Discovery of Novel Tricyclic 5H-Pyridazino[4,5-b]indoles as Potent Antitumor Agents: Design,Synthesis and Biological Evaluation

A novel series of 5H-pyridazino[4,5-b]indoles(L-01-L-32) was synthesized and characterized by means of ¹H NMR, MS and elemental analysis. The cytotoxicity of the target compounds against Bel-7402 and HT-1080 cell lines were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. Most of them exhibited moderate to excellent cytotoxicity, and six compounds(L-04, L-06, L-18, L-20, L-21 and L-23) possessed dramatically increased cytotoxicity superior to Gefitinib. Of these initial hits, compound L-21 displayed remarkable cytotoxicity against the tested cell lines with half maximal inhibitory concentration(IC₅₀) values of 4.6 and 2.1 μmol/L, respectively, which was 13.9- to 25.6-fold more potent than positive control.     

4-(5H-嘧啶并[5,4-b]吲哚-2-基-氨基)苯甲酰胺类化合物的设计、合成及抗肿瘤活性研究

设计、合成了19个未见文献报道的4-(5H-嘧啶并[5,4-b]吲哚-2-基-氨基)苯甲酰胺类衍生物,所有化合物结构均经~1H NMR、~(13)C NMR及HRMS确认。采用噻唑蓝(MTT)法测试了目标化合物对人结肠癌细胞(HCT116)、人乳腺癌细胞(MD-MBA-231)、大鼠神经胶质瘤细胞(C6)、人非小细胞肺癌细胞(A549)、人乳腺癌细胞(MCF-7)的体外抗肿瘤活性。所有化合物均表现出较好的抗肿瘤活性,其中5a、5b、5c、5e、5i、5p和5r对多个细胞株的抑制活性为阳性对照药品5-氟尿嘧啶的20～100倍;其中,以5b的抗肿瘤活性最为突出,对肿瘤细胞HCT116、MD-MBA-231、C6、A549、MCF-7的IC_(50)分别为3. 26、3. 06、0. 63、0. 68、2. 32μmol/L。初步研究结果表明,此类化合物对肿瘤细胞增殖有明显抑制作用,为新型抗肿瘤化合物的设计、合成提供了思路。     

Synthesis and Antioxidant,Anti-Inflammatory,and Analgesic Activity of Novel Polycyclic Pyrimido[4,5-b]quinolines

The behavior of the 2-methylthio-pyrimido[4,5-b]quinolin-4-one towards differently substituted amines is reported. Also, the reactivity of 3-aminothiazolo[3′,2′ :1,2]-pyrimido[4,5-b]quinoline-2-carbonitrile towards formic acid, urea, thiourea, formamide, and carbon disulfide is discussed. Some of the synthesized derivatives possess biological activities as anti-inflammatory and analgesic agents. Some of these selective biologically active compounds were screened for antioxidant properties.     

Recent progress in the chemistry of heterocycles incorporated oxazolo[4,5-b]pyridine and oxazolo[5,4-b]pyridine skeletons

Abstract

The present study describes recent advances in the chemistry of heterocycles incorporated oxazolo[4,5-b]pyridine and oxazolo[5,4-b]pyridine skeletons. The main sections included the synthesis of the investigated compounds from readily accessible aminopyridinol derivatives or aminopyridines. The reactivity of substituents attached to ring carbon or nitrogen atoms were discussed. In addition, the synthetic and biological evaluation of the inspected oxazolopyridines were highlighted. The purpose of this review is to discuss the chemistry of the title so far. The present study will support researchers in the fields of organic and medicinal chemistry to design and develop new protocols for the construction of new biological components.     

改进的2-巯基-5-甲氧基咪唑并[4,5-b]吡啶合成法

以2,6-二氯吡啶为起始原料,经甲氧基化、硝化、氨基化、还原及成环5步反应得到2-巯基-5-甲氧基咪唑并[4,5-b]吡啶,总收率45.7%。重点比较了2-氯-6-甲氧基吡啶和2,6-二氯吡啶硝化反应条件及收率的差异,讨论了水合肼、NaOH的用量对目标产物收率的影响。用1HNMR、MS和IR测试技术对目标产物结构进行了表征。     

Facile synthesis of some novel triazolo[3,4-b]thiadiazines and triazolo[4,3-b]tetrazines

4-Amino-5-ethyl-4H-1,2,4-triazole-3-thiol was used as a key intermediate for the synthesis of triazolo[3,4-b][1,3,4]thiadiazines, triazolo[4,3-b][1,2,4,5]tetrazines and Schiff’s base via reactions with various hydrazonoyl halides and salicyaldehyde, respectively. Moreover triazolyl-N-N′-triazole derivatives were prepared from reaction of Schiff’s base with various hydrazonoyl halides. The structures of all the newly synthesized heterocyclic compounds were established by considering elemental analysis and spectral data.     

Glycolic acid-supported cobalt ferrite-catalyzed one-pot synthesis of pyrimido[4,5-b]quinoline and indenopyrido[2,3-d]pyrimidine derivatives

Herein, one-pot synthesis of pyrimido[4,5-b]quinoline and indenopyrido[2,3-d]pyrimidine derivatives was developed by the three-component reaction of aldehydes, 6-amino-1,3-dimethyluracil, and 1,3-dicarbonyl compounds in the presence of glycolic acid-supported cobalt ferrite CoFe₂O₄@SiO₂@Si (CH₂)₃NHCOOCH₂COOH as a novel magnetic catalyst in ethanol at reflux conditions. Glycolic acid-supported cobalt ferrite was characterized via Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), and vibrating sample magnetometer (VSM). Moreover, the catalyst was easily recovered with magnetic separation and recycled at least for five times without significant loss of its catalytic activity. The products were formed in excellent yields over appropriate reaction times under environmentally friendly conditions. The high efficiency and easy isolation of catalyst from products with an external permanent magnet are some of the remarkable advantages of this method.     

New cascade reaction of azides with malononitrile dimer to polyfunctional [1,2,3]triazolo[4,5-b]pyridine

A new cascade reaction of azides with malononitrile dimer yielding polyfunctional [1,2,3]triazolo[4,5-b]pyridine was found. It was established that during the reaction of aryl azides with malononitrile dimer, under base catalysis, the formed intermediate triazole underwent spontaneous cyclization leading to the pyridine ring annulation. The obtained products have provided a new entry to [1,2,3]triazolo[4,5-b]pyridine.     

One pot synthesis of ethyl carboxylate and acetyl selenolo[2,3-b]quinoline derivatives and their tetra/pentacyclic systems

Abstract

Ethylcarboxylate and acetyl selenoloquinoline derivatives were prepared in a one pot synthesis via reaction of sodium hydrogen selenide and 2-chloro-3-cyano-4-methylquinoline followed by reactions with ethyl chloroacetate and chloro acetone respectively which used as precursors to synthesize many of tetra and pentacyclic systems. A new series of pyrimido [4′,5′:4,5]selenolo[2,3-b]quinoline, thiazino[2’,3’:4,5]selenolo[2,3-b]quinoline, oxazino[2',3':4,5]selenolo[3,2-b]quinoline, pyrido[2′,3′:4,5]selenolo[2,3-b]quinoline, pyrido[2′,3′:4,5]selenolo[2,3-b]quinoline-2-substituted selenyl and selenolo[2′,3′:5,6]pyrido[2″,3″:4,5]selenolo[2,3-b]quinoline derivatives were prepared. Elemental analysis, IR, ¹H NMR, ¹³ Abdel-Hafez, S. H.; Gobouri, A. A.; Alshanbari, N. A.; Gad El-Rab, S. M. F. Synthesis of Novel Vitamin E Containing Sulfa Drug Derivatives and Study Their Anti-Bacterial Activity. Med. Chem. Res. 2018, 27, 2341–2352. DOI: 10.1007/s00044-018-2240-7.[Crossref], [Web of Science ®] , [Google Scholar]C NMR and mass spectra confirmed the structures of the newly synthesized compounds.     

Green Method for the Synthesis of Benzo[f]pyrimido[4,5-b]quinoline Derivatives Catalyzed by Iodine in Aqueous Media

A convenient one-pot synthesis of benzo[f]pyrimido[4,5-b]quinoline derivatives is described via three-component reaction of benzaldehydes, naphthalen-2-amine, and barbituric acid at room temperature in aqueous media catalyzed by iodine. Compared with other methods, this three-component reaction used a green solvent, gave good yields, and was operationally simple.     

Synthesis of derivatives of imidazo[4,5-b]pyridine:Novel sulfur contained side chains for macrolide antibiotics

Two series of novel derivatives of imidazo[4,5-b]pyridine were synthesized.These compounds could be used as side chains of semisynthesised ketolide antibiotics.The side chains have free amine group which can attached to ketolide core.Macrolides with this kind of side chains will show obvious activities against erythromycin-resistant strains.The structure of the side chains was confirmed by ~1H,~(13)C NMR,MS,HMBC spectra.     

Synthesis of derivatives of imidazo[4,5-b]pyridine： Novel sulfur contained side chains for macrolide antibiotics

Two series of novel derivatives of imidazo[4,5-b]pyridine were synthesized. These compounds could be used as side chains of semisynthesised ketolide antibiotics. The side chains have free amine group which can attached to ketolide core. Macrolides with this kind of side chains will show obvious activities against erythromycin-resistant strains. The structure of the side chains was confirmed by ^1H, ^13C NMR, MS, HMBC spectra. 2007 Ping Sheng Lei. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.     

Design,synthesis and antiproliferative activity of novel 2,7-disubstituted triazolo[1,5-a]pyrimidines

In our efforts to identify novel potent anticancer agents, we synthesized a series of 2,7-disubstituted triazolo[1,5-a]pyrimidines (6–16). Their antiproliferative activity against Bel-7402, HT-1080 and WI-38 cell lines was tested by MTT assay in vitro. Four of the compounds (9–11 and 16) displayed promising antiproliferative activity superior to gefitinib, especially compound 9. A preliminary SAR study of these derivatives was performed.     

Synthesis of Some New Imidazo[4,5-B]Pyridine Derivatives Using 2-Cyanomethyl-1-Methyl-1H-Imidazo[4,5-B]Pyridine

Abstract

The reactions of 2-cyanomethyl-1-methyl-1H-imidazo[4,5-b]pyridine with isothiocyanates, nitroso compounds, acid chlorides, and thioglycolic acid were investigated. New imidazo[4,5-b]pyridine derivatives with various substituents in 2-position and derivatives of the new pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridine ring system were synthesized. The compounds obtained were tested in vitro for their tuberculostatic activity.     

One-Pot,Three-Component Synthesis of Pyrimido[4,5-b]quinoline-tetraone Derivatives in Water

Novel pyrimido[4,5-b]quinoline-tetraones were prepared by the three-component reaction of 2-hydroxynaphthalene-1,4-dione, 6-amino-uracils, and aromatic aldehydes in aqueous media and catalyzed by p-toluenesulfonic acid. This protocol provides a simple one-step procedure with the advantages of easy workup, good yield of products, and environmental friendliness.     

Synthesis,X-ray crystallographic studies,DFT calculations and nanostructural features of annulated imidazo[4,5-b]pyridine derivatives

Friedländer-type condensation of 5-amino-4-cyano-1-(phenyl/p-substitutedphenyl)imidazole with cycloalkanone was done by refluxing the mixture with a suspension of anhydrous aluminum chloride in dry 1,2-dichloroethane to produce 7-amino-3-aryl(5,6)cycloalkanoimidazolo[4,5-b]pyridine. Single X-ray crystallographic diffraction studies had shown that compounds had different types of heterodimeric, homodimeric π–π stacking, T-type stacking, and intermolecular hydrogen bonds which lead to nanostructure formation detected by scanning electron microscope. DFT calculation had also been performed to quantify heterodimeric π–π and T-stacking interactions.     

A concise synthesis of functionalized 2,3-dihydrofuro[3,2-b], [3,2-c], and [2,3-b]pyridines

A strategy for the efficient and rapid one-pot synthesis of 2-aryl-2,3-dihydrofuro[3,2-b], [3,2-c], and [2,3-b]pyridines from readily available o-nitropicolines and aromatic aldehydes is described. The key transformation involves reaction of o-nitropicolines with aromatic aldehydes in the presence of TBAF and Hünig's base giving rise to functionalized products having molecular complexity suitable for further manipulation.     

Synthesis of Some New Pyrazolo[3,4-b]Pyridlne and Pyrazolo[3,4-d]Pyrimidine Derivatives1

Several pyrazolo[3,4-b]pyridine (3,4) and pyrazolo-[3,4-d]pyrimidine (5-13) derivatives were prepared using 5-amino-l-(5-ethyl-5H-1,2,4-triazino[5,6-b]-indol-3-yl)-lH-pyrazole-4-carbonitrile (2) . The pyridine derivatives 3 and 4 were obtained by reaction of 2 with malononitrile and ethyl cyanoacetate, respectively, while pyrimidine analogs 5-13 were synthesized cither by a one-step or multi-step sequence.