Benzyl Substituents Research Articles

Synthesis of indole inhibitors of silent information regulator 1 (SIRT1), and their evaluation as cytotoxic agents

A series of achiral indole analogues of the selective sirtuin inhibitor EX-527 (a racemic, substituted 1,2,3,4 tetrahydrocarbazole) was designed to stabilize the bioactive conformation, and synthesized. These new indoles were evaluated against the isolated sirtuin enzymes SIRT1 and SIRT2, and against a panel of nine human cell lines. Structure-activity relationship studies demonstrated the influence of the substituent at position 3 of the indole. The most potent SIRT1 inhibitor 3h, bearing an isopropyl substituent, was as potent as EX-527, and more selective for SIRT1 over SIRT2. Compound 3g, bearing a benzyl substituent, inhibited both sirtuins at micromolar concentration and was more cytotoxic than EX-527 on several cancer cell lines.

Targeting organophosphorus compounds poisoning by novel quinuclidine-3 oximes: development of butyrylcholinesterase-based bioscavengers.

A library of 14 mono-oxime quinuclidinium-based compounds with alkyl or benzyl substituent were synthesized and characterized in vitro as potential antidotes for organophosphorus compounds (OP) poisoning treatment. We evaluated their potency for reversible inhibition and reactivation of OP inhibited human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) and evaluated interactions by molecular docking studies. The reactivation was notable for both AChE and BChE inhibited by VX, cyclosarin, sarin and paraoxon, if quinuclidinium compounds contained the benzyl group attached to the quinuclidinium moiety. Out of all 14, oxime Q8 [4-bromobenzyl-3-(hydroxyimino)quinuclidinium bromide] was singled out as having the highest determined overall reactivation rate of approximately 20,000M-1min-1 for cyclosarin-inhibited BChE. Furthermore, this oxime in combination with BChE exhibited a capability to act as a bioscavenger of cyclosarin, degrading within 2h up to 100-fold excess of cyclosarin concentration over the enzyme. Molecular modeling revealed that the position of the cyclohexyl moiety conjugated with the active site serine of BChE directs the favorable positioning of the quinuclidinium ring and the bromophenyl moiety of Q8, which makes phosphonylated-serine easily accessible for the nucleophilic displacement by the oxime group of Q8. This result presents a novel scaffold for the development of new BChE-based bioscavengers. Furthermore, a cytotoxic effect was not observed for Q8, which also makes it promising for further in vivo reactivation studies.

Poly(o‐xylylene)s via Cobalt‐Catalyzed Reductive Polymerization†

Summary of main observation and conclusionPoly(p‐xylylene)s (PPX) have found wide applications in various fields owing to their chemical robustness, low gas permeability and excellent dielectric properties. As a structural isomer of PPX, poly(o‐xylylene)s (POX), possessing a distinct main‐chain connectivity, are excellent candidates to pursue high‐performance materials; however, the investigation of POX is hampered by the lack of efficient synthetic methods. Herein, we report a straightforward way to access POXs through a cobalt‐catalyzed reductive polymerization. This method not only allows the direct preparation of electronically unmodified POXs, but also enables the copolymerization between o‐xylylene dibromides bearing different aryl or benzylic substituents. The glass transition temperatures of the copolymers can be finely tuned by varying the ratio between comonomers. The obtained POXs are solvent processible and amenable for thin‐film fabrication. As aryl bromide moiety remains untouched during the polymerization, post‐polymerization functionalization is easily achieved through Suzuki‐Miyaura coupling reaction. The chemistry also enables the copolymerization of xylylene dibromide regioisomers, thereby leading to diversified non‐conjugated polymers, whose backbones are rich in arylene moieties. Moreover, the use of the polymerization strategy to synthesize structurally novel porous polymers is demonstrated.

Phosphorylation Organocatalysts Highly Active by Design.

The activity of nucleophilic organocatalysts for alcohol/phenol phosphorylation was enhanced through attaching oligoether appendages to a benzyl substituent on imidazole- or aminopyridine-based active units, presumably because of stabilizing n-cation interactions of the ethereal oxygens with the positively charged aza-heterocycle in the catalytic intermediates, and was substantially higher than that of known benchmark catalysts for a range of substrates. Density functional theory calculations and the study of analogues having a lower potential for such stabilizing interactions support our hypothesis.

Polyacetylene polyelectrolyte via the non-catalyst polymerization of 2-ethynylpyridine using heptafluorobenzyl iodide

A new ionic polyacetylene having perfluorinated benzyl substituent, poly(2-ethynyl-N-heptafluorobenzylpyridinium iodide), was synthesized via the direct polymerization of the quaterinazed acetylenic pyridinium monomers. The polymerization proceeded homogeneously without any additional initiator or catalyst to give a moderate yield of polymer. The results of instrumental analyses on the molecular structure of polymer revealed that the polymer have polyacetylene backbone system with N-heptafluorobenzylicpyridinium iodide as substituent. The photoluminescence (PL) spectra of polymer exhibited that the PL peak is located at 550nm, corresponding to a photon energy of 2.26eV. The irreversible electrochemical behaviors of polymer between the doped and undoped peaks were observed in the cyclic voltammograms of polymer. The initial oxidation and reduction of poly(EHFBPI) occurred at 0.53V and -0.75V (vs Ag/AgNO3). HOMO level of poly(EHFBPI) was 5.27eV.

Antiplasmodial Activity of p-Substituted Benzyl Thiazinoquinone Derivatives and Their Potential against Parasitic Infections.

Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure–activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold.

NBOMes–Highly Potent and Toxic Alternatives of LSD

Recently, a new class of psychedelic compounds named NBOMe (or 25X-NBOMe) has appeared on the illegal drug market. NBOMes are analogs of the 2C family of phenethylamine drugs, originally synthesized by Alexander Shulgin, that contain a N-(2-methoxy)benzyl substituent. The most frequently reported drugs from this group are 25I-NBOMe, 25B-NBOMe, and 25C-NBOMe. NBOMe compounds are ultrapotent and highly efficacious agonists of serotonin 5-HT2A and 5-HT2C receptors (Ki values in low nanomolar range) with more than 1000-fold selectivity for 5-HT2A compared with 5-HT1A. They display higher affinity for 5-HT2A receptors than their 2C counterparts and have markedly lower affinity, potency, and efficacy at the 5-HT2B receptor compared to 5-HT2A or 5-HT2C. The drugs are sold as blotter papers, or in powder, liquid, or tablet form, and they are administered sublingually/buccally, intravenously, via nasal insufflations, or by smoking. Since their introduction in the early 2010s, numerous reports have been published on clinical intoxications and fatalities resulting from the consumption of NBOMe compounds. Commonly observed adverse effects include visual and auditory hallucinations, confusion, anxiety, panic and fear, agitation, uncontrollable violent behavior, seizures, excited delirium, and sympathomimetic signs such mydriasis, tachycardia, hypertension, hyperthermia, and diaphoresis. Rhabdomyolysis, disseminated intravascular coagulation, hypoglycemia, metabolic acidosis, and multiorgan failure were also reported. This survey provides an updated overview of the pharmacological properties, pattern of use, metabolism, and desired effects associated with NBOMe use. Special emphasis is given to cases of non-fatal and lethal intoxication involving these compounds. As the analysis of NBOMes in biological materials can be challenging even for laboratories applying modern sensitive techniques, this paper also presents the analytical methods most commonly used for detection and identification of NBOMes and their metabolites.

Catalytic Asymmetric Fluorination of Copper Carbene Complexes: Preparative Advances and a Mechanistic Rationale.

The Cu‐catalyzed reaction of substituted α‐diazoesters with fluoride gives α‐fluoroesters with ee values of up to 95 %, provided that chiral indane‐derived bis(oxazoline) ligands are used that carry bulky benzyl substituents at the bridge and moderately bulky isopropyl groups on their core. The apparently homogeneous solution of CsF in C6F6/hexafluoroisopropanol (HFIP) is the best reaction medium, but CsF in the biphasic mixture CH2Cl2/HFIP also provides good results. DFT studies suggest that fluoride initially attacks the Cu‐ rather than the C‐atom of the transient donor/acceptor carbene intermediate. This unusual step is followed by 1,2‐fluoride shift; for this migratory insertion to occur, the carbene must rotate about the Cu−C bond to ensure orbital overlap. The directionality of this rotatory movement within the C 2‐symmetric binding site determines the sense of induction. This model is in excellent accord with the absolute configuration of the resulting product as determined by X‐ray diffraction using single crystals of this a priori wax‐like material grown by capillary crystallization.

Extensive investigation of benzylic N-containing substituents on the pyrrolopyrimidine skeleton as Akt inhibitors with potent anticancer activity.

Continuous optimization of benzylic substituents on 1-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-phenylethan-1-one structure as Akt inhibitors was described in this paper. Particularly, compounds 8 and 14g exhibited high enzymatic potency against all Akt isoforms and antiproliferative effects in mantle cell lymphoma cell lines, as well as favorable cytotoxicities in patient primary cancer cells. Low micromolar doses of both 8 and 14g dose-dependently induced cell apoptosis and G2/M cell cycle arrest, also suppressed the phosphorylation level of Akt downstream targets GSK3β and S6.

The role of neutral donor ligands in the isoselective ring-opening polymerization of rac-β-butyrolactone.

Isoenriched poly-3-hydroxybutyrate (P3HB) is a biodegradable material with properties similar to isotactic polypropylene, yet efficient routes to this material are lacking after 50+ years of extensive efforts in catalyst design. In this contribution, a novel lanthanum aminobisphenolate catalyst (1-La) can access isoenriched P3HB through the stereospecific ring-opening polymerization (ROP) of rac-β-butyrolactone (rac-BBL). Replacing the tethered donor group of a privileged supporting ligand with a non-coordinating benzyl substituent generates a catalyst whose reactivity and selectivity can be tuned with inexpensive achiral neutral donor ligands (e.g. phosphine oxides, OPR3). The 1-La/OPR3 (R = n-octyl, Ph) systems display high activity and are the most isoselective homogeneous catalysts for the ROP of rac-BBL to date (0 °C: Pm = 0.8, TOF ∼190 h−1). Combined reactivity and spectroscopic studies provide insight into the active catalyst structure and ROP mechanism. Both 1-La(TPPO)2 and a structurally related catalyst with a tethered donor group (2-Y) operate under chain-end stereocontrol; however, 2-RE favors formation of P3HB with opposite tacticity (syndioenriched) and its ROP activity and selectivity are totally unaffected by added neutral donor ligands. Our studies uncover new roles for neutral donor ligands in stereospecific ROP, including suppression of chain-scission events, and point to new opportunities for catalyst design.

Investigations into the Structure/Antibacterial Activity Relationships of Cyclam and Cyclen Derivatives

A series of cyclam- and cyclen-derived salts are described in the present work; they were designed specifically to gain insights into their structure and antibacterial activity towards Staphylococcus aureus and Escherichia coli, used respectively, as Gram-positive and Gram-negative model organisms. The newly synthesized compounds are monosubstituted and trans-disubstituted tetraazamacrocycles that display benzyl, methylbenzyl, trifluoromethylbenzyl, or trifluoroethylbenzyl substituents appended on the nitrogen atoms of the macrocyclic ring. The results obtained show that the chemical nature, polarity, and substitution patterns of the benzyl groups, as well as the number of pendant arms, are critical parameters for the antibacterial activity of the cyclam-based salts. The most active compounds against both bacterial strains were the trans-disubstituted cyclam salts displaying CF3 groups in the para-position of the aromatic rings of the macrocyclic pendant arms. The analogous cyclen species presents a lower activity, revealing that the size of the macrocyclic backbone is an important requirement for the antibacterial activity of the tetraazamacrocycles. The nature of the anionic counterparts present on the salts was found to play a minor role in the antibacterial activity.

Electrostatic interactions between viologens and a sulfated β-cyclodextrin; formation of insoluble aggregates with benzyl viologens

Viologens are important compounds and are used in several applications. The interactions between viologens and a negatively charged cyclodextrin, sulfated β-cyclodextrin (sβ-CD), were studied using electrochemistry, 1H NMR and UV–Vis spectroscopy. Weak electrostatic interactions were found between the dicationic viologens (V2+) and the anionic cyclodextrin. The diffusion coefficient of ethyl viologen (EV2+) was reduced from 5.33 × 10−6 to 1.98 × 10−6 cm2 s−1 with an excess of sβ-CD. More significant electrostatic interactions were found between benzyl viologen (BV2+) and sβ-CD. The H atoms in the benzyl substituent, which appear as a singlet in the NMR experiment, were split into a multiplet in the presence of the sβ-CD, while the chemical shift of the H in the β position to the quaternary nitrogen, was shifted by 0.17 ppm in the presence of sβ-CD. Greater electrostatic interactions were evident between the benzyl radical cation (BV·+) and sβ-CD. Using cyclic voltammetry, reduction of the radical cation to the neutral benzyl viologen (BV0) was shifted by 230 mV to a lower potential, indicating that the reduction of the radical cation becomes considerably more difficult in the presence of sβ-CD. This was attributed to the formation of an insoluble BV·+:sβ-CD aggregate, which was also evident in rotating disc voltammetry, where the typical diffusion-limited currents were not observed and in spectroelectrochemistry experiments, where the deposition of the aggregate at the ITO electrode increased the absorbance of the radical species.

Reinvestigation of the synthesis of “covalent-assembly” type probes for fluoride ion detection. Identification of novel 7-(diethylamino)coumarins with aggregation-induced emission properties

An unprecedented C-3 functionalization of 4-(diethylamino)salicylaldehyde through a Friedel-Crafts type alkylation reaction has been discovered during the synthesis of “covalent-assembly”-based fluorescent probes for detection of fluoride ions. The resulting Friedel-Crafts adduct was successfully used for the preparation of two novel 8-substituted 7-(diethylamino)coumarin dyes. The photophysical study of these fluorophores has enabled us to highlight their remarkable aggregation-induced emission (AIE) properties characterized by a yellow-orange emission of aggregates in water. Therefore, 4-(tert-butyldimethylsilyloxy)benzyl substituent was identified as a novel AIE-active moiety which could be seen as a possible alternative to popular tetraphenylethylene (TPE).

Halogenation and μH Tautomerism of 7-Benzyl-7,8-dicarba-nido-undecaborate(−1) Anion

Deboration of 1-PhCH2-1,2-C2B10H11 by heating in ethanolic potassium hydroxide afforded Me4N+ [7-PhCH2-7,8-C2B9H11]− which was treated with excess halosuccinimide (NCS, NBS) in acetonitrile or with elemental iodine or bromine in methanol to obtain Me4N+ [7-PhCH2-9,11-X2-7,8-C2B9H9]− (X = Cl, Br, I). The reaction of 1-PhCH2-1,2-C2B10H11 with an equimolar amount of iodine gave a mixture of Me4N+·[7-PhCH2-11-I-7,8-C2B9H10]- and Me4N+[7-C6H5CH2-9-I-7,8-C2B9H10]− at a ratio 1:1.8 due to steric effect of the benzyl substituent. The 11B chemical shifts of each μ-H tautomer of Me4N+ [7-PhCH2-9,11-X2-7,8-C2B9H9]− (X = H, F, Cl, Br, I) were calculated at the DFT level of theory, and their contributions to the average 11B NMR spectrum and the corresponding tautomeric equilibrium constants were determined.

110th Anniversary: Properties of Imidazolium-Based Ionic Liquids Bearing Both Benzylic and n-Alkyl Substituents

Reports of imidazoliumionic liquids (ILs) with at least one benzylic substituent bound to the imidazolium cation are far less common than the ubiquitous 1-alkyl-3-methylimidazolium ILs ([Cnmim][X])...

Isatin derivatives bearing a fluorine atom. Part 1: Synthesis, hemotoxicity and antimicrobial activity evaluation of fluoro-benzylated water-soluble pyridinium isatin-3-acylhydrazones

A series of 1-fluorobenzylated isatins and water-soluble pyridinium isatin-3-acylhydrazones on their base were obtained. The biological evaluation of novel hydrazones showed a significant dependence of their antimicrobial activity on the position of fluorine atom in benzyl substituent. The best activity showed compounds containing a 2-fluoro-6-chlorobenzyl fragment with selective action against S. aureus. The absence of hemotoxicity of both fluorine-containing products and their some non-fluorinated analogues was shown.

Thiophene and phenothiazine electrochromic copolymers with dual-state emission via tuning the distance of π-π stacking

In order to prevent the aggregation-caused quenching effect and obtain novel electrochromic materials with dual-state emission, four kinds of novel thiophene and phenothiazine copolymers P1–P4 have been designed, synthesized, and characterized. By introducing ethyl, butyl, benzyl substituent groups on N atom of phenothiazine, respectively, we successfully obtained electrochromic and electrofluochromic bifunctional copolymers P2–P4 with dual-state emission, which is ascribed to the disappearing intermolecular interactions by extending the distance of π-π stacking. Furthermore, P1–P4 all exhibit good solubility in common organic solvents, high decomposition temperature and fast response time that show great potential in electrochromic displays and optoelectronic fields.

Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement

The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity.

Homoleptic ruthenium complexes with N-heterocyclic carbene ligands as photosensitizers in the photocatalytic generation of H2 from water

There is great interest in the catalytic photoreduction of water to give hydrogen as a fuel to harness solar energy and a series of ruthenium complexes has been synthesized and tested as photosensitizers in this photoreduction process. There are very few precedents for N-heterocyclic carbene complexes in this field. The complexes obtained in this work were of the type [Ru(:CˆNˆC:)2](PF6)2 and [Ru(NˆC:)3](PF6)2 with N-heterocyclic carbene ligands derived from pyridine and imidazole heterocycles with methyl or benzyl substituents. The photophysical properties of the complexes were studied. Some complexes were luminescent and, although the quantum yields were rather low, the lifetimes were quite high (1.5–1.7 μs). The emissive complexes behave as photosensitizers in the generation of H2 using [Co(bpy)3]Cl2 (bpy = 2,2′-bipyridine) as catalyst and triethanolamine (TEOA) as the sacrificial reductant through an oxidative quenching mechanism. The amount of hydrogen obtained was higher for the benzyl derivative.

Synthesis and biological activity of analogs of the antifungal antibiotic UK-2A. III. Impact of modifications to the macrocycle isobutyryl ester position.

Fenpicoxamid (Inatreq™ active), a new fungicide under development by Corteva Agriscience™, Agriculture Division of DowDuPont, is an isobutyryl acetal derivative of the antifungal antibiotic UK-2A. SAR studies around the picolinamide ring and benzyl substituents attached at positions 3 and 8, respectively, of the UK-2A bislactone macrocycle have recently been documented. This study focuses on replacement of the isobutyryl ester group in the 7 position. Thirty analogs, predominantly esters and ethers, were prepared and evaluated for inhibition of mitochondrial electron transport and in vitro growth of Zymoseptoria tritici, Leptosphaeria nodorum, Pyricularia oryzae and Ustilago maydis. Aliphatic substituents containing four to six carbon atoms deliver strong intrinsic activity, the pivaloate ester (IC50 1.44 nM) and the n-butyl, 1-Me-propyl, 3,3-diMe-propyl and 2-c-propyl propyl ethers (IC50 values = 1.08, 1.14, 1.15 & 1.32 nM, respectively) being the most active derivatives. QSAR modelling identified solvation energy (Esolv ) and critical packing parameters (vsurf_CP) as highly significant molecular descriptors for explaining relative intrinsic activity of analogs. Activity translation to fungal growth inhibition and disease control testing was significantly influenced by intrinsic activity and physical properties, the cyclopropanecarboxylate ester (log D 3.67, IC50 3.36 nM, Z. tritici EC50 12 μg L-1 ) showing the strongest Z. tritici activity in protectant tests. Substitution of the isobutyryl ester group of UK-2A generates analogs that retain strong antifungal activity against Z. tritici and other fungi. © 2019 Society of Chemical Industry.