Synthesis and Evaluation of 1,1′‐Hydrocarbylenebis(indazol‐3‐ols) as Potential Antimalarial Drugs

Bis(indazol‐3‐ol) derivatives ( 5 , 30–38 ) were prepared by alkylation of 3‐alkoxyindazoles with α,ω‐dibromides, followed by removal of the O‐protecting groups. These compounds were subsequently evaluated as inhibitors of biocrystallization of ferriprotoporphyrin IX (heme) to hemozoin, a Plasmodium detoxification specific process. Most bis(5‐nitroindazol‐3‐ols) were good inhibitors, however, a denitro analogue ( 38 ), the intermediate bis(3‐alkoxyindazoles) ( 15 – 29 ) as well as bis(indazolin‐3‐ones) ( 39 – 42 ) were not active, showing the importance of the NO₂ and OH groups in the inhibition process.     

Synthesis of β‐Aminonitrones by Regioselective Oxidation of 4H‐Imidazoles

A new regioselective synthesis for aminonitrones of type 4 via oxidative modification of 4H‐imidazoles 1 has been developed. An X‐ray structural analysis revealed an unexpected tautomeric fixation of the hydrogen atom in 4 . NMR investigations of the ¹⁵N‐labelled derivative 4b showed that this fixation is also present in solution. All new synthesized aminonitrones reported here are unusually stable which can be explained by contribution of anionic as well as cationic delocalized mesomeric structures. Treatment of 4 with acetic anhydride leads to formation of the O‐acylated hydroxylamine derivatives 5 .     

Retraction: Copper‐Catalyzed Cascade Reaction for Practical and Efficient Synthesis of Alkyl 2H‐Isoindole‐1‐carboxylates

The above article in Advanced Synthesis & Catalysis, published online on December 8, 2011, in Wiley Online Library (onlinelibrary.wiley.com), and in print Volume 353, Issue 18, 2011, pages 3330–3334 (DOI: 10.1002/adsc.201100451 ), has been retracted by agreement between the authors, the journal Editor, Joe P. Richmond, and Wiley‐VCH Verlag GmbH & Co. KGaA. The retraction has been agreed to for the following reasons. As determined by X‐ray analysis carried out by Jérôme Thibonnet and co‐workers, Université François Rabelais, Tours, the products reported are not isoindoles, but rather the corresponding indoles. The reaction mechanism reported is therefore also incorrect.     

Convenient Approach to 3,4‐Diarylisoxazoles Based on the Suzuki Cross‐Coupling Reaction

The Suzuki cross‐coupling reaction was found effective for rapid access to a series of 3,4‐diarylisoxazoles of pharmacological interest. The efficiency of this approach was demonstrated by the synthesis of the highly potent COX‐2‐selective inhibitor, 4‐(5‐methyl‐3‐phenyl‐4‐isoxazolyl)benzenesulfonamide (valdecoxib), and its analogues. Thus, the coupling reaction between (3‐aryl‐5‐methyl‐4‐isoxazolyl)boronic acids, prepared in situ from the corresponding bromides using triisopropyl borate, and aryl bromides containing a 4‐sulfonamide or 4‐methylsulfonyl group under the standard conditions [Pd(PPh₃)₄, Na₂CO₃, EtOH‐H₂O, reflux] yielded the target 3,4‐diarylisoxazoles in good yields.     

Heme Oxygenase Inhibition by 1‐Aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and Their Derivatives

Previous studies by our research group have been concerned with the design of selective inhibitors of heme oxygenases (HO‐1 and HO‐2). The majority of these were based on a four‐carbon linkage of an azole, usually an imidazole, and an aromatic moiety. In the present study, we designed and synthesized a series of inhibition candidates containing a shorter linkage between these groups, specifically, a series of 1‐aryl‐2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethanones and their derivatives. As regards HO‐1 inhibition, the aromatic moieties yielding best results were found to be halogen‐substituted residues such as 3‐bromophenyl, 4‐bromophenyl, and 3,4‐dichlorophenyl, or hydrocarbon residues such as 2‐naphthyl, 4‐biphenyl, 4‐benzylphenyl, and 4‐(2‐phenethyl)phenyl. Among the imidazole‐ketones, five ( 36 – 39 , and 44 ) were found to be very potent (IC₅₀<5 μM ) toward both isozymes. Relative to the imidazole‐ketones, the series of corresponding triazole‐ketones showed four compounds ( 54 , 55 , 61 , and 62 ) having a selectivity index >50 in favor of HO‐1. In the case of the azole‐dioxolanes, two of them ( 80 and 85 ), each possessing a 2‐naphthyl moiety, were found to be particularly potent and selective HO‐1 inhibitors. Three non‐carbonyl analogues ( 87 , 89 , and 91 ) of 1‐(4‐chlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone were found to be good inhibitors of HO‐1. For the first time in our studies, two azole‐based inhibitors ( 37 and 39 ) were found to exhibit a modest selectivity index in favor of HO‐2. The present study has revealed additional candidates based on inhibition of heme oxygenases for potentially useful pharmacological and therapeutic applications.     

Retracted: Copper‐Catalyzed Cascade Reaction for Practical and Efficient Synthesis of Alkyl 2H‐Isoindole‐1‐carboxylates

The copper‐catalyzed cascade reaction comprising the condensation/α‐arylation between 2‐halobenzaldehydes and α‐amino acid esters provides a straightforward methodology for the efficient synthesis of alkyl 2H‐isoindole‐1‐carboxylates.     

Synthesis and Biological Evaluation of 9‐Oxo‐9H‐indeno[1,2‐b]pyrazine‐2,3‐dicarbonitrile Analogues as Potential Inhibitors of Deubiquitinating Enzymes

High‐throughput screening highlighted 9‐oxo‐9H‐indeno[1,2‐b]pyrazine‐2,3‐dicarbonitrile ( 1 ) as an active inhibitor of ubiquitin‐specific proteases (USPs), a family of hydrolytic enzymes involved in the removal of ubiquitin from protein substrates. The chemical behavior of compound 1 was examined. Moreover, the synthesis and in vitro evaluation of new compounds, analogues of 1 , led to the identification of potent and selective inhibitors of the deubiquitinating enzyme USP8.     

Synthesis and Structure–Activity Relationship Studies of 2‐(1,3,4‐Oxadiazole‐2(3H)‐thione)‐3‐amino‐5‐arylthieno[2,3‐b]pyridines as Inhibitors of DRAK2

In recent years, DAPK‐related apoptosis‐inducing protein kinase 2 (DRAK2) has emerged as a promising target for the treatment of a variety of autoimmune diseases and for the prevention of graft rejection after organ transplantation. However, medicinal chemistry optimization campaigns for the discovery of novel small‐molecule inhibitors of DRAK2 have not yet been published. Screening of a proprietary compound library led to the discovery of a benzothiophene analogue that displays an affinity constant (K_d) value of 0.25 μM . Variation of the core scaffold and of the substitution pattern afforded a series of 5‐arylthieno[2,3‐b]pyridines with strong binding affinity (K_d=0.008 μM for the most potent representative). These compounds also show promising activity in a functional biochemical DRAK2 enzyme assay, with an IC₅₀ value of 0.029 μM for the most potent congener. Selectivity profiling of the most potent compounds revealed that they lack selectivity within the DAPK family of kinases. However, one of the less potent analogues is a selective ligand for DRAK2 and can be used as starting point for the synthesis of selective and potent DRAK2 inhibitors.     

A Simple Copper‐Catalyzed Cascade Synthesis of 2‐Amino‐1H‐indole‐3‐carboxylate Derivatives

We have developed a simple and efficient copper‐catalyzed method for the synthesis of 2‐amino‐1H‐indole‐3‐carboxylate derivatives via cascade reactions of substituted N‐(2‐halophenyl)‐2,2,2‐trifluoroacetamide with alkyl 2‐cyanoacetate or malononitrile under mild conditions, and the method is of wide practical application.     

Regioselective Synthesis of Naphtho‐fused Heterocycles via Palladium(0)‐Catalyzed Tandem Reaction of N‐Tosylhydrazones

We have developed a palladium(0)‐catalyzed tandem process which involves the cross‐coupling reaction of N‐tosylhydrazones with dibromide compounds followed by a sequence of intramolecular 5‐exo‐trig, 3‐exo‐trig cyclization, ring opening, and β‐hydride elimination to produce 6‐endo‐trig cyclized products. The strategy was successfully applied for the regioselective synthesis of substituted benzo[b]naphtho[2,1‐d]thiophenes, naphtho[1,2‐b]benzofurans, and benzo[a]carbazoles in moderate to excellent yields.

     

Chromophore‐Linked Substrate (CLS405): Probing Metallo‐β‐Lactamase Activity and Inhibition

Serine‐ and metallo‐β‐lactamases present a threat to the clinical use of nearly all β‐lactam antibiotics, including penicillins, cephalosporins, and carbapenems. Efforts to develop metallo‐β‐lactamase (MBL) inhibitors require suitable screening platforms to allow the rapid determination of β‐lactamase activity and efficient inhibition. Unfortunately, the platforms currently available are not ideal for this purpose. Further progress in MBL inhibitor identification requires inexpensive and widely applicable assays. Herein the identification of an inexpensive and stable chromogenic substrate suitable for use in assays of clinically relevant MBLs is described. (6R,7R)‐3‐((4‐Nitrophenoxy)methyl)‐8‐oxo‐7‐(2‐phenylacetamido)‐5‐thia‐1‐azabicyclo[4.2.0]oct‐2‐ene‐2‐carboxylic acid 5,5‐dioxide (CLS405) was synthesised in a three‐step protocol. CLS405 was then characterised spectroscopically, and its stability and kinetic properties evaluated. With a Δλ_max value of 100 nm between the parent and hydrolysis product, a higher analytical accuracy is possible with CLS405 than with commonly used chromogenic substrates. The use of CLS405 in assays was validated by MBL activity measurements and inhibitor screening that resulted in the identification of N‐hydroxythiazoles as new inhibitor scaffolds for MBLs. Further evaluation of the identified N‐hydroxythiazoles against a panel of clinically relevant MBLs showed that they possess inhibitory activities in the mid‐ to low‐micromolar range. The findings of this study provide both a useful tool compound for further inhibitor identification, and novel scaffolds for the design of improved MBL inhibitors with potential as antibiotics against resistant strains of bacteria.     

Aminopalladation‐Triggered Carbene Insertion Reaction: Synthesis of 2‐(1H‐Indol‐3‐yl)acetates

The first example of a nucleopalladation‐triggered carbene insertion reaction for the synthesis of C‐3 alkylated indole derivatives from ortho‐alkynyltrifluoroacetanilides and α‐diazoacetates is presented; it involves a palladium catalyst and a weak base in the open air. Yields range from 49–88% with excellent functional group tolerance. The reaction proceeds through intramolecular aminopalladation of alkynes followed by carbene insertion. Migratory insertion of the carbene into the σ‐indolylpalladium intermediate was favored over N H insertion.

     

Cover Picture: Structure–Activity Relationship Analysis of the Peptide Deformylase Inhibitor 5‐Bromo‐1H‐indole‐3‐acetohydroxamic Acid (ChemMedChem 2/2009)

The cover picture shows a “reverse” indole derivative in complex with Bacillus stearothermophilus peptide deformylase (PDF). This compound was selected from a structure–activity relationship study as a potent inhibitor of bacterial PDFs and shows antibacterial activity toward Bacillus subtilis as well as other pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. For more details, see the Full Paper by I. Artaud et al. on p. 261 ff.

     

Platinum‐Catalyzed Divergent Reactivity of α‐Hydroxyallenes: Synthesis of Dihydrofurans and α,β‐Unsaturated Ketones

α‐Allenols were catalytically transformed into dihydrofurans in the presence of platinum dichloride. Notably, using platinum dichloride along with silver triflate as the catalytic system, α,β‐unsaturated ketones were obtained. Therefore, the role of the silver salt may not just consist in the activation of the platinum precatalyst.

     

The Use of an Unusual Rearrangement Sequence for the Syntheses of 3‐(1‐Aminoalkylidene)‐3H‐thiophen‐2‐ones and two Examples of their Surprising Electrophilic‐Induced Dimerization Reactions

The reaction of 2‐amino‐3‐carbomethoxythiophene ( 1a ) and 2‐amino‐3‐carboethoxy‐4,5‐dimethylthiophene ( 1b ) with methyl‐ or ethylmagnesium chloride leads to new 3‐(1‐aminoalkylidene)‐3H‐thiophen‐2‐ones 4a—d in good yields (60—87%). Treatment of the compounds 4a and 4c with catalytic amounts of p‐TsOH in boiling CHCl₃ afforded the (±)‐4,4′‐bis‐(1‐aminoalkylidene)‐3′,4′‐4H,2′H‐[2,3′]bithiophenyl‐5,5′‐diones 9a and 9b as new interesting heterocycles in preparatively useful yields (60/mdash;65%).     

The Synthesis and Energetic Properties of 5,7‐Dinitrobenzo‐1,2,3,4‐tetrazine‐1,3‐dioxide (DNBTDO)

Energetic tetrazine‐1,3‐dioxide, 5,7‐dinitrobenzo‐1,2,3,4‐tetrazine‐1,3‐dioxide ( DNBTDO ), was synthesized in 45 % yield. DNBTDO was characterized as an energetic material in terms of performance (V_det 8411 m s⁻¹; p_{C J} 3.3×10¹⁰ Pa at a density of 1.868 g cm⁻³), mechanical sensitivity (impact and friction as a function of grain size), and thermal stability (T_dec 204 °C). DNBTDO exhibits a sensitivity slightly higher than that of RDX , and a performance slightly lower (96 % of RDX ).     

Structure–Activity Relationship Analysis of the Peptide Deformylase Inhibitor 5‐Bromo‐1H‐indole‐3‐acetohydroxamic Acid

SAR by NMR : A series of indole compounds derived from 5‐bromo‐1H‐indole‐3‐acetohydroxamic acid were synthesized. Their inhibitory activities were evaluated against purified peptide deformylases (PDFs), and their antibacterial activities against B. subtilis, E. coli (wild type and tolC), and a variety of pathogens were also determined. The potency of the best inhibitors was related to the NMR footprints of the respective acids with ¹⁵N‐labeled E. coli Ni‐PDF.

     

Microwave‐induced Fast Synthesis and Optical Resolution of 9H‐Carbazole‐2‐carboxylic Acids Enantiomers

Fast synthesis of a series 9H‐carabzole‐2‐carboxylic acids enantiomers 9—13 by N‐alkylation reaction of the carbazole and bromo ester under microwave irradiation is described using DMF as solvent. The HPLC optical resolution of these enantiomers were performed on amylose tris‐(phenylcarbamate)‐coated aminopropylated silica gel (ATPC) column.