A facile and efficient procedure for the synthesis of new benzimidazole-2-thione derivatives

A series of benzimidazole-2-thione derivatives was synthesized using a reaction between the macrocyclic aminal 16H,13H-5:12,7:14-dimethanedibenzo[d,i]-[1,3,6,8] tetraazecine (DMDBTA, 5) and various nucleophiles in the presence of carbon disulfide. A full chemical characterization using IR, 1H-, 13C-NMR and GC-MS analyses of the new compounds is provided. These compounds were separated from the reaction mixture by column chromatography (CC) in highly pure form in 15%-51.4% yield.     

Synthesis of new bis-1,2,4-triazole derivatives

A series of new 1,2/1,3-bis[o-(N-methylidenamino-3-aryl-5-phenyl-4H-1,2,4-triazole-4-yl)phenoxy]ethane/propane derivatives 4 were prepared in good yields by treatment of 4-amino-3-aryl-5-phenyl-4H-1,2,4-triazoles 2 with certain bis-aldehydes 1.Compounds 4 were reduced with NaBH(4) to afford the corresponding 1,2/1,3-bis[o-(N-methylamino-3-aryl-5-phenyl-4H-1,2,4-triazole-4-yl)phenoxy]ethane/propane derivatives 5. All new compounds were characterized by IR, (1)H-NMR, (13)C-NMR and mass spectral data.     

Synthesis and antifungal activity of novel sulfone derivatives containing 1,3,4-oxadiazole moieties

A series of new sulfone compounds containing 1,3,4-oxadiazole moieties were synthesized. The structures of these compounds were confirmed by spectroscopic data (IR, 1H- and 13C-NMR) and elemental analyses. Antifungal tests indicated that all the title compounds exhibited good antifungal activities against eight kinds of plant pathogenic fungi, and some showed superiority over the commercial fungicide hymexazol. Among them, compounds 5d, 5e, 5f, and 5i showed prominent activity against B. cinerea, with determined EC?? values of 5.21 μg/mL, 8.25 μg/mL, 8.03 μg/mL, and 21.00 μg/mL, respectively. The present work demonstrates that sulfone derivatives such as 5d containing a 1,3,4-oxadiazole moiety can be used as possible lead compounds for the development of potential agrochemicals.     

Synthesis of 11-aza-artemisinin derivatives using the Ugi reaction and an evaluation of their antimalarial activity

A series of new 11-aza-artemisinin derivatives were prepared from 11-aza-artemisinin using the Ugi reaction. An antimalarial activity evaluation against the FcB1 strain indicated that compounds 7, 10, and 16 had very strong inhibitory activity. Comparison of the activity among the synthetic derivatives of this series revealed that the length of the side chain R group on the amide nitrogen could be critical for their antimalarial properties.     

A new library of C-16 modified artemisinin analogs and evaluation of their anti-parasitic activities

A library of C-16 modified artemisinin analogs was prepared and their antimalarial as well as antileishmanial activities were evaluated. Synthesis of these compounds involved the conversion of artemisinin to its phenol derivatives 7 and 12, and subsequent parallel derivatization by introducing new chemical groups through ester, carbamate, sulfate, phosphate and isourea linkages. Comparison of in vitro antimalarial activities showed that C9-beta artemisinin analogs (8a-f) are more potent than the corresponding C9-alpha diastereomers (9a-f); however, their antileishmanial activities were in the same range. Many of the 10-deoxoartemisinin analogs studied here showed promising antiparasitic activities. For example, compounds 13a-e are approximately three times more active against drug resistant W2 strain of P. falciparum, compared to artemisinin (IC(50), approximately 0.2 - 0.6 nM; cf. artemisinin = 1.6 nM). Further, a number of compounds in this series were notably leishmanicidal, with activities comparable to or better than pentamidine (e.g., 13g and 13j). Detailed in vivo studies involving these active compounds are underway to identify lead candidates for further development.     

Design,synthesis, activity evaluation and QSAR studies of novel antimalarial 1,2,3-triazolo-β-lactam derivatives

This paper describes the synthesis of some new β-lactam derivatives containing the 1,2,3-triazole moiety. All the compounds were evaluated for their in vitro antimicrobial and antimalarial activities. Moderate to excellent antimalarial activities were encountered. The results showed that compounds 5a, 5c, 5f, 5i exhibited the most potent antimalarial activity with IC₅₀ values of 0.85, < 0.97, < 0.97, 1.81 µM against chloroquine-resistant P. falciparum K1 strain. A QSAR study highlights the structure–activity relationships that correlate the observed antimalarial activities with changes in the compounds’ structural features.     

"One-pot" synthesis and antimalarial activity of formamidine derivatives of 4-anilinoquinoline

Amodiaquine (AQ) is an antimalarial which is effective against chloroquino-resistant strains of Plasmodium falciparum but whose clinical use is severely restricted because of associated hepatotoxicity and agranulocytosis. "One-pot" synthesis of formamidines likely to be transformed into AQ derivatives is reported. Compared with AQ, the new compounds were devoid of in vitro cytotoxicity upon human embryonic lung cells and mouse peritoneal macrophages. One showed a potent in vivo activity in mice infected with P berghei. Transformation of this compound by reductive amination led to a new type of AQ derivatives that displayed an in vitro activity similar to that of AQ but did not lead to toxic quinone-imines.     

Microwave assisted synthesis,docking and antimalarial evaluation of hybrid PABA-substituted 1,3,5-triazine derivatives

A series of novel PABA-substituted 1,3,5-triazine derivatives were developed via microwave assisted synthesis and subsequently tested for antimalarial activity against chloroquine sensitive 3D7 strain of Plasmodium falciparum using chloroquine as standard. Antimalarial screening result showed that synthesized compounds exhibited IC₅₀ in the range of 4.46 to 79.72 μg mL⁻¹. Among the tested compounds, 4c and 4f showed significant antimalarial activity with low binding energies (BE) -172.32 and 160.41 kcal mol⁻¹ via interacting with Arg122 through the involvement of COOH of the phenyl linked to 1,3,5-triazine. In conclusion, these core scaffolds can be used for future antimalarial drug development.     

1,1'-(3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)diethanone as a building block in heterocyclic synthesis. Novel synthesis of some pyrazole and pyrimidine derivatives

A series of new bis(heterocycles) featuring thieno[2,3-b]thiophene rings was synthesized in a combinatorial manner. Intramolecular cyclization of enaminone derivatives with appropriate N-nucleophiles afforded the target compounds. All compounds were characterized by 1H-, 13C-NMR, GCMS, IR, and UV-Vis spectrometry. These compounds represent a new class of sulfur- and nitrogen-containing heterocycles that should also be of interest as new materials.     

A New and Efficient Synthesis of 2H-3, 1-Benzoxazine Compounds

2H-3, 1-Benzoxazine heterocyclic compounds are a series of potent nonsteroidal pro- gesterone receptor agonists1-3 and have many other applications such as carbonaceous electrode, plant growth regulating and anti-stress activities4-6, etc.. Comparing to other benzoxazine series, such as 1, 4-benzoxazine, 2H-1, 3-benzoxazine, etc., little attentions have been paid for this series of compounds. There is only one method for the preparation of 2H-3, 1-benzoxazine, e.g. cyclocondensation of o-amin…     

Synthesis and Antimicrobial Properties of New Thiosemicarbazide, 1,2,4-Triazole,and 1,3,4-Thiadiazole Derivatives of Sulfanylacetic Acid

Abstract

1,2,4-triazole and 1,3,4-thiadiazole derivatives are still considered a viable lead structure for the synthesis of more efficient antimicrobial agents having a broad spectrum of activity. This study presents the synthesis and antimicrobial evaluation of a new series of substituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Reaction of 4-phenyl-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thione with ethyl bromoacetate yields the corresponding ethyl acetate (1). In the subsequent reaction with 100% hydrazine hydrate, the hydrazide (2) was obtained, which was converted with isothiocyanates to new acyl derivatives of thiosemicarbazide (3a–l). The cyclization of these compounds in alkaline media resulted in the formation of new derivatives of 1,2,4-triazole (4a–i), whereas in acidic media new derivatives of 1,3,4-thiadiazole (5a,b,g) were obtained. All synthesized compounds were screened for their in vitro antimicrobial activities.     

Synthesis and plant-growth regulatory activities of novel imine derivatives containing 1H-1,2,4-triazole and thiazole rings

<正>Eleven new imine derivatives 6 containing 1H-1,2,4-triazole and thiazole rings were synthesized by the condensation of 5-((1H- 1,2,4-triazol-1-yl)methyl)-4-tert-butylthiazol-2-amine with various substituted benzaldehydes.The structures of the title compounds were characterized by ~1H NMR,MS and elemental analysis.The plant-growth regulatory activities of these compounds were evaluated.The primary bioassay results indicated that these target compounds exhibited promising plant-growth regulatory activities.     

Biological and Cheminformatics Studies of Newly Designed Triazole Based Derivatives as Potent Inhibitors against Mushroom Tyrosinase

A series of nine novel 1,2,4-triazole based compounds were synthesized through a multistep reaction pathway and their structures were scrutinized by using spectral methods such as FTIR, LC-MS, 1H NMR, and 13C NMR. The synthesized derivatives were screened for inhibitory activity against the mushroom tyrosinase and we found that all the synthesized compounds demonstrated decent inhibitory activity against tyrosinase. However, among the series of compounds, N-(4-fluorophenyl)-2-(5-(2-fluorophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazol-3-ylthio) acetamide exhibited more prominent activity when accompanied with the standard drug kojic acid. Furthermore, the molecular docking studies identified the interaction profile of all synthesized derivatives at the active site of tyrosinase. Based on these results, N-(4-fluorophenyl)-2-(5-(2-fluorophenyl)-4-(4-fluorophenyl)-4H-1,2,4-triazol-3-ylthio) acetamide could be used as a novel scaffold to design some new drugs against melanogenesis.     

Facile synthesis and herbicidal evaluation of 4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with 2-phenoxymethyl substituents

Series of 4H-3,1-benzoxazin-4-ones and 3H-quinazolin-4-ones with phenoxy-methyl substituents were rationally designed and easily synthesized via one-pot N-acylation/ring closure reactions of anthranilic acids with 2-phenoxyacetyl chlorides to yield the 4H-3,1-benzoxazin-4-ones, and subsequently substituted with amino derivatives to obtain the 3H-quinazolin-4-ones. The herbicidal evaluation was performed on the model plants barnyard grass (a monocotyledon) and rape (a dicotyledon), and most of the title compounds displayed high levels of phytotoxicity. The active substructure and inhibitory phenotype analysis indicated that these compounds could be attributed to the class of plant hormone inhibitors. A docking study of several representative compounds with the hormone receptor TIR1 revealed an appreciable conformational match in the active site, implicating these compounds are potential lead hits targeting this receptor.     

Preparation of 4,6-diaminopyrazolo[3,4-d] pyrimidines with variations in substitution at the 1- and 3-positions

A number of new derivatives of 4,6-diaminopyrazolo[3,4-d]pyrimidines substituted in the 1- and/or 3-positions have been obtained from reactions of guanidine carbonate with 1- and/or 3-substituted-5-amino-4-cyanopyrazoles. Use of triethanolamine as a reaction medium permitted preparation of certain derivatives which could not be obtained from the previously described fusion procedure. Some derivatives of 4-aminopyrazolo[3,4-d]pyrimidine with substitution at the 1 - and/or 3-positions were also obtained from reactions of formamide with the same 5-amino-4-cyanopyrazoles. The new compounds were screened for in vivo antimalarial activity, but were found inactive.     

Suzuki-Miyaura cross-coupling reaction as the key step for the synthesis of some new 4′-aryl and alkyl substituted analogues of amodiaquine and amopyroquine

A versatile methodology for the synthesis of some new 4-aminoquinoquinoline antimalarial drugs, using Csp²-Csp² and Csp²-Csp³ Suzuki-Miyaura cross-coupling reactions as a key step, is presented. The proposed strategy allowed the synthesis of 26 new amodiaquine (AQ) and amopyroquine (ApQ) derivatives. These new compounds constitute the base of the development of a new library, designed in order to obtain derivatives that present not only improved antimalarial activity, but also a better stability towards bioactivation in potentially toxic metabolites.     

Synthesis and antiplasmodial activity of 3-furyl and 3-thienylquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives

The aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenyl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC(50) less than 1 microM against the 3D7 strain. Derivative 1 demonstrated high potency (IC(50)= 0.63 microM) and good selectivity (SI=10.35), thereby becoming a new lead-compound.     

Complete and unambiguous assignments of 1H and 13C chemical shifts of new arylamino derivatives of ortho-naphthofuranquinones

Six new nor-beta-lapachones have been synthesized from reaction of 3-bromo-nor-beta-lapachone with arylamines. These derivatives have potent anticancer properties against several cell lines. Here, we report complete unambiguous assignments of (1)H and (13)C chemical shifts of the new compounds. The assignments were made using a combination of one- and two-dimensional NMR techniques ((1)H, (13)C, (1)H-(1)H COSY, (1)H-(13)C HSQC, and (1)H-(13)C HMBC).     

Synthesis of a new scaffold: the 7H,8H-pyrimido[1,6-b]pyridazin-6,8-dione nucleus

This paper describes a modified method of preparation of a number of alpha-aryl-alpha-(pyridazin-3-yl)-acetonitriles via the C-arylation reaction of the corresponding carbanionsof phenylacetonitriles using 3-chloropyridazine derivatives. KOH and DMSO were used inthe deprotonation process, which made the reaction very simple and safe to perform.Nitriles were obtained in the hydrolysis reaction to the corresponding alpha-aryl-alpha-(pyridazin-3-yl)-acetamide derivatives, which were next subjected to cyclization to afford the finalproducts. A number of new derivatives of 7H,8H-pyrimido[1,6-b]pyridazin-6,8-dione weresynthesized in the cyclocondensation reaction of respective alpha-aryl-alpha-(pyridazin-3-yl)-acetamides with diethyl carbonate in the presence of EtONa. The structure andcomposition of the new compounds were confirmed by IR, (1)H- and (13)C- NMR analysesand by elemental C, H and N analysis.     

Ligand-based virtual screening and in silico design of new antimalarial compounds using nonstochastic and stochastic total and atom-type quadratic maps

Malaria has been one of the most significant public health problems for centuries. It affects many tropical and subtropical regions of the world. The increasing resistance of Plasmodium spp. to existing therapies has heightened alarms about malaria in the international health community. Nowadays, there is a pressing need for identifying and developing new drug-based antimalarial therapies. In an effort to overcome this problem, the main purpose of this study is to develop simple linear discriminant-based quantitative structure-activity relationship (QSAR) models for the classification and prediction of antimalarial activity using some of the TOMOCOMD-CARDD (TOpological MOlecular COMputer Design-Computer Aided "Rational" Drug Design) fingerprints, so as to enable computational screening from virtual combinatorial datasets. In this sense, a database of 1562 organic chemicals having great structural variability, 597 of them antimalarial agents and 965 compounds having other clinical uses, was analyzed and presented as a helpful tool, not only for theoretical chemists but also for other researchers in this area. This series of compounds was processed by a k-means cluster analysis in order to design training and predicting sets. Afterward, two linear classification functions were derived in order to discriminate between antimalarial and nonantimalarial compounds. The models (including nonstochastic and stochastic indices) correctly classify more than 93% of the compound set, in both training and external prediction datasets. They showed high Matthews' correlation coefficients, 0.889 and 0.866 for the training set and 0.855 and 0.857 for the test one. The models' predictivity was also assessed and validated by the random removal of 10% of the compounds to form a new test set, for which predictions were made using the models. The overall means of the correct classification for this process (leave group 10% full-out cross validation) using the equations with nonstochastic and stochastic atom-based quadratic fingerprints were 93.93% and 92.77%, respectively. The quadratic maps-based TOMOCOMD-CARDD approach implemented in this work was successfully compared with four of the most useful models for antimalarials selection reported to date. The developed models were then used in a simulation of a virtual search for Ras FTase (FTase = farnesyltransferase) inhibitors with antimalarial activity; 70% and 100% of the 10 inhibitors used in this virtual search were correctly classified, showing the ability of the models to identify new lead antimalarials. Finally, these two QSAR models were used in the identification of previously unknown antimalarials. In this sense, three synthetic intermediaries of quinolinic compounds were evaluated as active/inactive ones using the developed models. The synthesis and biological evaluation of these chemicals against two malaria strains, using chloroquine as a reference, was performed. An accuracy of 100% with the theoretical predictions was observed. Compound 3 showed antimalarial activity, being the first report of an arylaminomethylenemalonate having such behavior. This result opens a door to a virtual study considering a higher variability of the structural core already evaluated, as well as of other chemicals not included in this study. We conclude that the approach described here seems to be a promising QSAR tool for the molecular discovery of novel classes of antimalarial drugs, which may meet the dual challenges posed by drug-resistant parasites and the rapid progression of malaria illnesses.