Aniline Substituents Research Articles

X-ray Structure of Eleven New N,N′-Substituted Guanidines: Effect of Substituents on Tautomer Structure in the Solid State

Guanidine-containing molecules are an interesting class of compounds within both medicinal and material sciences. Having knowledge of their tautomerism is key in designing guanidines that interact with biological and chemical receptors. However, there are limited data on the solid-phase structure of N,N′-substituted guanidines. Thus, eleven guanidines bearing a 4,6-dimethylpyrimidyl at one end and substituents of varying sizes and electronic properties at the other side, were synthesised, crystallised, and analysed by X-ray crystallography. Calculations of isolated molecules of tautomer energies and bond lengths were performed for comparison. One class of guanidines crystallised as a cis–trans tautomer with the shorter bond directed towards the pyrimidyl unit. When more electron-deficient aniline substituents were inserted, the crystallised tautomer changed to a cis–cis form where the shorter bond was directed towards the aniline. The switch in the tautomer structure is concluded to be due to both the electronic properties of the substituents and the intermolecular hydrogen bonding in the crystal lattice.

Novel Quinazoline Derivatives as Highly Effective A2A Adenosine Receptor Antagonists.

The adenosine A2A receptor (A2AR) has been identified as a therapeutic target for treating neurodegenerative diseases and cancer. In recent years, we have highlighted the 2-aminoquinazoline heterocycle as an promising scaffold for designing new A2AR antagonists, exemplified by 6-bromo-4-(furan-2-yl)quinazolin-2-amine 1 (Ki (hA2AR) = 20 nM). Here, we report the synthesis of new 2-aminoquinazoline derivatives with substitutions at the C6- and C7-positions, and the introduction of aminoalkyl chains containing tertiary amines at the C2-position to enhance antagonist activity and solubility properties. Compound 5m showed a high affinity for hA2AR with a Ki value of 5 nM and demonstrated antagonist activity with an IC50 of 6 µM in a cyclic AMP assay. Introducing aminopentylpiperidine and 4-[(piperidin-1-yl)methyl]aniline substituents maintained the binding affinities (9x, Ki = 21 nM; 10d, Ki = 15 nM) and functional antagonist activities (9x, IC50 = 9 µM; 10d, IC50 = 5 µM) of the synthesized compounds while improving solubility. This study provides insights into the future development of A2AR antagonists for therapeutic applications.

Discovery of Nelutroctiv (CK-136), a Selective Cardiac Troponin Activator for the Treatment of Cardiovascular Diseases Associated with Reduced Cardiac Contractility.

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

Enhanced β-Amyloid Aggregation in Living Cells Imaged with Quinolinium-Based Spontaneous Blinking Fluorophores.

Abnormal accumulation of intracellular and extracellular β-amyloid (Aβ) aggregates is closely related to the pathogenesis of Alzheimer's disease (AD). In this work, we use quinolinium derivatives with electron-rich aniline substituents as the skeletons to develop a set of spontaneous blinking fluorophores by the formation of long-lived radicals. These probes can target Aβ1-40 aggregates and exhibit strong deep-red emission upon binding to Aβ1-40 aggregates. More importantly, at the single-molecule level, these probes display spontaneous blinking, low duty cycle, and high photon output, which are suitable for the nanoscopic imaging of Aβ aggregates in living cells. The assembly process of the Aβ aggregates was then tracked with nanoscopic imaging. The elongation rate on the cell membrane was noticeably fast over that in the solution. This work provides a feasible strategy for the design of spontaneous blinking fluorophores for Aβ aggregates.

D 6 h Symmetric Radical Donor–Acceptor Nanographene Modulated Interfacial Carrier Transfer for High-Performance Perovskite Solar Cells

<i>D</i> ^{6 <i>h</i>} Symmetric Radical Donor–Acceptor Nanographene Modulated Interfacial Carrier Transfer for High-Performance Perovskite Solar Cells

Quinolizinium-based tunable pH fluorescent probes for imaging in live cells

A new class of quinolizinium-based tunable pH fluorescent probes for cell imaging was developed. The probes showed turn “On” fluorescence response upon acidification brought by a modulation of photoinduced electron transfer (PET) from the N,N-dialkyl aniline substituent to the quinolizinium core skeleton. These novel PET-based pH fluorescent probes displayed tunable emission properties in between 478 and 509 nm. Also, the probes exhibited tunable pH responsiveness with pKa ranging from <2.1 to 6.1 contributed by the steric effect of N,N-dialkyl anilines. They were successfully applied to in vivo pH sensing in lysosome in live cells.

Photochemical CO2 Reduction Using Rhenium(I) Tricarbonyl Complexes with Bipyridyl‐Type Ligands with and without Second Coordination Sphere Effects

AbstractThe effect of phenyl, phenol, aniline, amino, and CF3 substituents of the 2,2′‐bipyridine ligand in fac‐ReCl(L)(CO)3 (L=2,2′‐bipyridine derivative) catalysts on photochemical CO2 reduction in dimethylacetamide is examined, in order to understand the structure‐function relationships and to compare the catalytic activities with the previously published electrochemical results. All complexes including ReCl(bpy)(CO)3 have similar excited‐state lifetimes and emission spectra, but complex 1 with the Ph‐NH2 moiety exhibits a significantly larger molar absorption coefficient for its metal‐to‐ligand charge transfer (MLCT) band. All complexes we tested produce CO with only a negligible amount of H2 and formate in self‐sensitized systems in the presence of triethanolamine (TEOA) and in some cases, BIH (1,3‐dimethyl‐2‐phenyl‐2,3‐dihydro‐1H‐benzo[d]‐imidazole). The presence of the Ph‐NH2 moiety (complex 1) has a beneficial effect on both electrochemical and photochemical activity, allowing a turnover number (TON) of 32 and 120 for photochemical CO production (without and with BIH, respectively). In the case of the Ph‐OH group in the second coordination sphere (complexes 4 and 6), these complexes are active for photochemical CO2 reduction, despite the formation of a stable 6‐coordinate Re‐OPh intermediate via reductive deprotonation as previously observed under electrochemical conditions. Overall, BIH accelerates the rate of formation of the one‐electron reduced species (OERS) of the Re catalysts and allows higher turnover frequency (TOF) and TON for CO formation. The X‐ray structures of complexes 1 and 4 were determined to have distorted octahedral Re centres, and show π‐π stacking interactions with neighboring molecules as well as intramolecular hydrogen bonds to the internal chloride ligands. The unusually high absorptivity of the MLCT absorption of complex 1 has been explained by TD‐DFT calculations.

Enhanced Electrochemical CO2 Reduction by a Series of Molecular Rhenium Catalysts Decorated with Second-Sphere Hydrogen-Bond Donors.

A series of rhenium(I) fac-tricarbonyl complexes containing pendent arylamine functionality in the second coordination sphere have been developed and studied as electrocatalysts for carbon dioxide (CO2) reduction. Aniline moieties were appended at the 6 position of a 2,2'-bipyridine (bpy) donor in which the primary amine was positioned at the ortho- (1-Re), meta- (2-Re), and para- (3-Re) sites of the aniline substituent to generate a family of isomers. The relationship between the catalyst structure and activity was explored across the series, and the catalytic performance was compared to that of the benchmark catalyst Re(bpy)(CO)3Cl (ReBpy). Catalysts 1-Re, 2-Re, and 3-Re outperform the benchmark catalyst both in anhydrous acetonitrile and with added trifluoroethanol (TFE) as an external proton source. In the presence of TFE, the aniline-substituted catalysts convert CO2 to carbon monoxide (CO) with high Faradaic efficiencies (≥89%) and have superior turnover frequencies (TOFs) relative to ReBpy (72.9 s-1), with 2-Re having the highest TOF of the series at 239 s-1, a value that is twice that of the next most active catalyst. TOFs of 123 and 109 s-1 were observed for the ortho- and para-substituted aniline complexes (1-Re and 3-Re), respectively. Indeed, catalytic activities vary widely across the series, showing a high sensitivity to the position of the amine functionality relative to the rhenium active site. IR and UV-vis spectroelectrochemical experiments were conducted on the aniline-substituted systems, revealing important differences between the catalysts and mechanistic insight.

Novel triphenylamine polyamides bearing carbazole and aniline substituents for multi-colored electrochromic applications

A novel carbazolyl-derived diamine containing triphenylamine, 4,4′-bis[(4-aminophenyl)amino]-4″-carbazolyltriphenylamine (VI), was prepared via the reduction of 4,4′-bis[(4-nitrophenyl)amino]-4″-carbazolyltriphenylamine. A series of novel polyamides (PAs, individually denoted as VIIIA-VIIID) bearing carbazole-substituted triphenylamine units were subsequently prepared by direct polymerization of a novel diamine monomer (VI) and various aromatic diacids (VIIA-VIID). Cyclic voltammetry of the PAs cast onto an indium tin oxide (ITO) coated glass substrates revealed two reversible redox couples at 0.36–0.90 and 1.46–1.70 V under anodic scanning. Characterization of PA-VIIID showed that the resulting radical cations had excellent electrochromic properties, with their color changing from light yellow to green upon oxidation, and finally to dark blue in their fully oxidized form. Further, the optical contrast at 424 nm was 58.7%, while that at 820 nm was 74.2%. The coloring time at the specified wavelength of 424 nm was 3.4 s (during the oxidation process), the fading time was 3.9 s (during the reduction process), the coloring time at the specified wavelength of 820 nm was 3.9 s (during the oxidation process), and the fading time was 3.9 s (during the reduction process). In addition, the anodic coloring of the PA-VIIID showed a high coloring efficiency (CE = 203 cm2/C), and the long-term redox reversibility was measured according to the difference in the percentage of transmittance exhibited by PA-VIIID between 0.00 and 1.70 V.

Synthesis, biological evaluations and computational studies of N-(3-(-2-(7-Chloroquinolin-2-yl)vinyl) benzylidene)anilines as fungal biofilm inhibitors

In the present investigation, new chloroquinoline derivatives bearing vinyl benzylidene aniline substituents at 2nd position were synthesized and screed for biofilm inhibitory, antifungal and antibacterial activity. The result of biofilm inhibition of C. albicans suggested that compounds 5j (IC50 value = 51.2 μM) and 5a (IC50 value = 66.2 μM) possess promising antibiofilm inhibition when compared with the standard antifungal drug fluconazole (IC50 = 40.0 μM). Two compounds 5a (MIC = 94.2 μg/mL) and 5f (MIC = 98.8 μg/mL) also exhibited good antifungal activity comparable to standard drug fluconazole (MIC = 50.0 μg/mL). The antibacterial screening against four strains of bacteria viz. E. coli, P. aeruginosa, B. subtilis, and S. aureus suggested their potential antibacterial activity and especially all the compounds except 5g were found more active than the standard drug ciprofloxacin against B. subtilis. To further gain insights into the possible mechanism of these compounds in biofilm inhibition through the agglutinin like protein (Als), molecular docking and molecular dynamics simulation studies were carried out. Molecular modeling studies suggested the clear role in inhibition of this protein and the resulting biofilm inhibitory activity.

The first Pd-catalyzed Buchwald-Hartwig aminations at C-2 or C-4 in the estrone series.

A facile Pd-catalyzed C(sp2)–N coupling to provide a range of 2- or 4-[(subst.)phenyl]amino-13α-estrone derivatives has been achieved under microwave irradiation. The reactions were mediated with the use of Pd(OAc)2 as a catalyst and KOt-Bu as a base in the presence of X-Phos as a ligand. The desired products have been obtained in good to excellent yields. The nature and the position of the aniline substituent at the aromatic ring influenced the outcome of the couplings. 2-Amino-13α-estrone was also synthesized in a two-step protocol including an amination of 2-bromo-13α-estrone 3-benzyl ether with benzophenone imine and subsequent hydrogenolysis.

Synthesis of Polyquinolines via One-Pot Polymerization of Alkyne, Aldehyde, and Aniline under Metal-Free Catalysis and Their Properties

A novel synthetic route to polyquinolines with 6-substituted quinoline as the structural unit was developed based on the polymerization of alkyne–aldehyde monomers and aniline derivatives under the catalysis of Lewis acid B(C6F5)3. The polymerization was conducted in dichloroethane at 100 °C for 36 h under air atmosphere, affording polyquinolines with molecular weights up to 13 100 and good solubility in most organic solvents. The substituents in aniline exhibited significant effects on the molecular weight, yield, and solubility of the produced polyquinolines. The structures of prepared polymers were characterized and confirmed by GPC, NMR, and FT-IR. The thermogravimetry (TGA) and differential scanning calorimetry (DSC) analysis suggests that the polyquinolines are highly thermal stable. Further photoluminescence behaviors of the prepared polyquinolines were investigated. Based on the characterization results and small molecule reaction mechanism, the polymerization pathway of the polyquinolines was pro...

Synthesis of Mono‐substituted Anthraquinone Derivatives to be Used in the Purification of Lactate Dehydrogenase

Cibacron Blue 3G‐A has been previously used in biochemical laboratories for purification of enzymes containing the dinucleotide fold. Lactate dehydrogenase is one such enzyme that can be purified using Cibacron Blue 3G‐A in affinity chromatography. Rising costs and inaccessibility to Cibacron Blue 3G‐A have created a demand to find a more cost effective replacement. Electron withdrawing and donating properties of the anthraquinone core substituent groups are believed to affect the affinity of the core for various enzymes. A range of anthraquinone dyes were synthesized to determine the importance of the substituents' electronic properties with the coupling of ortho substituted aniline nucleophiles to the anthraquinone core via a diazonium salt link. The aniline substituents include: methyl, methoxy, chloro, and sulfonyl groups. For each anthraquinone dye synthesized, the λmax value was determined to effectively monitor the kinetics of the dyes. Spectrometric assays measured the oxidation of NADH to NAD+ determining the dye's affinity for enzymes containing the dinucleotide fold.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Reversible mechanofluorochromism of aniline-terminated phenylene ethynylenes.

Seven three-ring phenylene-ethynylene (PE) structural analogs, differing only in the lengths of alkyl chains on terminal aniline substituents, show 50-62 nm bathochromic shifts in emission maxima in response to mechanical force (mechanofluorochromism, MC). These shifts are fully reversible with heat or solvent fuming. Shearing of these solids yields a transition from green-emitting crystalline phases to orange-emitting amorphous phases as established by differential scanning calorimetry and X-ray diffraction. Molecules with shorter alkyl chain lengths required higher temperatures to recover the hypsochromically shifted crystalline phases after grinding, while the recovery with chain lengths longer than butyl occurred at room temperature. In addition to this structure-dependent thermochromism, these compounds retain their MC properties in polymer hosts to various extents. The crystalline phases of these materials have PE chromophores that are twisted due to non-covalent perfluoroarene-arene (ArF-ArH) interactions involving perfluorophenyl pendants and the terminal rings of the PE chromophore, resulting in interrupted conjugation and an absence of chromophore aggregation. The MC behavior of an analog without the perfluoroarene rings is severely attenuated. This work demonstrates the general utility of twisted PEs as stimuli-responsive moieties and reveals clear structure-property relationships regarding the effects of alkyl chain length on these materials.

Synthesis and Determination of the pKa Values of a Series of Bis(anilino)furazano[3, 4‐b]pyrazines

AbstractMitochondrial uncouplers such as bis(anilino)furazano[3, 4‐b]pyrazines are potentially useful as metabolic probes and as pharmaceutical treatments for obesity. The ongoing development of such molecules would be facilitated by an ability to predict and control the pKa value of the dissociable proton(s). In this work, new analogues based on the aforementioned scaffold were prepared utilising a novel method for incorporating the aniline substituents. The pKa values of these species were measured using a bracketing indicator method. The pKa values correlated well with, and showed a strong dependence on, the electronic nature of the substituent (including for those at the ortho position). The second deprotonation of these species was also evaluated, with a similar trend noted.

Antiparasitic Lead Discovery: Toward Optimization of a Chemotype with Activity Against Multiple Protozoan Parasites.

Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis present a significant burden across the developing world. Existing therapeutics for these protozoal neglected tropical diseases suffer from severe side effects and toxicity. Previously, NEU-1045 (3) was identified as a promising lead with cross-pathogen activity, though it possessed poor physicochemical properties. We have designed a library of analogues with improved calculated physicochemical properties built on the quinoline scaffold of 3 incorporating small, polar aminoheterocycles in place of the 4-(3-fluorobenzyloxy)aniline substituent. We report the biological activity of these inhibitors against Trypanosoma brucei (HAT), T. cruzi (Chagas disease), and Leishmania major (cutaneous leishmaniasis) and describe the identification of N-(5-chloropyrimidin-2-yl)-6-(4-(morpholinosulfonyl)phenyl)quinolin-4-amine (13t) as a promising inhibitor of L. major proliferation and 6-(4-(morpholinosulfonyl)phenyl)-N-(pyrimidin-4-yl)quinolin-4-amine (13j), a potent inhibitor of T. brucei proliferation with improved drug-like properties.

ChemInform Abstract: Reactivity and Regioselectivity in the Acylation of 2,4‐Diaminoquinazolines.

Abstract 2-(2-Aminophenyl)quinazoline-4-amines were selectively acylated at the phenylamino group by anhydrides, isocyanates or acyl chlorides, at room temperature. A similar selectivity was obtained in the reaction with ethoxymethylene derivatives and orthoesters. Acylation of the exocyclic imino substituent in the quinazolino-quinazoline tetracyclic structure also occurred under mild conditions with acetic anhydride and isocyanates. Hydrolysis to release the aniline substituent was performed with concd HCl (1 equiv at 60 °C) and with 3 M NaOH (3 equiv, rt), leading to the formylated derivative or cleaving the acyl group in the heterocyclic amine.

4-[5-(Benzofuran-2-yl)-1-phenyl-1H-pyrazol-3-yl]-N,N-dimethylaniline

In the title compound, C25H21N3O, the dihedral angles between the pyrazole ring and its phenyl, aniline and benzofuran (r.m.s. deviation = 0.006 Å) substituents are 47.64 (8), 4.00 (8) and 29.12 (7)°, respectively. The methyl C atoms of the aniline group deviate from their attached ring by 0.521 (3) and 0.010 (3) Å. In the crystal, aromatic π–π stacking between the pyrazole rings [centroid–centroid separation = 3.7899 (9) Å and slippage = 0.66 Å] generates inversion dimers.

Bacteriostatic activities of N-substituted tris-thioureas bearing amino acid and aniline substituents

GRAPHICAL ABSTRACT

Reactivity and regioselectivity in the acylation of 2,4-diaminoquinazolines

2-(2-Aminophenyl)quinazoline-4-amines were selectively acylated at the phenylamino group by anhydrides, isocyanates or acyl chlorides, at room temperature. A similar selectivity was obtained in the reaction with ethoxymethylene derivatives and orthoesters. Acylation of the exocyclic imino substituent in the quinazolino-quinazoline tetracyclic structure also occurred under mild conditions with acetic anhydride and isocyanates. Hydrolysis to release the aniline substituent was performed with concd HCl (1 equiv at 60 °C) and with 3 M NaOH (3 equiv, rt), leading to the formylated derivative or cleaving the acyl group in the heterocyclic amine.