新型2-胺基-1,3,4-噻二唑类化合物的合成及其抗肿瘤活性的研究

设计合成了一系列新型的N1-(5-取代基-1,3,4-噻二唑-2-基)-N3-取代苯基-脲类化合物,并测定了它们的抗肿瘤活性.标题化合物对肿瘤转移的生物活性实验是以荷Lewis肺癌小鼠为模型的.生物活性表明部分标题化合物对肿瘤的转移和肿瘤生长具有较好的抑制作用.其结构经元素分析、红外光谱及1H NMR确证.     

2-氨基-5-对羟基苯基-1,3,4-噻二唑及其席夫碱的合成

POCl3催化对羟基苯甲酸(1)和氨基硫脲(2)反应合成了5-(对羟基苯基)-2-氨基-1,3,4-噻二唑(3);3与水杨醛缩合制得对应的席夫碱,其结构经1H NMR和IR确征.合成3的较适宜反应条件为:150 mmol,250mmol,POCl3 30 mL,第一步于80℃反应80 min,第二步于110℃反应4 h,混合溶剂[V(DMF):V(水)=1∶2]的重结晶效果最好.在此条件下,3的收率达80.3%.     

含1,3,4-噻二唑α-氨基膦酸酯的合成及其表征

以硫代氨基脲为前体原料, 合成了两种2位为不同烷硫基的5-氨基-1,3,4噻二唑, 采用“一锅煮”的方法, 与不同的醛及亚磷酸酯合成了一系列含1,3,4-噻二唑的α-氨基磷酸酯, 所得产物均经IR, MS, 1H NMR, 31P NMR和元素分析确证结构.     

含1,3,4-噻二唑杂环的甲氧基丙烯酸酯类化合物的合成与杀菌活性研究

以多种取代苯甲酸为原料,通过酰化、醇解、肼解、亲核加成、脱水、亲核取代等多步反应,合成了16个未见文献报道的含1,3,4-噻二唑杂环的甲氧基丙烯酸酯类化合物,其结构均通过1H NMR,IR,MS,HRMS等予以表征确认,并对所有化合物进行了离体杀菌活性测试.结果表明:对水稻立枯和棉花枯萎病菌的防效好于番茄晚疫病菌,对西瓜炭疽病菌防效显著,其中化合物5a~5c,5g,6a~6c的抑制率均高于嘧菌酯,5g在100μg/mL下抑制率为77.5%.     

2-苯基-1,3,4-噻二唑衍生物的合成与活性评价

合成18个2-苯基-1,3,4噻二唑系列化合物并评价其对吲哚胺2,3-双加氧酶1(Indoleamine 2,3-Dioxygenase1,IDO1)抑制活性。生物上建立酶活性检测体系,检测2-苯基-1,3,4噻二唑类化合物的IDO1抑制活性。结果表明对18个噻二唑类化合物进行酶活性检测,分析得到相关的构效关系,其中A16表现出较好的IDO1抑制活性。     

含吡啶环的N-(1,3,4-噻二唑-2-基)苯甲酰胺类化合物的合成及其抑菌活性

以3-吡啶乙酸盐酸盐与氨基硫脲为原料经环化反应制备中间体2-氨基-5-(3-吡啶亚甲基)-1,3,4-噻二唑,后者与取代苯甲酰氯反应合成了一系列含吡啶环的N-(1,3,4-噻二唑-2-基)取代苯甲酰胺(3a~3k),其结构通过IR、~1H NMR、~(13)C NMR、MS和元素分析确证。用菌丝生长速率法测定了目标化合物对灰霉菌的离体抑菌活性,结果表明,部分化合物对病原菌有一定的抑制活性。     

含1,3,4-噁二唑和1,3,4-噻二唑的硫醚类化合物的合成

在KOH作用下,芳甲酰肼1a～1e与CS2环化生成5-芳基-2-巯基-1,3,4-噁二唑(2a～2e);将2a～2e与氯乙酸乙酯反应,生成2-(5-芳基-1,3,4-噁二唑)硫基乙酸乙酯(3a～3e);3a～3e肼解得2-(5-苯基-1,3,4-噁二唑-2-硫基)乙酰肼(4a～4e);4a～4e与芳酰基异硫氰酸酯5a～5d反应得到双酰基氨基硫脲衍生物A1～A19;A1～A19在H2SO4催化下环合得到目标化合物B1～B19;目标化合物的结构经IR,1H NMR,MS,HRMS确证.     

2-氨基-1,3,4-噻二唑的抗水稻白叶枯病机制的探讨

药师寺国人等于1971年发现2-氨基-1,3,4-噻二唑(ATDA)具有优越的抗水稻白叶枯病菌的性能,并发现这种性能可被烟酰胺抵消.一般认为,ATDA的作用与细菌细胞中烟酰胺的代谢有关.为了探明ATDA的活性与结构的关系,并从中找出有效的同类化合物,进一步了解这个药剂的抗病机制,我们合成了几类新的噻二唑化合物,连同以前报导的     

2-（1,3,4-噻二唑胺甲基）苯酚的合成及其杀菌活性

以2-氨基-5-烃基-1,3,4-噻二唑和水杨醛为原料,分别用"分步法"和"一锅法"经还原中间产物Schiff碱的CN双键合成了一系列2-((1,3,4-噻二唑基)胺甲基)苯酚类新化合物,"一锅法"的产率较高,为56%～80%。产物的结构用IR、1H NMR、13C NMR和MS进行了表征。初步测试了目标化合物的杀菌活性,证明化合物对赤星病菌具有较好的抑菌活性,当浓度为25 mg/L时,化合物3i的抑制率为76%,化合物3f、3h、3k和3l的为70%。     

一种水溶性1,3,4-噻二唑类化合物的合成及生物活性

噻二唑与芳香醛反应制得一系列苯腙化合物,该类化合物再与氯乙酰氯反应得到关键中间体3,中间体3与三乙胺反应最终得到水溶性目标产物,对所有目标产物进行了红外、核磁氢谱、质谱和元素分析表征。水溶性实验证明,该类化合物在25℃的水中均具有大于10g的溶解度。并且生物活性实验表明,该类化合物对枯草杆菌(B.subtilis),大肠杆菌(E.coli),普通变形杆菌(P.vulgaris)和金黄色葡萄球菌(S.aureus)都具有明显的抑菌活性。     

1,3,4-Thiadiazoles. XI. Synthesis and behaviour of 4-Alkyl-5-acyl-1,3,4-thiadiazolines

The synthesis of the title compounds from thiadiazolium salts and aldehydes, and their behaviour towards some nucleophiles and aldehydes are described.     

2-Amino-5-methyl-1,3,4-thiadiazole and 2-amino-5-ethyl-1,3,4-thiadiazole

The structures of 2-amino-5-methyl-1,3,4-thia­diazo­le, C₃H₅N₃S, and 2-amino-5-ethyl-1,3,4-thia­diazo­le, C₄H₇N₃S, have been determined for comparison with unsubstituted 2-amino-1,3,4-thia­diazo­le. Despite their different space groups (P2₁/n and Pbca, respectively), the packing modes of the methyl and ethyl derivatives are similar, with comparable three-dimensional hydrogen-bonding associations. This is in contrast to the hydrogen-bonding network in 2-amino-1,3,4-thia­diazo­le, which is one-dimensional and has denser packing. It is shown that both packing forms are different polymorphs of a specific subunit of each array.     

Synthesis and Anticancer Activity of 1,3,4-Thiadiazoles with 3-Methoxyphenyl Substituent

Based on the results of previous work, we designed and synthesized 1,3,4-thiadiazole derivatives. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and a normal cell line (fibroblasts). The results showed that all compounds displayed weak anticancer activity towards two breast cancer lines: an estrogen-dependent cell line (MCF-7) and an estrogen-independent cell line (MDA-MB-231). The compound most active towards MCF-7 breast cancer cells was SCT-4, which decreased DNA biosynthesis to 70% ± 3 at 100 µM. The mechanism of the anticancer action of 1,3,4-thiadiazole was also investigated. We choose a set of the most investigated proteins, which are attractive anticancer targets. In silico studies demonstrated a possible multitarget mode of action for the synthesized compounds but the most likely mechanism of action for the new compounds is connected with the activity of caspase 8.     

Exploring the Antiparasitic Activity of Tris-1,3,4-Thiadiazoles against Toxoplasma gondii-Infected Mice

Nitrogen-containing atoms in their core structures have been exclusive building blocks in drug discovery and development. One of the most significant and well-known heterocycles is the 1,3,4-thidiazole nucleus, which is found in a wide range of natural products and therapeutic agents. In the present work, certain tris-1,3,4-thiadiazole derivatives (6, 7) were synthesized through a multi-step synthesis approach. All synthesized compounds were characterized using different spectroscopic tools. Previously, thiadiazole compounds as anti-Toxoplasma gondii agents have been conducted and reported in vitro. However, this is the first study to test the anti-Toxoplasma gondii activity of manufactured molecular hybrids thiadiazole in an infected mouse model with the acute RH strain of T. gondii. All the observed results demonstrated compound (7)’s powerful activity, with a considerable reduction in the parasite count reaching 82.6% in brain tissues, followed by liver and spleen tissues (65.35 and 64.81%, respectively). Inflammatory and anti-inflammatory cytokines assessments proved that Compound 7 possesses potent antiparasitic effect. Furthermore, docking tests against TgCDPK1 and ROP18 kinase (two major enzymes involved in parasite invasion and egression) demonstrated compound 7’s higher potency compared to compound 6 and megazol. According to the mentioned results, tris-1,3,4-thiadiazole derivatives under test can be employed as potent antiparasitic agents against the acute RH strain of T. gondii.     

Transformation of 1,3,4-Oxadiazoles to 1,3,4-Thiadiazoles Using Thiourea

A new and convenient procedure for the direct conversion of 1,3,4-oxadiazoles to 1,3,4-thiadiazole using thiourea as thionating agent is described.     

Crystalline and Molecular Structure of 2-Amino-5-phenyl-1,3,4-thiadiazole

The crystalline and molecular structure of 2-amino-5-phenyl-1,3,4-thiadiazole was studied by the X-ray diffraction method. C₈H₇N₃S. Monoclinic crystals: a = 11.085(3), b = 7.544(3), c = 11.180(3) Å; = 115.22(2)°; V = 845.8(5) ų; dcalc = 1.404 g/cm³; (MoK ) = 0.325 mm^{- 1}; Z = 4; space group P2₁/c. Molecules of 2-amino-5-phenyl-1,3,4-thiadiazole in crystal form dimers through intermolecular hydrogen bonds, which are arranged in infinite layers parallel to the xy plane.     

Microwave Assisted Synthesis of 2-(4-Methoxylbenzoylamido)-5-Aryloxymethyl-1,3,4-Thiadiazoles

4-Methoxylbenzoyl chloride reacting with ammonium thiocyanate and aryloxyacetic acid hydrazides under phase transfer catalysis at room temperature gives 1-aryloxyacetyl-4-(4-methoxylbenzoyl)-thiosemicarbazides (Ia-m). Compounds Ia-m together with glacial acetic acid on exposure to microwave irradiation lead to the formation of 2-(4-methoxylbenzoylamido)-5-aryloxymethyl-1,3,4-thiadiazoles (IIa-m) in excellent yields.     

Synthesis and Preliminary Anticancer Activity Assessment of N-Glycosides of 2-Amino-1,3,4-thiadiazoles

The addition of 2-amino-1,3,4-thiadiazole derivatives with parallel iodination of differently protected glycals has been achieved using a double molar excess of molecular iodine under mild conditions. The corresponding thiadiazole derivatives of N-glycosides were obtained in good yields and anomeric selectivity. The usage of iodine as a catalyst makes this method easy, inexpensive, and successfully useable in reactions with sugars. Thiadiazole derivatives were tested in a panel of three tumor cell lines, MCF-7, HCT116, and HeLa. These compounds initiated biological response in investigated tumor models in a different rate. The MCF-7 is resistant to the tested compounds, and the cytometry assay indicated low increase in cell numbers in the sub- G1 phase. The most sensitive are HCT-116 and HeLa cells. The thiadiazole derivatives have a pro-apoptotic effect on HCT-116 cells. In the case of the HeLa cells, an increase in the number of cells in the sub-G1- phase and the induction of apoptosis was observed.     

Tetragonal-pyramidal complex of copper nitrate with 2-Amino-5-ethyl-1,3,4-thiadiazole

A complex compound of Cu(II) nitrate with 2-amino-5-ethyl-1,3,4-thiadiazole was synthesized and its structure was studied by the methods of IR spectroscopy and X-ray crystal analysis. The complex has the composition Cu(NO₃)₂(2-amino-5-ethyl-1,3,4-thiadiazole)₄ with four molecules of the heterocyclic ligand (coordination through nitrogen atoms of thiadiazole rings) and one of nitrate ions (the other is replaced in the second sphere) entering into the coordination sphere of the complex polyhedron. The internal coordination sphere of the complex has the form of a tetragonal pyramid with 2-amino-5-ethyl-1,3,4-thiadiazole ligands in the sites of its base and the oxygen atom of the nitrate ion in a slightly distorted vertex of the pyramid.