Basic Moiety Research Articles

UV-Photochemistry of the Disulfide Bond: Evolution of Early Photoproducts from Picosecond X-ray Absorption Spectroscopy at the Sulfur K-Edge.

We have investigated dimethyl disulfide as the basic moiety for understanding the photochemistry of disulfide bonds, which are central to a broad range of biochemical processes. Picosecond time-resolved X-ray absorption spectroscopy at the sulfur K-edge provides unique element-specific insight into the photochemistry of the disulfide bond initiated by 267 nm femtosecond pulses. We observe a broad but distinct transient induced absorption spectrum which recovers on at least two time scales in the nanosecond range. We employed RASSCF electronic structure calculations to simulate the sulfur-1s transitions of multiple possible chemical species, and identified the methylthiyl and methylperthiyl radicals as the primary reaction products. In addition, we identify disulfur and the CH2S thione as the secondary reaction products of the perthiyl radical that are most likely to explain the observed spectral and kinetic signatures of our experiment. Our study underscores the importance of elemental specificity and the potential of time-resolved X-ray spectroscopy to identify short-lived reaction products in complex reaction schemes that underlie the rich photochemistry of disulfide systems.

Discovery and Design of First Benzylamine-Based Ligands Binding to an Unlocked Conformation of the Complement Factor D.

Complement Factor D, a serine protease of the S1 family and key component of the alternative pathway amplification loop, represents a promising target for the treatment of several prevalent and rare diseases linked to the innate immune system. Previously reported FD inhibitors have been shown to bind to the FD active site in its self-inhibited conformation characterized by the presence of a salt bridge at the bottom of the S1 pocket between Asp189 and Arg218. We report herein a new set of small-molecule FD ligands that harbor a basic S1 binding moiety directly binding to the carboxylate of Asp189, thereby displacing the Asp189-Arg218 ionic interaction and significantly changing the conformation of the self-inhibitory loop.

Design and Development of Fluorescent Sensors with Mixed Aromatic Bicyclic Fused Rings and Pyridyl Groups: Solid Mediated Selective Detection of 2,4,6-Trinitrophenol in Water.

For a strategic incorporation of both π-electron-rich moieties and Lewis basic moieties acting as hydrogen bonding recognition sites in the same molecule, two new fluorescent sensors, N,N′-bis(anthracen-9-ylmethyl)-N,N′-bis(pyridin-2-ylmethyl)butane-1,4-diamine (banthbpbn, 1) and N,N′-bis(naphthalen-1-ylmethyl)-N,N′-bis(pyridin-2-ylmethyl)butane-1,4-diamine (bnaphbpbn, 2), have been developed for the selective detection of highly explosive 2,4,6-trinitrophenol (TNP) in water. Each of the two identical ends of these sensors that are linked with a flexible tetra-methylene spacer contains a mixed aromatic bicyclic fused ring (anthracene or naphthalene) and a pyridyl group. These are synthesized via the simple reduced Schiff base chemistry, followed by the nucleophilic substitution reaction under basic conditions in high yields. Both 1 and 2 were characterized by Fourier transform infrared, UV–vis, and NMR (1H and 13C) spectroscopy, and high-resolution mass spectrometry. The bulk phase purity of 1 and 2 and their stability in water were confirmed by powder X-ray diffraction (PXRD). Utilizing the effect of solvents on their emission spectra as determined by fluorescence spectroscopy, spectral responses for 1 and 2 toward various nitro explosives were recorded to determine a detection limit of 0.6 and 1.6 ppm, respectively, for TNP in water via the “turn-off” quenching response. Also, the detailed mechanistic investigation for their mode of action through spectral overlap, lifetime measurements, Stern–Volmer plots, and density functional theory calculations reveals that resonance energy transfer and photoinduced electron transfer processes, and electrostatic interactions are the key aspects for the turn-off response toward TNP by 1 and 2. In addition, the selectivity for TNP has been found to be more in 1 compared to 2. Both exhibit good recyclability and stability after sensing experiments, which is confirmed by PXRD and field-emission scanning electron microscopy.

Selective Low-Energy Carbon Dioxide Adsorption Using Monodisperse Nitrogen-Rich Hollow Carbon Submicron Spheres.

Monodisperse, nitrogen-doped hollow carbon spheres of submicron size were synthesized using hexamethoxymethylmelamine as both a carbon and nitrogen source in a short (1 h) microwave-assisted synthesis. After carbonization at 550 °C, porous carbon spheres with a remarkably high nitrogen content of 37.1% were obtained, which consisting mainly of highly basic pyridinic moieties. The synthesized hollow spheres exhibited high selectivity for carbon dioxide (CO2) over nitrogen and oxygen gases, with a capture capacity up to 1.56 mmol CO2 g-1. The low adsorption enthalpy of the synthesized hollow carbon spheres permits good adsorbent regeneration. Evaluation of the feasibility of scaling up shows their potential for large-scale applications.

Enhanced antibacterial activity of tetramethylguanidinium-conjugated linear polyethylenimine polymers

ABSTRACTIn the present study, varying amounts of tetramethylguanidinium moiety have been conjugated to linear polyethylenimine to obtain linear polyethylenimine-tmg (LPTG) polymers. Incorporation of hydrophobic and highly basic moiety in the polymeric backbone resulted in the significant improvement in the antibacterial activity which was confirmed by zone of inhibition and MIC assays. Further, the results of transmission electron microscopy and confocal studies revealed that the projected LPTG polymers possessed higher antibacterial activity than the native polymer. In addition, these modified polyethylenimine (PEI) polymers were capable of reducing auric chloride into stable gold nanoparticles. These polyamine-stabilized gold nanoparticles can be used in various biomedical applications.

Asymmetric Synthesis of Lysine Analogues with Reduced Basicity, and their Incorporation into Proteasome Inhibitors

Most known β2‐selective proteasome inhibitors suffer from relatively poor cell permeability as the result of a net positive charge caused by the basic moiety at P1. In this paper, we describe the synthesis of oligopeptide vinyl sulfones that contain different amino acids bearing amino groups with reduced basicity at P1 and/or P3. For this, we developed the first enantioselective synthesis of lysine(4‐ene) and lysine(4‐yne). These amino acids, as well as histidine and diaminopropionic‐acid‐glycine, were incorporated at the P1 and/or P3 positions of oligopeptide vinyl sulfones. All inhibitors were found to inhibit β2, but with a loss of potency compared to our most potent and selective β2 inhibitor, LU‐102. These results notwithstanding, our results provide important insights for the future design of β2‐selective proteasome inhibitors.

Synthesis and biological evaluation of NH2-acyl oseltamivir analogues as potent neuraminidase inhibitors

Neuraminidase inhibitors can deter nascent viruses from infecting intact cells by preventing their release from host cells. Herein, a neuraminidase inhibitor 11b absent of basic moieties was discovered in the process of searching for inhibitors targeting 150 cavity. It exhibited potent inhibitions against wild-type neuraminidases from group 1 (H5N1 and H1N1) and group 2 (H7N9) subtypes with IC50 values similar to those of oseltamivir carboxylate. Moreover, 11b showed moderate inhibitions against mutant neuraminidases from H5N1-H274Y and H1N1-H274Y with IC50 values of 2075 nM and 1382 nM, which were inferior to those of oseltamivir carboxylate (6095 nM and 4071 nM). The results were not consistent with the recognized SARs that a basic moiety was an indispensable part of a potent inhibitor.

Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation

Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons.

Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp=2.1, Kp,uu=1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists.

Colorimetric Ion Sensors Based on Polystyrenes Bearing Side Chain Triazole and Donor-Acceptor Chromophores.

Side chain clicked polystyrene derivatives formed by the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction showed colorimetric ion sensing behaviors when donor-acceptor chromophores, prepared by a [2+2] cylcoladdition-retroelectrocyclization between electron-rich alkynes and tetracyanoethylene (TCNE)/7,7,8,8-tetracyanoquinodimethane (TCNQ), were attached to the triazole rings. The metal ion sensing behaviors could be explained according to the theory of hard and soft acids and bases (HSAB). Hard acidic metal ions were mainly recognized by the hard basic anilino-nitrogen moieties, resulting in a decrease in the charge-transfer (CT) bands. In contrast, soft acidic metal ions led to a bathochromic shift in the CT bands due to the selective interactions with the soft basic cyano-nitrogen atoms. With the triazole spacers, more soft (and/or borderline) metal ions were recognized by the donor-acceptor chromophores probably due to more space for the various sized metal ions. The chemodocimetric anion sensing behaviors of the clicked polystyrenes were almost the same as those of the counter polystyrenes without the triazole spacers. Overall, the triazoles in this study do not serve as colorimetric sensor units towards both metal ions and anions, but they are effective spacers between the polymer main chain and ion sensing donor-acceptor side chain chromophores.

Enantiomeric Resolution of (RS)-Naproxen and Application of (S)- Naproxen in the Direct and Indirect Enantioseparation of Racemic Compounds by Liquid Chromatography: A Review.

(S)-Naproxen (Npx), an α-aryl propionic acid derivative, belongs to the class of Non-Steroidal Anti-Inflammatory Drugs and is easily available in pure (S)-form. (S)-Npx has been used as a chiral selector for chromatographic separation of a variety of racemates, using both direct and indirect methods, and has been found to be useful and successful as a basic chiral moiety. This review article describes methods for enantioseparation of (RS)-Npx, development of chiral stationary phases based on (S)-Npx and preparation of novel chiral derivatizing reagents synthesized from (S)-Npx along with their application for enantioseparation of several pharmaceutically important racemates.

Tertiary Amino Group in Cationic Gold Catalyst: Tethered Frustrated Lewis Pairs That Enable Ligand-Controlled Regiodivergent and Stereoselective Isomerizations of Propargylic Esters

The development of novel ligands specifically tailored for homogeneous gold catalysis is essential for a new generation of gold catalysis. In this work, we report the development of remotely functionalized biphenyl-2-ylphosphine ligands based on strategic positioning in cationic gold catalysts of frustrated Lewis pairs (FLP), that is, basic tertiary amine moieties and the acidic gold center. By rationally tuning the location and size of the basic group, these Lewis pairs exhibit little or modest quenching and importantly enable regiodivergent and stereoselective isomerizations of propargylic esters into synthetically versatile dienyl esters under exceptionally mild conditions. Notably, the implementation of the concept of FLP in gold catalysis is rare.

Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M4 (IC50s<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma Kp,uu=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp=5.37mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M1–5, despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan-muscarinic antagonist agents.

Adsorptive denitrogenation of model fuel by functionalized UiO-66 with acidic and basic moieties

Metal-organic frameworks (MOFs) are usually neutral in nature, even though they can be modified by introducing acidic or basic sites for various applications. However, MOFs with both acidic and basic sites are less common and have not been extensively studied. Here, for the first time, we have applied a MOF (UiO-66) containing both basic and acidic surface groups to the adsorptive removal of nitrogen-containing compounds (NCCs) from a model fuel. In order to introduce both acidic and basic sites in a MOF, aminated UiO-66 (UiO-66-NH2) was treated with 1,4-butanesultone to form UiO-66 functionalized with –NH– and –SO3H groups (UiO-66-NH-SO3H). The UiO-66-NH-SO3H MOF, bearing dual functional groups, exhibited much better performance in the removal of indole (IND) compared with the pristine (UiO-66), acidic (UiO-66-SO3H), and basic (UiO-66-NH2) MOFs. The maximum adsorption capacities of UiO-66-NH-SO3H for IND were 1.63 and 2.22 times to that of UiO-66 based on unit weight and surface area of MOFs, respectively. The superior performance of UiO-66-NH-SO3H (among all UiO-66 MOFs investigated) was attributed to the higher availability of H-bond acceptor sites in this material, compared with the other MOFs. Even though UiO-66-NH-SO3H showed lower adsorbed amounts of basic NCCs (such as quinoline, QUI), it exhibited improved adsorption performances at low (<600ppm) QUI concentrations (relevant for industrial applications), due to acid-base interactions. The UiO-66-NH-SO3H adsorbent can be reused several times by washing it with common solvents, such as ethanol. Therefore, MOFs functionalized with both acidic and basic sites, such as UiO-66-NH-SO3H investigated here, might be used in various applications, including adsorption and separation.

Mitigation strategy towards stabilizing the Electrochemical Interface under high CO and H2O containing reformate gas feed

Despite the enhanced CO tolerance of the high temperature polymer electrolyte membrane (HT PEMFC) technology, the synergistic effect of CO and steam in the anodic reformate gas feed was proven to result in serious performance reduction and operation instabilities, due to the dynamic disturbance of the electrochemical interface (EI). In this work a mitigation strategy is presented by controlling the hydrophilicity of the catalytic layer in order to achieve the optimum structure of the EI. The thin and continuous film distribution of the phosphoric acid (PA) inside the catalytic layer (CL) without blocking the pores is the main characteristic property that determines the good quality of the EI. As shown, a hydrophilic catalytic layer is preferable, since the acid, being at any hydration level, will be able to spread over the catalytic surface aiming to the formation of a thin and continuous film so as to maximize the extend of the EI without blocking the pores of the catalytic layer. This facilitates the uninterrupted transport of protons and the fast diffusion of the reacting gases. Herein, this was accomplished by modifying the surface properties of the CL through the anchoring of pyridine moieties on the MWCNTs, which plays the role of the Pt catalyst support. The basic pyridine moieties enhance the hydrophilicity of the nanotubes through the acid (PA)-base (pyridine) interaction so that the contact angle between a PA drop and the catalytic layer is very close to zero. The good affinity of the PA with the pyridine based catalytic layer secures the PA thin film distribution and continuity. More importantly it is not affected even at high hydration levels of the PA, when the partial pressure of steam is increased at values>20kPa. Otherwise, on conventional C supports, hydrated PA has the tendency to shrink and create ganglia leading to the disruption of the EI. The pyridine modified catalytic layers approach Pt surface utilization values as high as 80% as compared to 50% utilization measured for the case of conventional Pt/C catalytic layers.

Reactivity of the parent amido complexes of iridium with olefins: C-NH2 bond formation versus C-H activation.

Herein we report on the different chemical reactivity displayed by two mononuclear terminal amido compounds depending on the nature of the coordinated diene. Hence, treatment of amido-bridged iridium complexes [{Ir(μ-NH2)(tfbb)}3] (1; tfbb = tetrafluorobenzobarrelene) with dppp (dppp = bis(diphenylphosphane)propane) leads to the rupture of the amido bridges forming the mononuclear terminal amido compound [Ir(NH2)(dppp)(tfbb)] (3) in the first stage. On changing the reaction conditions, the formation of a C-NH2 bond between the amido moiety and the coordinated diene is observed and a new dinuclear complex [{Ir(1,2-η2-4-κ-C12H8F4N)(dppp)}2(μ-dppp)] (4) has been isolated. On the contrary, the diiridium amido-bridged complex [{Ir(μ-NH2)(cod)}2] (2; cod = 1,5-cyclooctadiene) in the presence of dppb (dppb = bis(diphenylphosphane)butane) allows the isolation of a mononuclear complex [Ir(1,2,3-η3-6-κ-C8H10)H(dppb)] (5), as a consequence of the extrusion of ammonia. The monitoring of the reaction of 2 with dppb (and dppp) allowed us to detect terminal amido complexes [Ir(NH2)(P-P)(cod)] (P-P = dppb (6), dppp (7)) in solution, as confirmed by an X-ray analysis of 7. Complex 7 was observed to evolve into hydrido species 5 at room temperature. DFT studies showed that C-H bond activation occurs through the deprotonation of one methylene fragment of the cod ligand by the highly basic terminal amido moiety instead of C-H oxidative addition to the Ir(i) center.

(S)-5-ethynyl-anabasine, a novel compound, is a more potent agonist than other nicotine alkaloids on the nematode Asu-ACR-16 receptor

Nematode parasites infect ∼2 billion people world-wide. Infections are treated and prevented by anthelmintic drugs, some of which act on nicotinic acetylcholine receptors (nAChRs). There is an unmet need for novel therapeutic agents because of concerns about the development of resistance. We have selected Asu-ACR-16 from a significant nematode parasite genus, Ascaris suum, as a pharmaceutical target and nicotine as our basic moiety (EC50 6.21 ± 0.56 μM, Imax 82.39 ± 2.52%) to facilitate the development of more effective anthelmintics.We expressed Asu-ACR-16 in Xenopus oocytes and used two-electrode voltage clamp electrophysiology to determine agonist concentration-current-response relationships and determine the potencies (EC50s) of the agonists.Here, we describe the synthesis of a novel agonist, (S)-5-ethynyl-anabasine, and show that it is more potent (EC50 0.14 ± 0.01 μM) than other nicotine alkaloids on Asu-ACR-16. Agonists acting on ACR-16 receptors have the potential to circumvent drug resistance to anthelmintics, like levamisole, that do not act on the ACR-16 receptors.

Assessment of the Blood-Brain Barrier Permeability of Potential Neuroprotective Aurones in Parallel Artificial Membrane Permeability Assay and Porcine Brain Endothelial Cell Models

Previously, several aurone derivatives were identified with promising neuroprotective activities. In developing these compounds to target the central nervous system (CNS), an assessment of their blood-brain barrier (BBB) permeability was performed using in vitro BBB models: parallel artificial membrane permeability assay-BBB which measures passive permeability and primary porcine brain endothelial cell model which enables determination of the involvement of active transport mechanism. Parallel artificial membrane permeability assay-BBB identified most compounds with high passive permeability, with 3 aurones having exceptional Pe values highlighting the importance of basic amine moieties and optimal lipophilicity for good passive permeability. Bidirectional permeability assays with porcine brain endothelial cell showed a significant net influx permeation of the aurones indicating a facilitated uptake mechanism in contrast to donepezil, a CNS drug included in the evaluation which only displayed passive permeation. From pH-dependent permeability assay coupled with data analysis using pCEL-X software, intrinsic transcellular permeability (Po) of a representative aurone 4-3 was determined, considering factors such as the aqueous boundary layer that may hinder accurate in vitro to in vivo correlation. The Po value determined supported the in vivo feasibility of the aurone as a CNS-active compound.

Synthesis of Pyridazine-Based α-Helix Mimetics.

A versatile synthesis of pyridazine-based small molecule α-helix mimetics (A) is presented. Modular C-C, C-N, and C-O bond-forming reactions allow for the inclusion of a variety of aliphatic, basic, aromatic, and heteroaromatic side chain moieties. This robust synthesis is suitable for the preparation of small pyridazine-based libraries.

Is the Formation of Poly-CO2 Stabilized by Lewis Base Moieties in N- and S-Doped Porous Carbon?

The polymerization of CO2 by Lewis basic moieties has been recently proposed to account for the high adsorption ability of N and S-doped porous carbon materials formed from the pyrolysis of sulfur or nitrogen containing polymers in the presence of KOH. Ab initio calculations performed on the ideal CO2 tetramer complex LB-(CO2)4 (LB = NH3, H2O, H2S) showed no propensity for stabilization. A weak association is observed using Lewis acid species bound to oxygen (LA = H+, AlF3, AlH3, B4O6); however, the combination of a Lewis acid and base does allow for the formation of polymerized CO2 (i.e., LB-C(O)O-[C(O)O]n-C(O)O-LA). While the presence of acid moieties in porous carbon is well known, and borate species are experimentally observed in KOH activated porous carbon materials, the low stability of the oligomers calculated herein, is insufficient to explain the reported poly-CO2.