Tertiary Amine Moiety Research Articles

Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood-Brain Barrier via Structure-Property Relationship Investigation: Methylenedioxy-Cinnamicamide Containing Tertiary Amine Side Chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 μmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals.

Spontaneous Curvature Induction in an Artificial Bilayer Membrane.

Maintaining lipid asymmetry across membrane leaflets is critical for functions like vesicular traffic and organelle homeostasis. However, a lack of molecular-level understanding of the mechanisms underlying membrane fission and fusion processes in synthetic systems precludes their development as artificial analogs. Here, we report asymmetry induction of a bilayer membrane formed by an extended π-conjugated molecule with oxyalkylene side chains bearing terminal tertiary amine moieties (BA1) in water. Autogenous protonation of the tertiary amines in the periphery of the bilayer by water induces anisotropic curvature, resulting in membrane fission to form vesicles and can be monitored using time-dependent spectroscopy and microscopy. Interestingly, upon loss of the induced asymmetry by extensive protonation using an organic acid restored bilayer membrane. The mechanism leading to the compositional asymmetry in the leaflet and curvature induction in the membrane is validated by density functional theory (DFT) calculations. Studies extended to control molecules having changes in hydrophilic (BA2) and hydrophobic (BA3) segments provide insight into the delicate nature of molecular scale interactions in the dynamic transformation of supramolecular structures. The synergic effect of hydrophobic interaction and the hydrated state of BA1 aggregates provide dynamicity and unusual stability. Our study unveils mechanistic insight into the dynamic transformation of bilayer membranes into vesicles.

Spontaneous Curvature Induction in an Artificial Bilayer Membrane

AbstractMaintaining lipid asymmetry across membrane leaflets is critical for functions like vesicular traffic and organelle homeostasis. However, a lack of molecular‐level understanding of the mechanisms underlying membrane fission and fusion processes in synthetic systems precludes their development as artificial analogs. Here, we report asymmetry induction of a bilayer membrane formed by an extended π‐conjugated molecule with oxyalkylene side chains bearing terminal tertiary amine moieties (BA1) in water. Autogenous protonation of the tertiary amines in the periphery of the bilayer by water induces anisotropic curvature, resulting in membrane fission to form vesicles and can be monitored using time‐dependent spectroscopy and microscopy. Interestingly, upon loss of the induced asymmetry by extensive protonation using an organic acid restored bilayer membrane. The mechanism leading to the compositional asymmetry in the leaflet and curvature induction in the membrane is validated by density functional theory (DFT) calculations. Studies extended to control molecules having changes in hydrophilic (BA2) and hydrophobic (BA3) segments provide insight into the delicate nature of molecular scale interactions in the dynamic transformation of supramolecular structures. The synergic effect of hydrophobic interaction and the hydrated state of BA1 aggregates provide dynamicity and unusual stability. Our study unveils mechanistic insight into the dynamic transformation of bilayer membranes into vesicles.

L-Proline catalyzed multi-component synthesis of N-pyridyl-tetrahydroisoquinolines and their α-C(sp3)-H oxygenation.

Herein, we report an effective multi-component synthesis that starts with readily available starting materials and accesses poly-substituted pyridine derivatives by using L-proline as a benign catalyst. This process uses cyclic amines, aldehydes, and malononitrile in a condensation reaction to produce a variety of pyridine derivatives under mild conditions. Furthermore, depending on the catalysts used, the selective synthesis of an amide and/or an aldehyde functionality is achieved through α-C(sp3)-H oxygenation of the tertiary amine moiety in the resultant pyridine derivatives. The pyridine ring's nitrogen atom plays a crucial role in accelerating C-H oxygenation at the α-position of the tertiary amine, highlighting the synthetic versatility and usefulness of this method.

Biofilm heterogeneity-adaptive photoredox catalysis enables red light-triggered nitric oxide release for combating drug-resistant infections

The formation of biofilms is closely associated with persistent and chronic infections, and physiological heterogeneity such as pH and oxygen gradients renders biofilms highly resistant to conventional antibiotics. To date, effectively treating biofilm infections remains a significant challenge. Herein, we report the fabrication of micellar nanoparticles adapted to heterogeneous biofilm microenvironments, enabling nitric oxide (NO) release through two distinct photoredox catalysis mechanisms. The key design feature involves the use of tertiary amine (TA) moieties, which function as sacrificial agents to avoid the quenching of photocatalysts under normoxic and neutral pH conditions and proton acceptors at acidic pH to allow deep biofilm penetration. This biofilm-adaptive NO-releasing platform shows excellent antibiofilm activity against ciprofloxacin-resistant Pseudomonas aeruginosa (CRPA) biofilms both in vitro and in a mouse skin infection model, providing a strategy for combating biofilm heterogeneity and biofilm-related infections.

Anti-viral, anti-bacterial, but non-cytotoxic nanocoating for reusable face mask with efficient filtration, breathability, and robustness in humid environment

We fabricated a multi-use face mask with anti-bacterial and anti-viral, but non-cytotoxic properties by adding a functional nanocoating on an electrospun nanofiber filter. The nanocoating consists of a copolymer synthesized from dimethyaminomethyl styrene (DMAMS) monomer containing anti-microbial tertiary amine moiety, and a biocompatible crosslinker, ethylene glycol dimethylacrylate (EGDMA). Initiated chemical vapor deposition process is utilized to deposit the nanocoating in order to impart desired functionalities conformally onto the nanofiber filter without deforming its highly porous structure. The synthesized non-cytotoxic copolymer of p(DMAMS-co-EGDMA), or pDE film showed excellent biocidal efficacy of > 99.995% and > 99.985% against Escherichia coli O157: H7 (E. coli O157: H7) and Staphylococcus aureus, respectively. The pDE-coated nanofiber filter shows a filtration efficiency of 91% with extremely low air resistance of ∼ 50 Pa. In highly humid conditions, the pDE-coated nanofiber filter shows long-term anti-microbial efficacy of 99.89% for E. coli O157: H7 up to 168 h, 99.21%, and 99.23% for human influenza virus (H1N1) strain A/Puerto Rico/8/1934 and human beta-coronavirus strain OC43 up to 100 h, without sacrificing breathability, and filtration performance. Furthermore, the surface-modified filter can easily eliminate dead pathogens with a simple water rinse, which enabled the full retention of the filtration efficiency even in six washing cycles, proving excellent reusability. We envision the highly breathable, antimicrobial, multi-use face mask will serve as an environmentally free platform for personal protective equipment against future viral threats.

Tuning fluorescence of dapoxetine by blocking of photoinduced electron transfer (PET): Application in real human plasma.

Photoinduced electron transfer (PET) is the most common mechanism proposed to account for quenching of fluorophores. Herein, the intrinsic fluorescence of dapoxetine (DPX) hydrochloride is in the "OFF" state, owing to the deactivation effect of PET. When the amine moiety is protonated, the fluorescence is restored. Protonation of the nitrogen atom of the tertiary amine moiety in DPX leads to "ON" state of fluorescence due to hindrance of the deactivating effect of PET by protonation of the amine moiety. This permits specific and sensitive determination of DPX in human plasma [lower limit of quantification (LLOQ) = 30.0 ]. The suggested method adopts protonation of DPX using 0.25 M hydrochloric acid in anionic micelles [6.94 mM sodium dodecyl sulfate (SDS)] leads to a marked enhancement of DPX-fluorescence, after excitation at 290 nm.

Structural features localizing the ferroptosis inhibitor GIF-2197-r to lysosomes.

We previously reported that N,N-dimethylaniline derivatives are potent ferroptosis inhibitors. Among them, the novel aminoindan derivative GIF-2197-r (the racemate of GIF-2115 (R-form) and GIF-2196 (S-form)) is effective at a concentration of 0.01 μM due to its localization to lysosomes and ferrous ion coordination capacity. The current study demonstrates that the aliphatic tertiary amine moiety of GIF-2197-r is responsible for lysosomal localization. Although N,N-dimethylaniline derivatives cannot form chelate structures with Fe2+, density functional theory computation demonstrates that they can form stable monodentate complexes with a hydrated ferrous ion, likely due to the highly electron-rich nature of the (dialkylamino)phenyl ring. Furthermore, the results suggest that the aliphatic tertiary amine moiety contributes to stabilizing the complexation. These findings could prove useful for developing improved lysosomotropic ferroptosis inhibitors for neurodegenerative diseases.

Green synthesis of quaternized chitosan nanogel using emulsion-photopolymerization as redox-responsive drug carrier

We report the green synthesis of trimethyl chitosan-functionalized poly(2-hydroxyethyl methacrylate) (PHEMA-TMC) nanogels via surfactant-free emulsion photopolymerization. TMC, a quaternized derivative of chitosan, was synthesized through methylation of chitosan, resulting in quaternary and tertiary amine groups as the main substitution products. TMC tertiary amine moiety and riboflavin (RF) acted as a redox photo-initiating system to generate free radicals for the polymerization under light irradiation. The effects of polymerization parameters such as irradiation time, concentrations of TMC and RF were investigated using MBA as crosslinker. Under the optimal condition of 1 % TMC, 4 % HEMA, 0.8 μM RF, 5 % MBA, and 4 h of polymerization time, the cationic PHEMA-TMC nanogel was synthesized with 76 % monomer conversion and an average diameter of about 106 nm. Moreover, the disulfide-crosslinked PHEMA-TMC nanogel was also synthesized using the disulfide dimethacrylate crosslinker, which exhibited a redox-induced degradation and release of encapsulated melatonin, potentially useful as a redox-responsive drug delivery carrier.

Multifunctionalization of PTFE membrane surface for biofouling resistance and oil/water separation performance improvement

Polytetrafluoroethylene (PTFE) is considered as one of the most promising membrane materials for oil-water separation, mainly because of its excellent chemical and mechanical stability. But its inherent strong hydrophobicity, which can cause the membrane easy fouled by bacteria, limits the application of PTFE membrane. We designed a new surface modification approach, through which hydrophilic and antibacterial PTFE membranes can be fabricated conveniently by combining polymerized dopamine (PDA) and thiolactone chemistries. A copolymer (P(DMAEMA-co-TlaAm)) containing thiolactone and tertiary amine moieties were synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization and attached onto the PDA coated PTFE membrane surface, together with glucosamine, via the thoilactone chemistry. Due to efficient glycosylation, the membrane exhibits great hydrophilicity. Water contact angle of the membrane surface dropped from 123° to 13°. Pure water flux of the membrane reached 2490 L m−2 h−1 bar−1, which is 2.7 times that of the original membrane. Also, the separation efficiency of the iso-paraffin emulsion reached 97.5 % at a membrane flux of 90 L m−2 h−1 bar−1. Notably, in addition to the hydrophilicity provided by glucosamine, the modified membranes also showed decent antibacterial property because of the introduction of tertiary amine groups. The bacteria inhibition rate against Staphylococcus aureus reached 99 %.

The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals

This article reports the outcome of an in silico analysis of more than 12,000 small molecule drugs and drug impurities, identifying the nitrosatable structures, assessing their potential to form nitrosamines under relevant conditions and the challenges to determine compound-specific AIs based on data available or read-across approaches for these nitrosamines and their acceptance by health authorities. Our data indicate that the presence of nitrosamines in pharmaceuticals is likely more prevalent than originally expected. In total, 40.4 % of the analyzed APIs and 29.6 % of the API impurities are potential nitrosamine precursors. Most structures identified through our workflow could form complex API-related nitrosamines, so-called nitrosamine drug substance related impurities (NDSRIs), although we also found structures that could release the well-known small and potent nitrosamines NDMA, NDEA, and others. Due to common structural motifs including secondary or tertiary amine moieties, whole essential drug classes such as beta blockers and ACE inhibitors are at risk. To avoid the risk of drug shortages or even the complete loss of therapeutic options, it will be essential that the well-established ICH M7 principles remain applicable for nitrosamines and that that the industry and regulatory authorities keep an open communication not only about the science but also to make sure there is a good balance between risk and benefit to patients.

A Robust Strategy for Photoinitiated Macromolecular Thiol‐Ene Radical Coupling Reaction with High‐Efficiency Based on a RAFT‐Generated Thiol‐Terminated PDPA Reactant

AbstractThiol‐ene radical coupling reaction exhibits high chemical selectivity and rapid kinetics. In particular, the experiment of photoinitiated reaction has the advantages of facile operation and short reaction time. However, there are few reports on its application in macromolecular thiol‐ene coupling reaction in the presence of polymeric chains containing amine moieties. On the one hand, an amine agent itself may be involved in photoreaction; and on the other hand, amine moieties can create an alkaline environment, which may retard thiol‐ene radical reaction. In this paper, a well‐defined A(B‐L)2 type miktoarm star copolymer unit is investigated and synthesized, together with further A(B‐L)2C type one, by employing macromolecular thiol‐ene radical coupling reactions. In two copolymers, A, B, and C are poly(ε‐caprolactone) (PCL), poly(2‐(diisopropylamino) ethyl methacrylate) (PDPA), and poly(2‐methacryloyloxyethyl phosphorylcholine) (PMPC) arms, respectively, and L is terpyridine (tpy) ligand group and locates at the end of B arm. Especially, the synthesis of A(B‐L)2 type molecular architecture involved that a PDPA reactant (tpy‐PDPA‐SH) contains both a thiol end‐group and pendant tertiary amine moieties. Herein, such a macromolecular thiol‐ene radical coupling reaction is investigated and a robust synthesis strategy is reported.

Chlorination of methotrexate in water revisited: Deciphering the kinetics, novel reaction mechanisms, and unexpected microbial risks

Chlorination of a typical anticancer drug with annually ascending use and global prevalence (methotrexate, MTX) in water has been studied. In addition to the analysis of kinetics in different water/wastewater matrices, high-resolution product identification and in-depth secondary risk evaluation, which were eagerly urged in the literature, were performed. It was found that the oxidation of MTX by free available chlorine (FAC) followed first-order kinetics with respect to FAC and first-order kinetics with respect to MTX. The pH-dependent rate constants (kapp) ranged from 170.00 M−1 s−1 (pH 5.0) to 2.68 M−1 s−1 (pH 9.0). The moiety-specific kinetic analysis suggested that 6 model substructures of MTX exhibited similar reactivity to the parent compound at pH 7.0. The presence of Br− greatly promoted MTX chlorination at pH 5.0–9.0, which may be ascribed to the formation of bromine with higher reactivity than FAC. Comparatively, coexisting I− or humic acid inhibited the degradation of MTX by FAC. Notably, chlorination effectively abated MTX in different real water matrices. The liquid chromatography-high resolution mass spectrometry analysis of multiple matrix-mediated chlorinated samples indicated the generation of nine transformation products (TPs) of MTX, among which seven were identified during FAC oxidation for the first time. In addition to the reported electrophilic chlorination of MTX (the major and dominant reaction pathway), the initial attacks on the amide and tertiary amine moieties with C-N bond cleavage constitute novel reaction mechanisms. No genotoxicity was observed for MTX or chlorinated solutions thereof, whereas some TPs were estimated to show multi-endpoint aquatic toxicity and higher biodegradation recalcitrance than MTX. The chlorinated mixtures of MTX with or without Br− showed a significant ability to increase the conjugative transfer frequency of plasmid-carried antibiotic resistance genes within bacteria. Overall, this work thoroughly examines the reaction kinetics together with the matrix effects, transformation mechanisms, and secondary environmental risks of MTX chlorination.

A new nitrogen rich porous organic polymer for ultra-high CO2 uptake and as an excellent organocatalyst for CO2 fixation reactions

The steady increase in the carbon dioxide (CO2) concentration in the atmosphere is causing serious environmental threats like global warming and climate change. Thus to mitigate this issue, suitable adsorbent cum catalyst for high CO2 capture and its fixation to reactive organics is very much essential. In this context, we have synthesized a new porous cross-linked organic polymer DAT-1 through the radical polymerization of divinylbenzene, triallylamine and 2,4,6-tris(allyloxy)− 1,3,5-triazine. DAT-1 possesses high degree of flexibility, with exceptionally large BET surface area (1105 m2g−1) along with bimodal porosity. Furthermore, due to the presence of triazine unit along with tertiary amine moieties inside the porous architecture of DAT-1 with very rich in basic N-sites could make it as an excellent adsorbent for the unprecedented CO2 capture (73.3 mmol g−1 at 30 bar pressure / 273 K). Further, it exhibits excellent catalytic activity for the conversion of simple terminal epoxides to bio-derived sterically hindered epoxides to cyclic carbonate by utilizing carbon dioxide as C1 resource. Basicity associated with N-rich sites at the surface of the high surface area porous organic polymer is responsible for record CO2 capture and its excellent catalytic activity for the CO2 fixation on epoxides for the synthesis of value added cyclic carbonates.

Integrated CO2 Capture and Hydrogenation to Produce Formate in Aqueous Amine Solutions Using Pd-Based Catalyst

Integrated CO2 capture and hydrogenation to produce formate offers a sustainable approach for reducing carbon dioxide emissions and producing liquid hydrogen carriers (formate) simultaneously. In the current study, three different types of aqueous amine solutions including monoethanolamine (MEA), diethanolamine (DEA) and triethanolamine (TEA) were investigated as CO2-capturing and hydrogenation agents in the presence of a Pd/NAC catalyst. The effect of amine structures on the CO2 absorption products and formate yield was investigated thoroughly. It was found that the formate product was successfully produced in the presence of all three aqueous amine solutions, with tertiary amine TEA accounting for the highest formate yield under the same CO2 loadings. This is due to the fact that primary and secondary amine moieties in MEA and DEA are responsible for the formation of CO2 adducts of carbamate and bicarbonate, whereas the tertiary amine moiety in TEA is responsible for the formation of hydrogenation-favorable bicarbonate as the solo CO2 absorption product. A high yield of formate of 82.6% was achieved when hydrogenating 3 M TEA with 0.3 mol CO2/mol amine solution in the presence of a Pd/NAC catalyst. In addition, the physio-chemical properties of the Pd/NAC catalyst analyzed using TEM, XRD and XPS characterization were applied to rationalize the superior catalytic performance of the catalyst. The reaction mechanism of integrated CO2 capture and hydrogenation to produce formate in aqueous amine solutions over Pd/NAC catalyst was proposed as well.

Simple Phenotypic Sensor for Visibly Tracking H2O2 Fluctuation to Detect Plant Health Status.

Hydrogen peroxide (H2O2), as a main component of reactive oxygen species (ROS), serves as a key signaling molecule relevant to plant stress response and health status. Many strategies have been developed for detecting or quantifying H2O2 concentration. However, reports on simply, visibly tracking H2O2 fluctuation in vivo are limited. Here, for visibly tracking the plant H2O2 wave, a green fluorescent phenotypic probe was designed by merging a H2O2-sensitive tertiary amine moiety with the core fluorophore tetraphenylethene skeleton. The green fluorescence emission is quenched up to 52% by H2O2 with good sensitivity, selectivity, and reversibility within the plant physiological range of 10-100 μM H2O2. In response to various abiotic stresses, including mechanical damage, high salt, strong light and drought, fluorescence fluctuations, response to H2O2 concentration alterations in vivo was visible to the naked eye under irradiation of commercially available UV light (365 nm) after simple injection of this H2O2 probe solution into seedling leaves. This phenotypic fluorescent H2O2 probe illustrates great potential as early sensors of plant health under stress without the aid of skillful operation and specialized equipment.

Acrylamide-Based Pd-Nanoparticle Carriers as Smart Catalysts for the Suzuki–Miyaura Cross-Coupling of Amino Acids

AbstractPolyacrylamide-based waterborne microgels were prepared with copolymerized carboxylic acid and tertiary amine moieties. The colloidal gels were loaded with palladium nanoparticles and utilized for the Suzuki–Miyaura cross-coupling of amino acids and peptides. The thermoresponsive properties of the prepared microgels were characterized by means of photon correlation spectroscopy (PCS) at solvent conditions of the catalytic reaction. The localization and morphology of the incorporated nanoparticles were characterized with transmission electron microscopy (TEM). Palladium-catalyzed Suzuki–Miyaura cross-coupling of N α-Boc-4-iodophenylalanine and N α-Boc-7-bromotryptophan with phenylboronic acid was carried out under ambient atmosphere in water at 20, 37, and 60 °C, respectively. The properties of the thermoresponsive microgel showed a strong influence on the reactivity and selectivity towards the respective substrate. For the amine containing microgels, a recyclability for up to four cycles without loss in activity could be realized. Furthermore, the systems showed good catalytic activity regarding Suzuki–Miyaura cross-coupling of halogenated amino acids in selected tri- and tetrapeptides.

Study on the novel usnic acid derivatives: Design, synthesis, X-Ray crystal structure of Cu(II) complex and anti-AD activities

More and more evidence suggested that bio-metals including iron, zinc and copper play an important role in Alzheimer's disease (AD). Metal chelation agents may play an important role through promoting the metal homeostasis for AD treatment. In this study, UA (usnic acid), a natural product with antioxidant activity and metal chelation sites was selected as a lead compound. Different types of tertiary amine groups were introduced to synthesize four UA derivatives 1–4 as metal chelators and cholinesterase inhibitors since tertiary amine moiety was the key pharmacophore to inhibit cholinesterase. And the related activities such as antioxidant, anti-cholinesterase and metal chelation were evaluated. Results showed that 1–4 displayed excellent anti-oxidant activity, with lowest IC50 of 0.433 µM for ·OH scavenging ability and 8.808 µM for ·O2− scavenging ability. The mechanisms of anti-oxidant activities were furtherly studied by cyclic voltammetry. Besides, 1–4 also showed good anti-cholinesterase activities with lowest IC50 of 0.269 µM for acetylcholinesterase (AChE) and 0.361 µM for butyrylcholinesterase (BuChE). The results of molecular docking with AChE and BuChE were consistent with the experimental results. 1–4 displayed obvious chelating abilities with Cu(II) and Fe(III) by UV–vis spectra analysis and the metal complexes also showed good anti-AD activities. Interestingly, single crystal of Cu(II) complex of the hydrolyzed mono-substituted ligand was obtained which further substantiated the metal binding ability and provided clues to the anti-AD activities of the metal complex. Meanwhile, hydrolysis ratio of 4 was also tested by HPLC. Finally, BBB permeability of 1–4 was acceptable by ADMET prediction. Overall, these findings demonstrated that compounds 1–4 might be considered as potential candidates in the anti-AD therapy.

Ynamide-Mediated Thioamide and Primary Thioamide Syntheses.

Environmentally friendly ynamide-mediated thioamidation of monothiocarboxylic acids with amines or ammonium hydroxide for the syntheses of thioamides and primary thioamides is described. Simple and mild reaction conditions enable the reaction to tolerate a wide variety of functional groups such as hydroxyl group, ester, tertiary amine, ketone, and amide moieties. Readily available NaSH served as the sulfur source, avoiding the use of toxic, expensive, and malodorous organic sulfur reagents and making this strategy environmentally friendly and practical. Importantly, the stereochemical integrity of α-chiral monothiocarboxylic acids was maintained during the activation step and subsequent aminolysis process, thus offering a racemization-free strategy for peptide C-terminal modification. Furthermore, a number of thioamide-modified drugs were prepared in good yields by using this protocol and the synthesized primary thioamides were transformed into backbone thiazolyl modified peptides.