Design,Synthesis, and Biological Evaluation of 3‐Benzazepin‐1‐ols as NR2B‐Selective NMDA Receptor Antagonists

Cleavage and reconstitution of a bond in the piperidine ring of ifenprodil ( 1 ) leads to 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols, a novel class of NR2B‐selective NMDA receptor antagonists. The secondary amine 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ol ( 12 ), which was synthesized in six steps starting from 2‐phenylethylamine 3 , represents the central building block for the introduction of several N‐linked residues. A distance of four methylene units between the basic nitrogen atom and the phenyl residue in the side chain results in high NR2B affinity. The 4‐phenylbutyl derivative 13 (WMS‐1405, K_i=5.4 nM ) and the conformationally restricted 4‐phenylcyclohexyl derivative 31 (K_i=10 nM ) represent the most potent NR2B ligands of this series. Whereas 13 shows excellent selectivity, the 4‐phenylcyclohexyl derivative 31 also interacts with σ₁ (K_i=33 nM ) and σ₂ receptors (K_i=82 nM ). In the excitotoxicity assay the phenylbutyl derivative 13 inhibits the glutamate‐induced cytotoxicity with an IC₅₀ value of 360 nM , indicating that 13 is an NMDA antagonist.     

Synthesis, σ Receptor Affinity,and Pharmacological Evaluation of 5‐Phenylsulfanyl‐ and 5‐Benzyl‐Substituted Tetrahydro‐2‐benzazepines

In accordance with a novel strategy for generating the 2‐benzazepine scaffold by connecting C6–C1 and C3–N building blocks, a set of 5‐phenylsulfanyl‐ and 5‐benzyl‐substituted tetrahydro‐2‐benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ₁ affinity was achieved for 2‐benzazepines with linear or branched alk(en)yl residues containing at least an n‐butyl substructure. The butyl‐ and 4‐fluorobenzyl‐substituted derivatives, (±)‐5‐benzyl‐2‐butyl‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 b ) and (±)‐5‐benzyl‐2‐(4‐fluorobenzyl)‐2,3,4,5‐tetrahydro‐1H‐2‐benzazepine ( 19 m ), show high selectivity over more than 50 other relevant targets, including the σ₂ subtype and various binding sites of the N‐methyl‐D ‐aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition‐enhancing activity. Compound 19 m did not have any antidepressant‐like effects in mice.     

Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists

To determine the eutomers of potent GluN2B‐selective N‐methyl‐d ‐aspartate (NMDA) receptor antagonists with a 3‐benzazepine scaffold, 7‐benzyloxy‐3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols (S)‐ 2 and (R)‐ 2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers of (S)‐ 2 and (R)‐ 2 provided the enantiomeric phenols (S)‐ 3 and (R)‐ 3 [3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine‐1,7‐diol] and methyl ethers (S)‐ 4 and (R)‐ 4 . All enantiomers were obtained with high enantiomeric purity (≥99.7 % ee). The absolute configurations were determined by CD spectroscopy. R‐configured enantiomers turned out to be the eutomers in receptor binding studies and two‐electrode voltage clamp experiments. The most promising ligand of this compound series is the R‐configured phenol (R)‐ 3 , displaying high GluN2B affinity (K_i=30 nm ), high inhibition of ion flux (IC₅₀=61 nm ), and high cytoprotective activity (IC₅₀=93 nm ). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.     

Pd‐complex‐catalyzed synthesis of oligomers having a recurring benzodiazaborole unit in the main chain

BACKGROUND: Rigid‐rod oligomers and polymers comprising a recurring benzodiazaborole unit show high thermal stability and intriguing optical and electrochemical properties due to the expanded electron system through the B? C and B? N bonds in the main chain by the use of the p_z orbital on boron. However, the conventional method for the preparation of these oligomers and polymers often requires polycondensation under severe conditions. In this study, we report the synthesis of oligomers comprising a recurring benzodiazaborole unit using the Stille reaction under mild conditions. In addition, we describe their chemical properties and solid‐state structures. RESULTS: The reaction of 3,3′‐diaminobenzidine with 4‐bromophenylboronic acid and benzeneboronic acid yielded 2,2′‐bis(4‐bromophenyl)‐2,3,2′,3′‐tetrahydro‐1H,1′H‐[5,5′]bi(benzo[1,3,2]diazaborolyl) (1) and 2,2′‐biphenyl‐2,3,2′,3′‐tetrahydro‐1H,1′H‐[5,5′]bi(benzo[1,3,2]diazaborolyl), respectively. Pd‐complex‐catalyzed polycondensation of 1 with bis(tributyltin) and bis(tributylstannyl)acetylene in N,N‐dimethylformamide provided oligomers comprising a recurring benzodiazaborole unit in 98 and 97% yields, respectively. CONCLUSION: The oligomers comprising a recurring benzodiazaborole unit were obtained under mild reaction conditions in high yields. The expansion of the electron system through the B? C and B? N bonds of the oligomers was confirmed by UV‐visible spectroscopy. The oligomers were photoluminescent in solution and electrochemically active in a film, and they assumed self‐assembled stacked structures in the solid state. Copyright © 2008 Society of Chemical Industry     

Evaluation of 5H-Thiazolo[3,2-α]pyrimidin-5-ones as Potential GluN2A PET Tracers

We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on a 5H-thiazolo[3,2-α]pyrimidin-5-one scaffold. The metabolic stability and overall properties could be optimized satisfactorily, although binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7-(((2-fluoroethyl)(3-fluorophenyl)amino)-methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo-[3,2-α]pyrimidin-5-one ([¹⁸F] 7b ) as a radioligand providing good-quality images in autoradiographic studies, as well as a tritiated derivative, 2-(7-(((2-fluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-α]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([³H₂] 15b ), which was used for the successful development of a radioligand binding assay. These are valuable new tools for the study of GluN2A-containing NMDA receptors, and for the optimization of allosteric modulators binding to the pharmacophore located at the dimer interface of the GluN1-GluN2A ligand-binding domain.     

8‐Benzyltetrahydropyrazino[2,1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases

8‐Benzyl‐substituted tetrahydropyrazino[2,1‐f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual‐target‐directed A₁/A_2A adenosine receptor antagonists were identified. Several compounds showed triple‐target inhibition; one of the best compounds was 8‐(2,4‐dichloro‐5‐fluorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐f]purine‐2,4(1H,3H)‐dione ( 72 ) (human AR: K_i A₁ 217 nM , A_2A 233 nM ; IC₅₀ MAO‐B: 508 nM ). Dichlorinated compound 36 [8‐(3,4‐dichlorobenzyl)‐1,3‐dimethyl‐6,7,8,9‐tetrahydropyrazino[2,1‐f]purine‐2,4(1H,3H)‐dione] was found to be the best triple‐target drug in rat (K_i A₁ 351 nM , A_2A 322 nm; IC₅₀ MAO‐B: 260 nM ), and may serve as a useful tool for preclinical proof‐of‐principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease‐modifying treatment of neurodegenerative diseases are expected to show advantages over single‐target therapeutics.     

Structural Exploration of (3S,6S)‐6‐Benzhydryl‐N‐benzyltetrahydro‐2H‐pyran‐3‐amine Analogues: Identification of Potent Triple Monoamine Reuptake Inhibitors as Potential Antidepressants

To further explore the basic structural motifs (3S,6S)‐6‐benzhydryl‐N‐benzyltetrahydro‐2H‐pyran‐3‐amine and (2S,4R,5R)‐2‐benzhydryl‐5‐(benzylamino)tetrahydro‐2H‐pyran‐4‐ol, developed by our research group, for monoamine transport inhibition, we designed and synthesized various structurally altered analogues. The new compounds were tested for their affinities for the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET) in rat brain by measuring their capacity to inhibit the uptake of [³H]DA, [³H]5‐HT, and [³H]NE, respectively. Our results point to novel compounds with a TUI, DNRI, SNRI, or SSRI profile. Among the TUIs, compound 2 g exhibited a balanced potency for all three monoamine transporters (K_i: 60, 79, and 70.3 nM for DAT, SERT, and NET, respectively). In the rat forced swim test, compound 2 g produced a significant decrease in immobility in drug‐treated rats relative to vehicle, indicating a potential antidepressant property.     

Synthesis and in vivo Evaluation of Fluorine‐18 and Iodine‐123 Pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine Derivatives as PET and SPECT Radiotracers for Mapping A2A Receptors

Imaging agents that target adenosine type 2A (A_2A) receptors play an important role in evaluating new pharmaceuticals targeting these receptors, such as those currently being developed for the treatment of movement disorders like Parkinson′s disease. They are also useful for monitoring progression and treatment efficacy by providing a noninvasive tool to map changes in A_2A receptor density and function in neurodegenerative diseases. We previously described the successful evaluation of two A_2A‐specific radiotracers in both nonhuman primates and in subsequent human clinical trials: [¹²³I]MNI‐420 and [¹⁸F]MNI‐444. Herein we describe the development of both of these radiotracers by selection from a series of A_2A ligands, based on the pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]pyrimidine core of preladenant. Each of this series of 16 ligands was found to bind to recombinant human A_2A receptor in the low nanomolar range, and of these 16, six were radiolabeled with either fluorine‐18 or iodine‐123 and evaluated in nonhuman primates. These initial in vivo results resulted in the identification of 7‐(2‐(4‐(4‐(2‐[¹⁸F]fluoroethoxy)phenyl)piperazin‐1‐yl)ethyl)‐2‐(furan‐2‐yl)‐7H‐pyrazolo[4,3‐e][1,2,4]triazolo[1,5‐c]pyrimidin‐5‐amine ([¹⁸F]MNI‐444) and 7‐(2‐(4‐(2‐fluoro‐4‐[¹²³I]iodophenyl)piperazin‐1‐yl)ethyl)‐2‐(furan‐2‐yl)‐7H‐imidazo[1,2‐c]pyrazolo[4,3‐e]pyrimidin‐5‐amine ([¹²³I]MNI‐420) as PET and SPECT radiopharmaceuticals for mapping A_2A receptors in brain.     

Synthesis of 6‐amino acid substituted 4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines

In the presence of Na₂CO₃ (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐(1,3‐dioxo‐butyl)oxymethyl‐1,2,3,4‐tetrahydrocarboline ( 1 ) were transformed into (1S,3S)‐ and (1R,3S)‐1‐(2,2‐dimethoxyethyl)‐2‐(1,3‐dioxobutyl)‐3‐hydroxymethyl‐1,2,3,4‐tetrahydrocarboline ( 2 ), which were cyclized to (6S)‐3‐acetyl‐6‐hydroxymethyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizine ( 4 ), via(6S,12bS)‐ and (6S,12bR)‐3‐acetyl‐2‐hydroxyl‐6‐hydroxymethyl‐1,2,3,4,6,7,12,12b‐octahydro‐4‐oxoindolo[2,3‐a]quinoline ( 3 ). (6S)‐ 4 was coupled with Boc‐Gly, Boc‐L‐Asp(β‐benzyl ester), or Boc‐L‐Gln to give 6‐amino acid substituted (6S)‐3‐acetyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizines 5a , 5b , or 5c , respectively. After the removal of Boc from (6S)‐ 5a (6S)‐3‐acetyl‐6‐glycyl‐4,6,7,12‐tetrahydro‐4‐oxoindolo[2,3‐a]quinolizine ( 6 ) was obtained. The anticancer activities of (6S)‐ 5 and (6S)‐ 6 in vitro were tested.     

Iridium‐Catalyzed Transfer Hydrogenation of 1,10‐Phenanthrolines using Formic Acid as the Hydrogen Source

The iridium‐catalyzed highly regioselective transfer hydrogenation of a variety of 2‐substituted and 2,9‐disubstituted 1,10‐phenanthrolines under mild conditions with formic acid as the hydrogen source is described. In the presence of a catalytic amount of the iridium complex [Cp*IrCl₂]₂, the transfer hydrogenation proceeded smoothly in 1,4‐dioxane under ligand‐free conditions, exclusively leading to a range of 1,2,3,4‐tetrahydro‐1,10‐phenanthroline products in high yields. The catalyst generated in situ from [Cp*IrCl₂]₂ and (R,R)‐(CF₃)₂C₆H₃SO₂‐dpen [N‐(2‐amino‐1,2‐diphenylethyl)‐3,5‐bis(trifluoromethyl)benzenesulfonamide] could efficiently catalyze the asymmetric transfer hydrogenation of these 1,10‐phenanthrolines in isopropyl alcohol (i‐PrOH) to afford chiral 1,2,3,4‐tetrahydro‐1,10‐phenanthrolines in high yields with up to >99% ee. The key to the success of the reduction is the choice of solvent and hydrogen source.

     

Synthesis and in Vitro Characterisation of Ifenprodil‐Based Fluorescein Conjugates as GluN1/GluN2B N‐Methyl‐D‐aspartate Receptor Antagonists

GluN2B‐containing NMDA receptors are involved in many important physiological functions and play a pivotal role in mediating pain as well as in several neurodegenerative disorders. We aimed to develop fluorescent probes to target the GluN2B subunit selectively in order to allow better understanding of the relationships between receptor localisation and physiological importance. Ifenprodil, known as the GluNR2B antagonist of reference, was chosen as the template for the elaboration of probes. We had previously reported a fluorescein conjugate that was shown (by confocal microscopy imaging of DS‐red‐labelled cortical neurons) to bind specifically to GluN2B. To elaborate this probe, we explored the influence of both the nature and the attachment point of the spacer between the fluorophore and the parent compound, ifenprodil. We performed chemical modifications of ifenprodil at the benzylic position and on the phenol ring by introducing secondary amine or amide functions and evaluated alkyl chains from two to 20 bonds either including or not including secondary amide functions as spacers. The previously developed probe was found to display the greatest activity in the inhibition of NMDA‐induced Ca²⁺ influx by calcium imaging experiments on HEK293 cells transfected with the cDNA encoding for GluN1‐1A and GluN2B. Further investigations revealed that this probe had a neuroprotective effect equivalent to that of ifenprodil in a standard test for neurotoxicity. Despite effects of lesser amplitude with these probes relative to ifenprodil, we demonstrated that they displaced [³H]ifenprodil in mouse brain slices in a similar manner.     

Highly Enantioselective Phase‐Transfer Catalytic α‐Alkylation of α‐tert‐Butoxycarbonyllactams: Construction of β‐Quaternary Chiral Pyrrolidine and Piperidine Systems

A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers.     

Ethylene/1‐octadecene copolymerization using [η5:η1‐C5Me4‐4‐R1‐6‐R‐C6H2O]TiCl2 catalysts

Copolymerization of ethylene with 1‐octadecene was studied using [η⁵:η¹‐C₅Me₄‐4‐R₁‐6‐R‐C₆H₂O]TiCl₂ [R₁ = ^tBu (1), H (2, 3, 4); R = ^tBu (1, 2), Me (3), Ph (4)] as catalysts in the presence of Al(i‐Bu)₃ and [Ph₃C][B(C₆F₅)₄]. The effect of the concentration of comonomer in the feed and Al/Ti molar ratio on the catalytic activity and molecular weight of the resultant copolymer were investigated. The substituents on the phenyl ring of the ligand affect considerably both the catalytic activity and comonomer incorporation. The 1 /Al(i‐Bu)₃/[Ph₃C][B(C₆F₅)₄] catalyst system exhibits the highest catalytic activity and produces copolymers with the highest molecular weight, while the 2 /Al(i‐Bu)₃/[Ph₃C][B(C₆F₅)₄] catalyst system gives copolymers with the highest comonomer incorporation under similar conditions. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Discovery of Aporphine Analogues as Potential Antiplatelet and Antioxidant Agents: Design,Synthesis, Structure–Activity Relationships,Biological Evaluations,and in silico Molecular Docking Studies

To explore the potential of aporphine alkaloids, a novel series of functionalized aporphine analogues with alkoxy (OCH₃, OC₂H₅, OC₃H₇) functional groups at C1/C2 of ring A and an acyl (COCH₃ and COPh) or phenylsulfonyl (SO₂Ph and SO₂C₆H₄‐3‐CH₃) functionality at the N6 position of ring B of the aporphine scaffold were synthesized and evaluated for their arachidonic acid (AA)‐induced antiplatelet aggregation inhibitory activity and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) free‐radical‐scavenging antioxidant activity, with acetylsalicylic acid and ascorbic acid as standard references, respectively. The preliminary structure–activity relationship related to AA‐induced platelet aggregation inhibitory activity results showed that the aporphine analogues 1‐[1,2,9,10‐tetramethoxy‐6a,7‐dihydro‐4H‐dibenzo[de,g]quinolin‐6(5H)‐yl]ethanone and 1‐[2‐(benzyloxy)‐1,9,10‐trimethoxy‐6a,7‐dihydro‐4H‐dibenzo[de,g]quinolin‐6(5H)‐yl]ethanone to be the best compounds of the series. Moreover, the DPPH free‐radical‐scavenging antioxidant activity results demonstrated that the aporphine analogues 1,2,9,10‐tetramethoxy‐6‐(methylsulfonyl)‐5,6,6a,7‐tetrahydro‐4H‐dibenzo[de,g]quinoline, 2‐ethoxy‐1,9,10‐trimethoxy‐6‐(methylsulfonyl)‐5,6,6a,7‐tetrahydro‐4H‐dibenzo[de,g]quinoline, 1‐ethoxy‐2,9,10‐trimethoxy‐6‐(methylsulfonyl)‐5,6,6a,7‐tetrahydro‐4H‐dibenzo[de,g]quinoline, 2,9,10‐trimethoxy‐6‐(methylsulfonyl)‐1‐propoxy‐5,6,6a,7‐tetrahydro‐4H‐dibenzo[de,g]quinoline, and 1‐(benzyloxy)‐2,9,10‐trimethoxy‐6‐(methylsulfonyl)‐5,6,6a,7‐tetrahydro‐4H‐dibenzo[de,g]quinoline were the best compounds of the series. Moreover, in silico molecular docking simulation studies of the active analogues were also performed.     

Synthesis and Characterization of 1,5‐Dinitro‐2,6‐bis(trinitromethyl)‐3a,4a,7a,8a‐tetrahydro‐[1,4]dioxino[2,3‐d:5,6‐d′]diimidazole (DNTNDI)

The polynitro imidazole derivative 1,5‐dinitro‐2,6‐bis(trinitromethyl)‐3a,4a,7a,8a‐tetrahydro‐[1,4]dioxino[2,3‐d:5,6‐d′]diimidazole (DNTNDI) was synthesized through nitration of 2‐(dinitromethylene)‐1H‐imidazol‐4‐ol in HNO₃/Ac₂O followed by cyclization of the di‐enol. It was characterized by NMR, IR, elemental analysis, and single‐crystal X‐ray diffraction analysis. Compound DNTNDI crystallizes in the orthorhombic space group P2(1)2(1)2(1). The thermal decomposition was studied with thermogravimetry/derivative thermogravimetry (TG/DTG) in a nitrogen atmosphere with a heating rate of 5 K min⁻¹. The TG/DTG analysis indicated that DNTNDI has 97.64 % mass loss between 127 °C and 173 °C by undergoing exothermic decomposition. The density of DNTNDI was determined as 1.906 g cm⁻³ at 293 K with an Ultrapycno 1000 Pycnometer. The denotation velocity and denotation pressure of DNTNDI were calculated as 9325 m s⁻¹ and 40 GPa by applying the LOTUSES (version 1.4) code, respectively. The oxygen balance of DNTNDI is 0 and its oxygen content amounts to 51.78 %, which is superior to that of new generation of chlorine‐free oxidizer ammonium dinitramide (ADN).     

Structural Optimization of Berberine as a Synergist to Restore Antifungal Activity of Fluconazole against Drug‐Resistant Candida albicans

We have conducted systematic structural modification, deconstruction, and reconstruction of the berberine core with the aim of lowering its cytotoxicity, investigating its pharmacophore, and ultimately, seeking novel synergistic agents to restore the effectiveness of fluconazole against fluconazole‐resistant Candida albicans. A structure–activity relationship study of 95 analogues led us to identify the novel scaffold of N‐(2‐(benzo[d][1,3]dioxol‐5‐yl)ethyl)‐2‐(substituted phenyl)acetamides 7 a – l , which exhibited remarkable levels of in vitro synergistic antifungal activity. Compound 7 d (N‐(2‐(benzo[d][1,3]dioxol‐5‐yl)ethyl)‐2‐(2‐fluorophenyl)acetamide) significantly decreased the MIC₈₀ values of fluconazole from 128.0 μg mL^?1 to 0.5 μg mL^?1 against fluconazole‐resistant C. albicans and exhibited much lower levels of cytotoxicity than berberine toward human umbilical vein endothelial cells.     

Direct Preparation of 7‐Allyl‐ and 7‐Arylindolines

Addition of allyl halides to the organolithium species derived from lithiation of N‐tert‐butoxycarbonylindoline with sec‐butyllithium (sec‐BuLi) and tetramethylethylenediamine (TMEDA) occurs regioselectively by S_N2 allylation. In contrast, the organolithium species can be transmetalated to the mixed zinc cuprate that undergoes regioselective S_N2′ allylations. Transmetalation to the organozinc chloride allows a Negishi‐type cross‐coupling reaction with aryl bromides using palladium catalysis with triphenylphosphine (PPh₃) as ligand. The chemistry was applied to a very short synthesis of 7‐prenylindole and of the alkaloid vasconine.     

Retracted: Palladium‐Catalyzed Decarboxylative Selective Acylation of 4H‐Benzo[d][1,3]oxazin‐4‐one Derivatives with α‐Oxo Carboxylic acids via Preferential Cyclic Imine‐N‐Directed Aryl C−H Activation

The benzoxazine scaffolds are of much interest as they are found in a large array of natural products and pharmaceutical drugs with diverse activities. We have developed a palladium‐catalyzed decarboxylative selective mono‐ and bis‐acylation of 4H‐benzo[d][1,3]oxazin‐4‐one derivatives with α‐oxo carboxylic acids via preferential cyclic imine‐N‐directed C−H activation. 2‐Aryl‐4H‐benzo[d][1,3]oxazin‐4‐one was acylated with a variety of substituted phenylglyoxylic acids to produce the corresponding products. It was observed that electron‐donating groups (CH₃, OCH₃) at any position of the aromatic ring of phenylglyoxylic acid provided good to excellent yields, whereas phenylglyoxylic acids containing electron‐withdrawing groups (COCH₃, CN, NO₂) gave the products in moderate yields. Interestingly when the reaction was performed with silver triflate (AgOTf) in place of silver nitrate (AgNO₃) in the presence of 4 equivalents of glyoxylic acid, the bis‐acylated product was obtained together with a small amount of mono‐acylated product. This is the first report of acylation of 2‐aryl‐4H‐benzo[d][1,3]oxazin‐4‐ones via C−H activation. The notable features of this reaction are acylation with more challenging heteroarene‐oxo carboxylic acids and alkyl oxo carboxylic acids. This new protocol provides an easy and efficient access to a variety of o‐acyl‐4H‐benzo[d][1,3]oxazin‐4‐one derivatives which are of pharmaceutical importance.

     

Catalyst‐Free Domino Reaction of 1‐Acryloyl‐1‐N‐arylcarbamylcyclopropanes with Amines: One‐Pot Approach to 2,3,6,7‐Tetrahydro‐1H‐pyrrolo[3,2‐c]pyridin‐4(5H)‐ones

A facile one‐pot, catalyst‐free reaction has been developed for the synthesis of 2,3,6,7‐tetrahydro‐1H‐pyrrolo[3,2‐c]pyridin‐4(5H)‐ones from readily available 1‐acryloyl‐1‐N‐arylcarbamylcyclopropanes and amines using a domino ring‐opening/cyclization/aza‐addition sequence.

     

Identification of a Small‐Molecule Inhibitor of HIV‐1 Assembly that Targets the Phosphatidylinositol (4,5)‐bisphosphate Binding Site of the HIV‐1 Matrix Protein

The development of drug resistance remains a critical problem for current HIV‐1 antiviral therapies, creating a need for new inhibitors of HIV‐1 replication. We previously reported on a novel anti‐HIV‐1 compound, N²‐(phenoxyacetyl)‐N‐[4‐(1‐piperidinylcarbonyl)benzyl]glycinamide ( 14 ), that binds to the highly conserved phosphatidylinositol (4,5)‐bisphosphate (PI(4,5)P₂) binding pocket of the HIV‐1 matrix (MA) protein. In this study, we re‐evaluate the hits from the virtual screen used to identify compound 14 and test them directly in an HIV‐1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2‐(4‐{[3‐(4‐fluorophenyl)‐1,2,4‐oxadiazol‐5‐yl]methyl})‐1‐piperazinyl)‐N‐(4‐methylphenyl)acetamide ( 7 ), 3‐(2‐ethoxyphenyl)‐5‐[[4‐(4‐nitrophenyl)piperazin‐1‐yl]methyl]‐1,2,4‐oxadiazole ( 17 ), and N‐[4‐ethoxy‐3‐(1‐piperidinylsulfonyl)phenyl]‐2‐(imidazo[2,1‐b][1,3]thiazol‐6‐yl)acetamide ( 18 ), with compound 7 being the most potent of these hits. Mechanistic studies on 7 demonstrated that it directly interacts with and functions through HIV‐1 MA. In accordance with our drug target, compound 7 competes with PI(4,5)P₂ for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P₂ binding site of MA decreased the antiviral effect of compound 7 . Additionally, compound 7 displays a broadly neutralizing anti‐HIV activity, with IC₅₀ values of 7.5–15.6 μM for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti‐HIV‐1 therapeutics.