Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides.

Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization.

Design, Synthesis, and Biological Evaluation of Novel PARP-1 Inhibitors Based on a 1H-Thieno[3,4-d] Imidazole-4-Carboxamide Scaffold.

A series of poly(ADP-ribose)polymerase (PARP)-1 inhibitors containing a novel scaffold, the 1H-thieno[3,4-d]imidazole-4-carboxamide moiety, was designed and synthesized. These efforts provided some compounds with relatively good PARP-1 inhibitory activity, and among them, 16l was the most potent one. Cellular evaluations indicated that the anti-proliferative activities of 16g, 16i, 16j and 16l against BRCA-deficient cell lines were similar to that of olaparib, while the cytotoxicities of 16j and 16l toward human normal cells were lower. In addition, ADMET prediction results indicated that these compounds might possess more favorable toxicity and pharmacokinetic properties. This study provides a basis for our further investigation.

New synthetic AICAR derivatives with enhanced AMPK and ACC activation.

5-Aminoimidazole-4-carboxamide riboside (AICAR) has an important role in the regulation of the cellular metabolism showing a broad spectrum of therapeutic activities against different metabolic processes. Due to these proven AICAR properties, we have designed, synthesized and tested the biological activity of two ribose-modified AICAR derivatives, named A3 and A4, in comparison to native AICAR and its 5'-phosphorylated counterpart ZMP. Our findings have shown that A3 and A4 derivatives induce the phosphorylation of 5'-AMP activated protein kinase α (AMPKα), which leads to the inhibition of acetyl-CoA carboxylase (ACC), and down-regulate the activity of the extracellular signal-regulated kinases (ERK1/2). Cytotoxicity tests demonstrated that A3 and A4 do not significantly reduce cell viability up to 24 h. Taken together our results indicate that A3 and A4 have a comparable activity to AICAR and ZMP at 0.5 and 1 mM suggesting their potential use in future pharmacological strategies relating to metabolic diseases.

Eficiência do fungicida do grupo químico das carboxamida + estrobilurina no controle da ferrugem asiática em diferentes estádios da soja / Efficiency of fungicide from the carboxamide + strobilurin chemical group in the control of asian rust in different soybean stages / Eficiencia del fungicida del grupo químico de carboxamida + estrobilurina en el control de la oxidación asiática en diferentes etapas de soya

Para estabelecer o momento adequado da aplicação do fungicida no controle da ferrugem asiática (Phakospsora pachyrhizi) da soja, avaliou-se o estádio de aplicação do fungicida do grupo químico carboxamida + estrobirulina (ELATUS®), sob condições de campo. O delineamento experimental foi em blocos casualizados com oito tratamentos e quatro repetições. Cada bloco foi formado por quatro linhas de cinco metros de comprimento com área total de 9 m². Os tratamentos foram: T1 - uma aplicação no estádio V5; T2 - uma aplicação no estádio R1; T3 - uma aplicação no estádio R3; T4 - uma aplicação no estádio R5; T5 - duas aplicações, uma no estádio V5 e uma 21 dias após a primeira (DAA1); T6 - duas aplicações, uma no estádio R1 e uma a 21 DAA1; T7 - três aplicações; uma no estádio V5, a segunda 21 DAA1 e a terceira 21 DAA2 e T8 - Testemunha (controle). A partir dos estudos realizados foi avaliado o índice de severidade da doença, o número de plantas m-1, a massa de mil grãos e o rendimento de grãos. As médias observadas foram submetidas à análise de variância (ANOVA) e teste de Duncan (p ≤ 0,05). Os resultados obtidos mostraram diferenças significativas na severidade da doença, peso de mil grãos e no rendimento. Os tratamentos que apresentaram a menor severidade e maior rendimento de grãos foram T5 e T6 com duas aplicações no estádio V5 e 21 DAA e R1 e 21 DAA. Recomenda-se a aplicação do fungicida ELATUS® em duas vezes, sendo uma no estádio V5 e 21 dias após ou uma no estádio R1 e outra 21 dias após, procedimento esses que mostrou uma boa eficiência no controle do fungo e aumento no rendimento de grãos.

The purpose of this study was to establish the best moment for applying fungicide in the control of Asian rust (Phakospsora pachyrhizi) in soybean. In order to do so, the application stage of the fungicide from the carboxamide + strobirulin chemical group (ELATUS®) was assessed under field conditions. A randomized block experimental design with eight treatments and four replications was used. Each block was formed by four lines of five meters in length with a total area of 9 m². The treatments were: T1 - one application at the V5 stage; T2 - on application at the R1 stage; T3 - one application at the R3 stage; T4 - one application at the R5 stage; T5 - two applications, one at V5 and the other, 21 days after the 1st application (DAA1); T6 - two applications, one at R1 and the other at 21 DAA1; T7 - three applications: one at V5, the second 21 DAA1, and the third 21 DAA2; and T8 ­ control. The disease severity index, number of plants m-1, the mass of one thousand grains and grain yield were assessed. The observed means were submitted to the analysis of variance (ANOVA) and Duncan's test (p ≤ 0.05). The results showed significant differences in disease severity, weight of a thousand grains, and yield. The treatments with the lowest severity and highest grain yield were T5 and T6 with two applications at V5 and 21 DAA, and R1 and 21 DAA, respectively. ELATUS® is recommended to be applied twice, one at V5 and the second application 21 days after the first one, or one at R1 and the other 21 days after it, which presented good efficiency in fungus control and an increase in grain yield.

Para determinar el momento apropiado de la aplicación de fungicidas en el control de la oxidación asiática (Phakospsora pachyrhizi) de la soya, se evaluó la etapa de aplicación de fungicidas del grupo químico carboxamida + estrobirulina (ELATUS®), en condiciones de campo. El diseño experimental fue de bloques al azar con ocho tratamientos y cuatro repeticiones. Cada bloque estaba formado por cuatro filas de cinco metros de largo con una superficie total de 9 m². Los tratamientos fueron: T1 - una aplicación en la etapa V5; T2 - una aplicación en la etapa R1; T3 - una aplicación en la etapa R3; T4 - una aplicación en la etapa R5; T5 - dos aplicaciones, una en la fase V5 y otra 21 días después de la primera (DAA1); T6 - dos aplicaciones, una en la fase de R1 y otra 21 DAA1; T7 - tres aplicaciones; uno en el estadio V5, la segunda 21 DAA1, y la tercera 21 DAA2 y T8 ­ Testigo (control). A partir de los estudios realizados se evaluó el índice de gravedad de la enfermedad, el número de plantas m-1, peso de mil granos y el rendimiento de granos. Los resultados obtenidos han sido sometidos al análisis de varianza (ANOVA) y a la prueba de Duncan (p ≤ 0,05). Los resultados mostraron diferencias significativas en la gravedad de la enfermedad, peso de mil granos y en el rendimiento. Los tratamientos que presentaron menor gravedad y el más alto rendimiento de granos fueron T5 y T6 con dos aplicaciones a la etapa V5, 21 DAA, R1 y 21 DAA. Se recomienda la aplicación del fungicida ELATUS® dos veces, una en la fase V5 y 21 días después, o una en la etapa R1 y otra después de 21 días, procedimiento esos que mostraron una buena eficiencia en el control de hongos y aumento del rendimiento de granos.

Synthesis of 5-Aminoimidazole-4-Carboxamide Riboside (AICAR) and Its Derivatives Using Inosine as Starting Material.

This unit contains four basic protocols describing the synthesis of 5-aminoimidazole-4-carboxamide riboside (AICAR), 5-aminoimidazole-4-carboxamide riboside (ZPM), their 4-N functionalized derivatives, and two sugar-modified analogs of AICAR. The first and second basic protocols reveal the importance of solid-phase synthesis to obtain novel AICAR and ZMP imidazole-modified analogs in a short time, whereas the third and fourth basic protocols allow for the rapid preparation of 5'-F-AICAR and D-ribityl AICA.

Thiophene carboxamide inhibitors of JAK2 as potential treatments for myleoproliferative neoplasms.

A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.

Synthesis of new acadesine (AICA-riboside) analogues having acyclic D-ribityl or 4-hydroxybutyl chains in place of the ribose.

The antiviral activity of certain acyclic nucleosides drew our attention to the fact that the replacement of the furanose ring by an alkyl group bearing hydroxyl(s) could be a useful structural modification to modulate the biological properties of those nucleosides. Herein, we report on the synthesis of some novel acadesine analogues, where the ribose moiety is mimicked by a D-ribityl or by a hydroxybutyl chain.

Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction.

Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase-LEDGF/p75 interaction in vitro. Following a structure-activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound's structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency.

Synthesis and antifungal activity of N-(substituted pyridinyl)-1-methyl(phenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives.

A series of N-(substituted pyridinyl)-1-methyl(phenyl)-3-trifluoromethyl-1H-pyrazole-4-carboxamide derivatives were synthesized. All target compounds were characterized by spectral data (¹H-NMR, ¹³C-NMR, IR, MS) and elemental analysis and were bioassayed in vitro against three kinds of phytopathogenic fungi (Gibberella zeae, Fusarium oxysporum, Cytospora mandshurica). The results showed that some of the synthesized N-(substituted pyridinyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxamides exhibited moderate antifungal activities, among which compounds 6a, 6b and 6c displayed more than 50% inhibition activities against G. zeae at 100 µg/mL, which was better than that of the commercial fungicides carboxin and boscalid.

Novel synthetic methods for N-cyano-1H-imidazole-4-carboxamides and their fungicidal activity.

A novel synthetic method of N-cyanocarboxamides has been developed with advantages of mild reaction condition, simpler procedure and easy reactant-product isolation compared with the existing methods. Using this novel method, 16 new N-cyano-1H-imidazole-4-carboxamide derivatives were synthesized and their structures were characterized by spectrum analysis. Further antifungal activity study showed that most of the newly synthesized compounds have good antifungal activity selectively against Rhizoctonia solani among the six fungi tested. Particularly, compound 12h was identified as the most promising candidate with an EC(50) of 2.63 µg/mL against R. solani.

Solid-phase synthesis of a new diphosphate 5-aminoimidazole-4-carboxamide riboside (AICAR) derivative and studies toward cyclic AICAR diphosphate ribose.

The solid-phase synthesis of the first example of a new diphosphate AICAR derivative is reported. The new substance is characterized by the presence of a 5'-phosphate group while a second phosphate moiety is installed on a 5-hydroxypentyl chain attached to the 4-N-position of AICAR. Cyclization of the diphosphate derivative by pyrophosphate bond formation allowed for the formation of a novel AICAR-based cyclic ADP-ribose (cADPR) mimic.

One-pot synthesis of 2-amino-indole-3-carboxamide and analogous.

An efficient one-pot, two-step solution-phase synthetic method was developed to synthesize twenty-three 2-amino-indole-3-carboxamides (3) from 2-halonitrobenzene (1) or heterocyclic analogous and cyanoacetamides (2). In this sequence, first, intermediate 2-cyano-2-(2-nitrophenyl)acetamide (4) was generated under basic condition via S(NAr) reaction; after direct addition of hydrochloric acid solution, FeCl(3), and Zn powder, indole 3 was generated via reduction/cyclization process.

Probing the cannabinoid CB1/CB2 receptor subtype selectivity limits of 1,2-diarylimidazole-4-carboxamides by fine-tuning their 5-substitution pattern.

The cannabinoid CB(1)/CB(2) receptor subtype selectivity in the 1,2-diarylimidazole-4-carboxamide series was boosted by fine-tuning its 5-substitution pattern. The presence of the 5-methylsulfonyl group in 11 led to a greater than approximately 840-fold CB(1)/CB(2) subtype selectivity. The compounds 10, 18 and 19 were found more active than rimonabant (1) in a CB(1)-mediated rodent hypotension model after oral administration. Our findings suggest a limited brain exposure of the P-glycoprotein substrates 11, 12 and 21.

Toward synthesis of the isosteric sulfonate analogues of the AT-III binding domain of heparin.

D-glucuronate and l-iduronate containing disaccharides related to the antithrombin-binding pentasaccharide of heparin, in which one of the sulfate esters is systematically replaced by a sodium sulfonatomethyl moiety, were synthesized. The sulfonic acid group was introduced by stereoselective radical addition onto the exomethylene moiety of the appropriate glycoside derivatives, and the resulting sulfonatomethyl glucosides were used as acceptors.

Parallel synthesis of an imidazole-4,5-dicarboxamide library bearing amino acid esters and alkanamines.

The imidazole-4,5-dicarboxylic acid scaffold is readily derivatized with amino acid esters and alkanamines to afford compounds with intramolecularly hydrogen bonded conformations that mimic substituted purines and therefore are hypothesized to be potential inhibitors of kinases through competitive binding to the ATP site. In this work, a total of 126 dissymmetrically disubstituted imidazole-4,5-dicarboxamides with amino acid ester and alkanamide substituents were prepared by parallel synthesis. The library members were purified by column chromatography on silica gel and the purified compounds characterized by LC-MS with LC detection at 214 nm. A selection of the final compounds was also analyzed by (1)H-NMR spectroscopy. The analytically pure final products have been submitted to the Molecular Library Small Molecule Repository (MLSMR) for screening in the Molecular Library Screening Center Network (MLSCN) as part of the NIH Roadmap.

Synthesis and evaluation of novel 1-(2-acylhydrazinocarbonyl)-cycloalkyl carboxamides as interleukin-1beta converting enzyme (ICE) inhibitors.

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).

Indole-2-carboxamidines as novel NR2B selective NMDA receptor antagonists.

A novel series of indole-2-carboxamidine derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substituents on the indole skeleton as well as the substitution of the benzyl moiety on the biological activity of the compounds was studied. Compound 5a was po active in the formalin test in mouse.

Ring opening reactions: synthesis of AICAR analogs as potential antimetabolite agents.

In an attempt to improve the AzA selectivity of the 2-(aryl)alkylthio derivatives of adenosine, we planned the synthesis of the corresponding derivatives of the 5-N-ethylcarboxamidoadenosine (NECA). For this purpose, we designed the synthesis of 2-mercapto-NECA to be pursued by means of an opening-closure method We obtained the open AICAR analog; however, ring closure efforts failed to give the desired compound. The newly synthesized AICAR derivative could potentially be endowed with antiviral or antitumoral activity.

N-Arylpiperazine-1-carboxamide derivatives: a novel series of orally active nonsteroidal androgen receptor antagonists.

A novel series of N-arylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic properties were evaluated. Reporter assays indicated that trans-2,5-dimethylpiperazine derivatives are potent AR antagonists, and in this series trans-N-4-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,4-difluorophenyl)-2,5-dimethylpiperazine-1-carboxamide (18 g, YM-175735) exhibited the most potent antiandrogenic activity. Compared to bicalutamide, YM-175735 is an approximately 4-fold stronger AR antagonist and has slightly increased antiandrogenic activity, suggesting that YM-175735 may be useful in the treatment of prostate cancer.

Synthesis of a methylene analog of 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide monophosphate (ZMP).

A novel ZMP analog 3 was synthesized from inosine in 10 steps, and exhibited small but significant inhibitory activity toward protein kinase C.