Concise Synthesis and Antimicrobial Activities of New Substituted 5‐Isoxazolpenicillins

The synthesis of a series of new 5‐isoxazolpenicillins is described, which were obtained by coupling substituted isoxazoles with 6‐APA. Concise large‐scale synthesis of 3,5‐disubstituted isoxazoles by 1,3‐dipolar cycloaddition using copper(I) as catalyst was also investigated. Representative compounds were assayed for antimicrobial activities, showing satisfactory antimicrobial activities against Gram‐negative bacteria.     

Antiviral and Antibacterial Activities of N‐(4‐Substituted phenyl) Acetamide Derivatives Bearing 1,3,4‐Oxadiazole Moiety

In this paper, a series of N‐(4‐substituted phenyl) acetamide derivatives bearing 1,3,4‐oxadiazole moiety were synthesised. Preliminary bioassays revealed that these compounds not only exhibited favourable antiviral activities toward tobacco mosaic virus (TMV) but also demonstrated sustained inhibition activities against plant pathogenic bacteria, including Xanthomonas oryzae pv. oryzae, Ralstonia solanacearum, and Xanthomonas axonopodis pv. citri. Among the derivatives, TC ₈ and TC ₂₀ exerted the strongest curative activities against TMV, with half‐maximal effective concentration (EC₅₀) values of 239.5 and 236.2 µg/mL, respectively, which were comparable to that of ningnanmycin (EC₅₀=273.2 µg/mL). Given their simple synthesis, the target compounds can serve as alternative antiviral candidates.     

Synthesis and Antiviral Bioactivity of Novel 2‐Substituted Methlthio‐5‐(4‐Amino‐2‐Methylpyrimidin‐5‐yl)‐1,3,4‐Thiadiazole Derivatives

A series of novel 2‐substituted methlthio‐5‐(4‐amino‐2‐methylpyrimidin‐5‐yl‐)‐1,3,4‐thiadiazole derivatives were synthesized, characterized and evaluated for antiviral activities against tobacco mosaic virus (TMV). The preliminary biological results indicated that most compounds exhibit excellent antiviral activity against TMV in vivo. Among these compounds, compounds 9c , 9i , and 9p displayed the similar curative effect against TMV (EC₅₀ = 287.05–322.47 µg/mL) to that of the commercial agent Ningnanmycin (EC₅₀ = 301.83 µg/mL). In particular, compound 9d demonstrated the best curative effect against TMV (EC₅₀ = 266.21 µg/mL), which was better than that of commercial Ningnanmycin.     

A Facile Synthesis of Substituted 2‐(5‐(Benzylthio)‐1,3,4‐oxadiazol‐2‐yl)pyrazine Using Microwave Irradiation and Conventional Method with Antioxidant and Anticancer Activities

A series of novel substituted 2‐(5‐(benzylthio)‐1,3,4‐oxadiazol‐2‐yl)pyrazine derivatives ( 6a – n ) were synthesized under microwave irradiation and conventional conditions with less reaction time with good to excellent yields. All the synthesized compounds were screened for antioxidant and anticancer activities. Out of the 14 prepared derivatives, compounds 6f and 6m were most potent and active with antioxidant and anticancer activities, respectively. Also, the developed technique was simple, easy, and less time consuming.     

Synthesis of 3‐Substituted Benzpyrid‐4‐imino‐2‐oxime Derivatives

Pyrazolone, Isoxazolone, Pyrimidinone, Pyrimidinothione, thiazolidinone and β‐lactam incorporating 2‐oximino benzpyrid‐4‐one derivatives have been synthesized by cyclocondensation addition reaction and cycloaddition of hydrazine hydrate, phenyl hydrazine, hydroxylamine, urea, thiourea, mercapto acetic acid, and chloroacetylchloride, respectively.     

Synthesis and Cytotoxicity of 6‐Pyrrolidinyl‐2‐(2‐Substituted Phenyl)‐4‐Quinazolinones

In our continuing search for potential anticancer candidates, 2‐(3‐methoxyphenyl)‐6‐pyrrolidinyl‐4‐quinazolinone ( JJC‐1 ) was selected as the lead compound. Starting 5‐pyrrolidinyl‐2‐aminobenzamide was prepared using standard methodology from 5‐chloro‐2‐nitrobenzoic acid by reaction with SOCl₂, NH₃, pyrrolidine, and H₂. The starting benzamide then was reacted with 2‐substituted benzaldehyde or benzoyl chloride in N,N‐dimethylacetamide (DMAC) in the presence of NaHSO₃ at 150 °C. Thermal cyclodehydration/dehydrogenation gave the target 6‐pyrrolidinyl‐2‐(2‐substituted phenyl)‐4‐quinazolinones ( 15–22 ). These target compounds were assayed for their cytotoxicity in vitro against six cancer cell lines, including human monocytic leukemia cells (U937), mouse monocytic leukemia cells (WEHI‐3), human hepatoma cells (HepG2, Hep3B) and human lung carcinoma cells (A549, CH27). Most of them exhibited significant cytotoxic effect toward U937 and WEHI‐3 cells, with EC₅₀ values ranging from 0.30 to 10.10 μM. Compound 19 was investigated further for its action mechanisms. Preliminary findings indicated that compound 19 induced G2/M arrest and apoptosis on U937 cells.     

Synthesis and Anticancer Activity of New Substituted Pyrazoles and Their Derived 1,2,4‐Triazoles and Sugar Derivatives

New substituted pyrazole, thiazole, and 1,2,4‐triazole derivatives were synthesized. The sugar hydrazones, their acetylated derivatives as well as their derived acyclic C‐nucleoside analogs, and the thioglycosides of the 1,2,4‐traizole derivatives were also prepared. The antitumor activity of some of the synthesized compounds were studied, and a number of the tested compounds showed significant activities.     

Synthesis,Crystal Structure and Anticancer Activities of Tetrahydropyrido[4,3‐d]dihydropyrimidine‐2‐thiones

A new series of tetrahydropyrido[4,3‐d]dihydropyrimidine‐2‐thiones ( 3a–3x ) were designed and synthesized. Their structures were confirmed by ¹H NMR, IR, MS and elemental analysis, and the conformation of compound 3j was confirmed by X‐ray diffraction. Preliminary bioassays indicated that most of the target compounds presented good antiproliferative activities against leukemic K562 cells, ovarian cancer HO‐8910 cells and liver cancer SMMC‐7721 cells in vitro. Among them the compounds 3i and 3m afford the best activity, the IC₅₀ of them were 3.22 and 3.65 µg/mL against leukemic K562 cells, respectively, which were lower than the anticancer drug of clinical practice 5‐FU (IC₅₀=8.56 µg/mL). Preliminary mechanism of action studies revealed that compound 3i caused DNA fragmentation and activated caspase‐3/7 in leukemic K562 cells.     

A Novel Synthesis of 4‐Pyridazineacetic Acids via Ring Expansion of N‐Cyanomethylated 3‐Pyrazoline‐4‐acetic Acids

A novel synthetic route to 4‐pyridazineacetic acids 10 – 12 has been achieved by the ring‐expansion reaction of N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 – 9 . 1H‐Pyrazole‐4‐acetic acids 1 – 3 were reacted with iodoacetonitrile in the presence of triethylamine in refluxing acetonitrile to give the corresponding C‐cyanomethylated 1H‐pyrazole‐4‐acetic acids 4 – 6 as major products together with N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 8 as minor products. On the other hand, reactions of 1 and 3 with chloroacetonitrile in the presence of triethylamine in refluxing chloroform afforded the corresponding N‐cyanomethylated 3‐pyrazoline‐4‐acetic acids 7 and 9 as major products. Thermal treatment of 7 – 9 with sodium hydride in N,N‐dimethylformamide caused ring expansion to yield the corresponding 4‐pyridazineacetic acids 10 – 12 .     

Design,Synthesis and Herbicidal Activities of Tetrahydroisoindoline‐1,3‐dione Derivatives Containing Alkoxycarbonyl Substituted 2‐Benzoxazolinone

Several different alkoxycarbonyl‐substituted 2‐benzoxazolinone moieties have been incorporated into a tetrahydroisoindoline‐1,3‐dione scaffold to provide 25 compounds ( 1a – 1u and 2a – 2d ). The structures of these compounds were confirmed by ¹H and ¹³C NMR, HRMS and X‐ray single‐crystal diffraction. Some of these compounds ( 1g , 1h , 1j , 1k ) exhibited excellent herbicidal activities against Abutilon theophrasti, Amaranthus retroflexus and Echinochloa crus‐galli at a rate of 375 g AI·ha^?1. Among them, compounds 1h and 1j displayed the best post‐emergence herbicidal effect against Abutilon theophrasti with ED₅₀ values of 1.8 and 5.3 g AI·ha^?1, respectively, which are superior to that of the commercial acifluorfen (44.3 g AI·ha^?1). Field trials demonstrated that compound 1h exhibited similar herbicidal activity to a high concentration atrazine, and found to be safer for maize than atrazine. The results of this study therefore show that compound 1h could potentially be used as a post‐emergence herbicide for maize fields.     

A New and Efficient One‐Pot Synthesis of 2‐Fluoroalkyl Substituted Indoles

A new simple and efficient one‐pot synthesis of 2‐fluoroalkyl substituted indoles from 2‐aminobenzyl alcohols with fluorine‐containing carboxylic acids in the presence of Ph₃P, CCl₄, and NEt₃ is described. Various kinds of 2‐fluoroalkyl substituted indole derivatives can be conveniently prepared.     

Collective Synthesis of 4‐Hydroxy‐2‐pyridone Alkaloids and Their Antiproliferation Activities

A collective synthesis of 4‐hydroxy‐2‐pyridone alkaloids—specifically, pretenellin B, prebassianin B, farinosone A, militarione D, pyridovericin, and torrubiellone C—has been achieved. Key steps include using a strategic convergent method to synthesize the densely substituted pyridone key intermediate by Suzuki–Miyaura cross‐coupling reaction, a divergent synthesis approach of target molecules by aldol condensation of pyridone intermediate with homologous aldehydes, and an iterative synthesis of homologous aldehydes with all‐trans‐polyene backbones. Interestingly, among the six tumor cell lines investigated, torrubiellone C was found to induce potent and apoptotic inhibitory activities on Jurkat T cells with IC₅₀ values of 7.05 μM . Hence, this approach could potentially contribute to the synthesis of bioactive small‐molecule libraries as well as drug discovery.     

Synthesis and Hill Inhibitory Activity of New Substituted 3‐Aryl‐5‐cyano‐6‐methylthio Pyrimidine‐2, 4‐diones

Novel substituted derivatives of 3‐aryl‐5‐cyano‐6‐methylthiopyrimidine‐2, 4‐diones were synthesized by the reaction of ethyl 2‐cyano‐3,3′‐dimethylthioacrylate with arylureas in good yields. The structures of all title compounds were evaluated by elemental analyses and ¹H NMR spectra and compound 2c was also confirmed by X‐ray diffraction. Hill reaction inhibitory activity of title compounds was assayed.     

Synthesis and Biological Activities of 3‐Substituted Analogues of Tenuazonic Acid

A series of tenuazonic acid analogues in which the acetyl group was replaced with electron‐withdrawing substituents have been synthesized with the aim of obtaining molecules with various bioactivities. Substituents such as cyano, sulfonyl, and amido were introduced at the 3‐position of the pyrrolidine‐2,4‐dione nucleus of tenuazonic acid. 3‐Cyano and sulfonyl pyrrolidine‐2,4‐dione compounds ( 2 and 6 ) were prepared via a Dieckmann cyclization as key step. 3‐Amido pyrrolidine‐2,4‐dione compounds ( 9 ) were prepared by a microwave‐assisted amidation reaction from corresponding 3‐carboxylate derivative. The target compounds were evaluated; their herbicidal, fungicidal, and insecticidal activities, and the preliminary bioassay data showed that some 3‐cyanopyrrolidine‐2,4‐diones 2 gave good insecticidal activity, whereas some 3‐amido compounds 9 exhibited moderate to strong fungicidal activity against Pythium dissimile at 20 mg/L.     

Synthesis of 1,3,4‐Oxadiazoles and 1,3‐Thiazolidinones Containing 1,4,5,6‐Tetrahydro‐6‐pyridazinone

The reaction of 1,4,5,6‐tetrahydro‐6‐pyridazinone‐3‐carboxylic acid hydrazides ( 1 ) with aromatic aldehydes afforded 1,4,5,6‐tetrahydro‐6‐pyridazinone‐3‐carbonyl aromatic aldehyde hydrazones ( 2a‐2g ). Heterocyclic derivatives linked 1,3,4‐oxadiazole obtained by cyclocondensation of 2a‐2g with acetic anhydride in absolute ethanol, and 2a‐2g cyclized with mercaptoacetic acid in DMF in the presence of anhydrous ZnCl₂ afforded the 1,3‐thiazolidinone derivatives. The structures of the new compounds were established by elemental analyses, IR, ¹H NMR and MS spectral data.     

Recent Advances in Chemistry of Condensed 4‐Thiazolidinones

The syntheses of condensed 4‐thiazolidinone and its various derivatives are reviewed for the first time. Condensed 4‐thiazolidinones are important scaffolds and versatile substrates in heterocyclic chemistry, as they can be used for the synthesis of a large variety of biologically active compounds such as thiazolotriazines and as raw material for the drug synthesis. The high reactivity of active methylene group next to the carbonyl of the thiazolidin ring represents useful targets for many organic reactions.     

Synthesis of New Gluco‐, Galacto‐, and Mannopyranosylthiazoles,Thiazolidinones, and Pyranosylthiazlidin‐4‐ones from Sugar Thiosemicarbazone Derivatives

A new series of potentially biological active derivatives, namely alkyl‐2‐((4‐oxo‐2‐(phenylimino)‐3‐(β‐d ‐pyranosyl‐2‐ylamino)thiazolidine‐5‐ylidene)acetate ( 5a–f ), 4‐(4‐bromophenyl)thiazol‐2(3H)‐ylidene)hydrazinyl)‐β‐d ‐pyranosyl ( 4a–c ), and 5‐(4‐bromophenyl)‐2‐(phenylimino)‐3‐(β‐d ‐pyranosyl‐2‐ylamino)thiazolidine‐4‐one ( 6 ) were synthesized via a reaction of the sugar thiosemicarbazone derivatives with 2,4′‐dibromoacetophenone, dialkylacetylenedicarboxylate, and ethylbromoacetate, respectively. The structures of the synthesized compounds were established by spectroscopic methods (FT‐IR, ¹H NMR, ¹³C NMR, and 2D NMR) and elemental analyses. Furthermore, the effect of various solvents at reflux and also ambient temperature on the reactions of the sugar thiosemicarbazone with 2,4′dibromoacetophenone, diethyl acetylenedicarboxylate, and dimethyl acetylenedicarboxylate was investigated. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:200–207, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21083     

Quinolone Analogues 12: Synthesis and Tautomers of 2‐Substituted 4‐Quinolones and Related Compounds

The 4‐quinolone‐2‐carboxylates 4a,b were converted into the 4‐quinolone‐2‐carbohydrazides 5a,b , hydrazones 6,7,10 , and related compounds 8,9,11 . The 4‐methoxyquinoline‐2‐carboxylate 12 was also transformed into the 4‐methoxyquinoline‐2‐carbohydrazide 13 , which was modified to the hydrazone 14 and related compound 15 . The antimicrobial activities of compounds 6b and 14 are described together with the 4‐oxo and 4‐hydroxy tautomers of compounds 4‐11 in deuteriodimethyl sulfoxide and deuteriotrifluoroacetic acid.