound 1 was 60.0 mg/L. The LD_(50) of compound 1 for E. ilishaeformis was 234.3 mg/L with a safe concentration of 64.1 mg/L. This study firstly demonstrated that compound 1 has potent antiparasitic efficacy against I. multifiliis, and it could be a good candidate drug for chemotherapy and control of I. multifiliis infections.
引文
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Heinecke RD,Buchmann K.Control of Ichthyophthirius multifiliis using a combination of water filtration and sodium percarbonate:Dose-response studies.Aquaculture,2009,288:32-35
Hu J,Zhang WD,Liu RH,et al.Benzophenanthridine alkaloids from Zanthoxylum nitidum(ROXB.)DC,and their analgesic and anti-inflammatory activities.Chemistry and Biodiversity,2006,3(9):990-995
Klesius P,Rogers W.Parasitisms of catfish and other farm-raised food fish.Journal of the American Veterinary Medical Association,1995,207(11):1473-1478
Lahnsteiner F,Weismann T.Treatment of ichthyophthiriasis in rainbow trout and common carp with common and alternative therapeutics.Journal of Aquatic Animal Health,2007,19(3):186-194
Ling F,Wang JG,Liu QF,et al.Prevention of Ichthyophthirius multifiliis infestation in goldfish(Carassius auratus)by potassium ferrate(Ⅵ)treatment.Veterinary Parasitology,2010,168(3-4):212-216
Lom J,DykováI.Protozoan parasites of fishes.Reviews in Fish Biology and Fisheries,1994,4(1):133-134
Meng FY,Zuo GY,Hao XY,et al.Antifungal activity of the benzo[c]phenanthridine alkaloids from Chelidonium majus Linn against resistant clinical yeast isolates.Journal of Ethnopharmacology,2009,125(3):494-496
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Picón-Camacho SM,Taylor NGH,Bron JE,et al.Effects of long duration,low dose bronopol exposure on the control of Ichthyophthirius multifiliis(Ciliophora),parasitizing rainbow trout(Oncorhynchus mykiss Walbaum).Veterinary Parasitology,2012,186(3-4):237-244
Rowland SJ,Mifsud C,Nixon M,et al.Use of formalin and copper to control ichthyophthiriosis in the Australian freshwater fish silver perch(Bidyanus bidyanus Mitchell).Aquaculture Research,2009,40:44-54
Shen YF.Protozoology.Beijing:Science Press,1999,455-456[沈韫芬.原生动物学.北京:科学出版社,1999,455-456]
Shinn AP,Picón-Camacho SM,Bron JE,et al.The anti-protozoal activity of bronopol on the key life-stages of Ichthyophthirius multifiliis Fouquet,1876(Ciliophora).Veterinary Parasitology,2012,186(3-4):229-236
Straus DL,Hossain MM,Clark TG,et al.Strain differences in Ichthyophthirius multifiliis to copper toxicity.Disease of Aquatic Organism,2009a,83:31-36
Straus DL,Meinelt T.Acute toxicity of peracetic acid(PAA)formulations to Ichthyophthirius multifiliis theronts.Parasitology Research,2009b,104(5):1237-1241
Wahli T,Schmitt M,Meier W.Evaluation of alternatives to malachite green oxalate as a therapeutant for ichthyophthiriosis in rainbow trout Oncorhynchus mykiss.Journal of Applied Ichthyology,1993,9(3-4):237-249
Wang GX,Zhou Z,Jiang DX,et al.In vivo anthelmintic activity of five alkaloids from Macleaya microcarpa(Maxim)Fedde against Dactylogyrus intermedius in Carassius auratus.Veterinary Parasitology,2010,171(3-4):305-313
Wang WL,Song LJ,Wang GP,et al.Synthesis and evaluation of the antischistosomal activity against S.japonicum of1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives.Chinese Journal of Organic Chemistry,2013,33(12):2588-2595[王文龙,宋丽君,王古平,等.1-甲基-1,2,3,4-四氢异喹啉衍生物的合成及抗日本血吸虫活性评价.有机化学,2013,33(12):2588-2595]
Yao JY,Xu Y,Yin WL,et al.Evaluation of nystatin isolated from Streptomyces griseus SDX-4 against the ciliate,Ichthyophthirius multifiliis.Parasitology Research,2015,114(4):1425-1431
Yao JY,Zhou ZM,Li XL,et al.Antiparasitic efficacy of dihydrosanguinarine and dihydrochelerythrine from Macleaya microcarpa against Ichthyophthirius multifiliis in richadsin(Squaliobarbus curriculus).Veterinary Parasitology,2011,183(1-2):8-13
Yao,JY,Shen JY,Li XL,et al.Effect of sanguinarine from the leaves of Macleaya cordata against Ichthyophthirius multifiliis in grass carp(Ctenopharyngodon idella).Parasitology Research,2010,107:1035-1042
Heinecke RD,Buchmann K.Control of Ichthyophthirius multifiliis using a combination of water filtration and sodium percarbonate:Dose-response studies.Aquaculture,2009,288:32-35
Hu J,Zhang WD,Liu RH,et al.Benzophenanthridine alkaloids from Zanthoxylum nitidum(ROXB.)DC,and their analgesic and anti-inflammatory activities.Chemistry and Biodiversity,2006,3(9):990-995
Klesius P,Rogers W.Parasitisms of catfish and other farm-raised food fish.Journal of the American Veterinary Medical Association,1995,207(11):1473-1478
Lahnsteiner F,Weismann T.Treatment of ichthyophthiriasis in rainbow trout and common carp with common and alternative therapeutics.Journal of Aquatic Animal Health,2007,19(3):186-194
Ling F,Wang JG,Liu QF,et al.Prevention of Ichthyophthirius multifiliis infestation in goldfish(Carassius auratus)by potassium ferrate(Ⅵ)treatment.Veterinary Parasitology,2010,168(3-4):212-216
Lom J,DykováI.Protozoan parasites of fishes.Reviews in Fish Biology and Fisheries,1994,4(1):133-134
Meng FY,Zuo GY,Hao XY,et al.Antifungal activity of the benzo[c]phenanthridine alkaloids from Chelidonium majus Linn against resistant clinical yeast isolates.Journal of Ethnopharmacology,2009,125(3):494-496
Navarro V,Delgado G.Two antimicrobial alkaloids from Bocconia arborea.Journal of Ethnopharmacology,1999,66(2):223-226
Picón-Camacho SM,Taylor NGH,Bron JE,et al.Effects of long duration,low dose bronopol exposure on the control of Ichthyophthirius multifiliis(Ciliophora),parasitizing rainbow trout(Oncorhynchus mykiss Walbaum).Veterinary Parasitology,2012,186(3-4):237-244
Rowland SJ,Mifsud C,Nixon M,et al.Use of formalin and copper to control ichthyophthiriosis in the Australian freshwater fish silver perch(Bidyanus bidyanus Mitchell).Aquaculture Research,2009,40:44-54
Shen YF.Protozoology.Beijing:Science Press,1999,455-456[沈韫芬.原生动物学.北京:科学出版社,1999,455-456]
Shinn AP,Picón-Camacho SM,Bron JE,et al.The anti-protozoal activity of bronopol on the key life-stages of Ichthyophthirius multifiliis Fouquet,1876(Ciliophora).Veterinary Parasitology,2012,186(3-4):229-236
Straus DL,Hossain MM,Clark TG,et al.Strain differences in Ichthyophthirius multifiliis to copper toxicity.Disease of Aquatic Organism,2009a,83:31-36
Straus DL,Meinelt T.Acute toxicity of peracetic acid(PAA)formulations to Ichthyophthirius multifiliis theronts.Parasitology Research,2009b,104(5):1237-1241
Wahli T,Schmitt M,Meier W.Evaluation of alternatives to malachite green oxalate as a therapeutant for ichthyophthiriosis in rainbow trout Oncorhynchus mykiss.Journal of Applied Ichthyology,1993,9(3-4):237-249
Wang GX,Zhou Z,Jiang DX,et al.In vivo anthelmintic activity of five alkaloids from Macleaya microcarpa(Maxim)Fedde against Dactylogyrus intermedius in Carassius auratus.Veterinary Parasitology,2010,171(3-4):305-313
Wang WL,Song LJ,Wang GP,et al.Synthesis and evaluation of the antischistosomal activity against S.japonicum of1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives.Chinese Journal of Organic Chemistry,2013,33(12):2588-2595[王文龙,宋丽君,王古平,等.1-甲基-1,2,3,4-四氢异喹啉衍生物的合成及抗日本血吸虫活性评价.有机化学,2013,33(12):2588-2595]
Yao JY,Xu Y,Yin WL,et al.Evaluation of nystatin isolated from Streptomyces griseus SDX-4 against the ciliate,Ichthyophthirius multifiliis.Parasitology Research,2015,114(4):1425-1431
Yao JY,Zhou ZM,Li XL,et al.Antiparasitic efficacy of dihydrosanguinarine and dihydrochelerythrine from Macleaya microcarpa against Ichthyophthirius multifiliis in richadsin(Squaliobarbus curriculus).Veterinary Parasitology,2011,183(1-2):8-13
Yao,JY,Shen JY,Li XL,et al.Effect of sanguinarine from the leaves of Macleaya cordata against Ichthyophthirius multifiliis in grass carp(Ctenopharyngodon idella).Parasitology Research,2010,107:1035-1042