Morpholine Moiety Research Articles

N-Heterocyclic Compounds, In silico Molecular Docking Studies, and In vitro Enzyme Inhibition Effect against Acetylcholinesterase Inhibitors.

This work contains the synthesis of seven new N-heterocyclic compounds bearing imidazole, benzimidazole, pyridine, and morpholine moieties. We aimed to synthesize N-heterocyclic compounds for a more effective drug candidate to increase the amount of acetylcholine in synapses in Alzheimer's disease. All compounds were characterized by 1H NMR, 13C NMR, FTIR and elemental analysis. Enzyme inhibition activity of all compounds against acetylcholinesterase was investigated, which is an indirect treatment for Alzheimer's. Molecular docking was applied to estimate the binding energy of these compounds to the acetylcholinesterase. All compounds were synthesized from reactions of 2 equivalents of N-heterocyclic starting material and 1 equivalent of 4,4'-bis(chloromethyl)-1,1'-biphenyl. The inhibition parameters of IC50 and Ki were calculated by the spectrophotometric method. AutoDock4 was used to define the binding pose of the compounds. Ki values were found in the range of 80.03 ± 19.64 to 5014.98 ± 1139.60 nM for AChE as an enzyme inhibition strategy, which is an important parameter for the treatment of neurodegenerative such as Alzheimer's disease. In this study, molecular docking is exerted to predict the binding energy of heterocyclic compounds (especially 2, 3, and 5) against acetylcholinesterase enzyme. Their docking binding energies are in good agreement with experimental findings. These new syntheses are drugs that can be used as AChE inhibitors in Alzheimer's disease.

Lysosome-targeted fluorescence probe for discriminating cysteine from homocysteine/glutathione and assessing autophagy in drug-induced liver injury

Autophagy inhibition is an early cause of drug-induced liver injury (DILI). Cysteine (Cys) levels in lysosomes are associated with autophagy. Detecting Cys in lysosomes visually is a new requirement for DILI early diagnosis and efficacy assessment. Hence, the development of excellent fluorescent probes that can detect Cys in lysosomes with reliability, selectivity, and sensitivity is needed. In this work, a lysosome-targeted fluorescent probe LTCP for discriminating Cys from Hcy/GSH has been developed based on the sulfonylbenzoxadiazole (SBD) chromophore containing a morpholine moiety. Encounter of LTCP with Cys will trigger a sequential aromatic substitution-rearrangement reaction yielding an amino SBD derivative product and generate an obvious orange response fluorescence (λex/λem: 440/583 nm), while encounter with Hcy/GSH forms an alksulfydryl SBD derivative product via one-step aromatic substitution reaction and elicits a clear different green fluorescence (λex/λem: 400/520 nm). With the help of confocal fluorescence imaging using probe LTCP, an increase of lysosomal Cys level is observed after Rapa activates autophagy, whereas Cys concentration decreases after 3-MA inhibits autophagy in HepG2 cells. Additionally, LTCP was successfully applied for high-fidelity imaging of Cys changes in autophagy during liver injury induced by acetaminophen (APAP).

Discovery of 3-((3-amino-1H-indazol-4-yl)ethynyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (AKE-72), a potent Pan-BCR-ABL inhibitor including the T315I gatekeeper resistant mutant

BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of < 0.5 nM, and 9 nM against BCR-ABLWT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 < 10 nM, TGI = 154 nM). In addition, AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.

Cu(II) and Zn(II) Complexes of New 8-Hydroxyquinoline Schiff Bases: Investigating Their Structure, Solution Speciation, and Anticancer Potential.

We report the synthesis and characterization of three novel Schiff bases (L1-L3) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with amines containing morpholine or piperidine moieties. These were reacted with CuCl2 and ZnCl2 yielding six new coordination compounds, with the general formula ML2, where M = Cu(II) or Zn(II) and L = L1-L3, which were all characterized by analytical, spectroscopic (Fourier transform infrared (FTIR), UV-visible absorption, nuclear magnetic resonance (NMR), or electron paramagnetic resonance (EPR)), and mass spectrometric techniques, as well as by single-crystal X-ray diffraction. In the solid state, two Cu(II) complexes, with L1 and L2, are obtained as dinuclear compounds, with relatively short Cu-Cu distances (3.146 and 3.171 Å for Cu2(L1)4 and Cu2(L2)4, respectively). The free ligands show moderate lipophilicity, while their complexes are more lipophilic. The pKa values of L1-L3 and formation constants of the complex (for ML and ML2) species were determined by spectrophotometric titrations, with the Cu(II) complexes showing higher stability than the Zn(II) complexes. EPR indicated the presence of several species in solution as pH varied and binding modes were proposed. The binding of the complexes to bovine serum albumin (BSA) was evaluated by fluorescence and circular dichroism (CD) spectroscopies. All complexes bind BSA, and as demonstrated by CD, the process takes several hours to reach equilibrium. The antiproliferative activity was evaluated in malignant melanoma cells (A375) and in noncancerous keratinocytes (HaCaT). All complexes display significant cytotoxicity (IC50 < 10 μM) but modest selectivity. The complexes show higher activity than the free ligands, the Cu(II) complexes being more active than the Zn(II) complexes, and approximately twice more cytotoxic than cisplatin. A Guava ViaCount assay corroborated the antiproliferative activity.

Exploration of intramolecular charge transfer in para-substituted nitrobenzofurazan: Experimental and theoretical analyses

The present work aims at exploring the high electrophilic character of 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) toward the morpholine group by an SNAr reaction in acetonitrile or water (thereafter referred to as NBD-Morph). The electron-donating ability of the morpholine causes intra-molecular charge transfer (ICT). In this report, we present a comprehensive study on the optical characteristics using UV–Vis, photoluminescence (cw-PL) and its time-resolved (TR-PL) to determine the properties of the emissive intramolecular charge transfer (ICT) in the NBD-Morph donor–acceptor system. An exhaustive theoretical investigation utilizing the density functional theory (DFT) and its extension TD-DFT methods is an essential complement of experiments to rationalize and understand the molecular structure and related properties. The findings from QTAIM, ELF, and RDG analyses establish that the bonding between morpholine and NBD moieties is of the electrostatic or hydrogen bond type. In addition, the Hirshfeld surfaces have been established to explore the types of interactions. Further, the non-linear optical (NLO) responses of the compound have been examined. The structure–property relationships obtained through the combined experimental and theoretical offer valuable insights for designing efficient NLO material.

Synthesis of tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives linked morpholine moiety as CDK2 inhibitors.

With the aim of developing cyclin-dependent kinase 2 (CDK2) inhibitors with strong antibreast cancer efficacy, new tricyclic and tetracyclic benzo[6,7]cycloheptane derivatives were synthesized. The newly synthesized tri- and tetracyclic derivatives were achieved from the reaction of 4-(4-morpholin-4-yl-phenyl)-1,3,4,5,6,7-hexahydro-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-thione (5) with α-haloketone derivatives as hydrazonyl chlorides, phenacyl bromide derivatives, chloroacetone, and ethyl substituted acetate derivatives. The MCF-7 and MDA-MB-231 breast cancer cell lines were utilized to examine the anticancer properties. Compounds 5 and 8 were shown to be the most effective, with half-maximal inhibitory concentration (IC50 ) values between 5.73 and 9.11 µM, which are on the level with doxorubicin. Mechanistic studies showed that 5 and 8 caused tumor cell death by inducing apoptosis and they also produced cancer arrest in the S phase of the cell cycle. In addition, compounds 5 and 8 showed strong anti-CDK2 action (IC50 = 0.112 and 0.18 µM, respectively) comparable to roscovitine (IC50 = 0.127 µM). Moreover, the docking result demonstrated that derivatives 5 and 8 fit into the CDK2 active site in the proper orientation.

Acidic pH-Triggered Live-Cell Lysosome Specific Tracking, Ratiometric pH Sensing, and Multicolor Imaging by Visible to NIR Switchable Cy-7 Dyes.

We have demonstrated an efficient synthetic route with crystal structures for the construction of acidic pH-triggered visible-to-NIR interchangeable ratiometric fluorescent pH sensors. This bioresponsive probe exhibits pH-sensitive reversible absorption/emission features, low cytotoxicity, a huge 322 nm bathochromic spectral shift with augmented quantum yield from neutral to acidic pH, high sensitivity and selective targeting ability of live-cell lysosomes with ideal pKa , off-to-on narrow NIR absorption/fluorescence signals with high molar absorption coefficient at acidic lysosomal lumen, and in-situ live-cell pH-activated ratiometric imaging of lysosomal pH. Selective staining and ratiometric pH imaging in human carcinoma live-cell lysosomes were monitored by dual-channel confocal laser scanning microscope using a pH-activatable organic fluorescent dye comprising a morpholine moiety for lysosome targeting and an acidic pH openable oxazolidine ring. Moreover, real-time tracking of lysosomes, 3D, and multicolor live-cell imaging have been achieved using the synthesized pH-activatable probe.

Investigation of morpholine isosters for the development of a potent, selective and metabolically stable mTOR kinase inhibitor

Upregulation of mechanistic target of rapamycin (mTOR) signaling drives various types of cancers and neurological diseases. Rapamycin and its analogues (rapalogs) are first generation mTOR inhibitors, and selectively block mTOR complex 1 (TORC1) by an allosteric mechanism. In contrast, second generation ATP-binding site inhibitors of mTOR kinase (TORKi) target both TORC1 and TORC2. Here, we explore 3,6-dihydro-2H-pyran (DHP) and tetrahydro-2H-pyran (THP) as isosteres of the morpholine moiety to unlock a novel chemical space for TORKi generation. A library of DHP- and THP-substituted triazines was prepared, and molecular modelling provided a rational for a structure activity relationship study. Finally, compound 11b [5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine] was selected due its potency and selectivity for mTOR kinase over the structurally related class I phosphoinositide 3-kinases (PI3Ks) isoforms. 11b displayed high metabolic stability towards CYP1A1 degradation, which is of advantage in drug development. After oral administration to male Sprague Dawley rats, 11b reached high concentrations both in plasma and brain, revealing an excellent oral bioavailability. In a metabolic stability assay using human hepatocytes, 11b was more stable than PQR620, the first-in-class brain penetrant TORKi. Compound 11b also displayed dose-dependent anti-proliferative activity in splenic marginal zone lymphoma (SMZL) cell lines as single agent and when combined with BCL2 inhibition (venetoclax). Our results identify the THP-substituted triazine core as a novel scaffold for the development of metabolically stable TORKi for the treatment of chronic diseases and cancers driven by mTOR deregulation and requiring drug distribution also to the central nervous system.

Synthesis, single crystal characterization and anti-AD activities of a novel complex of Cu(II) with in situ formed protonated chrysin derivative ligand

Alzheimer's disease (AD), the most common form of neurodegeneration disorder in adults, is becoming the overwhelming burden on the healthcare and economic system. In this study, chrysin derivative with the morpholine moiety was designed, synthesized and evaluated based on the multi targets directed ligands strategy for the treatment of AD centered with therapeutic attempts to restore metal homeostasis. It selectively coordinated with the important bio-metal ions related AD, especially Cu2+. Notably, single crystals of both 1 and 1-Cu(II) were obtained and the single crystal structures were characterized by X-ray crystal diffraction, which provided a basis to further explore the possible structure-activity relationship at the molecular level. Compound 1 and 1-Cu(II) complex showed potent anti-oxidative activities, with respect to both ·OH and ·O2− scavenging properties In addition, 1 had good inhibitory activity on Aβ1–42 aggregation, and it could target copper dyshomeostasis through extracting Cu2+ from the amyloids. The studies in silico showed that 1 had brain availability and peroral bioavailability. Taken together, compound 1, as the derivative of chrysin, might be a promising advanced lead candidate for the development of new anti-AD drugs and it may provide a useful template for studying the structure-activity relationships of biometal-coordinating drugs.

Water-soluble dual lysosome/mitochondria-targeted fluorescent probe for detection of SO2 in water, food, herb, and live cells

In this paper, we present a new donor-π bridge-acceptor type fluorescent probe, MIB, which bears two organelle-targeted groups, namely positively charged benzothiazole group for mitochondria and morpholine moiety for lysosomes. In aqueous solution, the nucleophilic addition of HSO3- (as SO2 donor) to MIB blocked its long-range π-conjugation and ICT process and resulted in significant optical signal changes (blue-shifted UV absorbance and fluorescence), which enabled colorimetric and ratiometric fluorescent detection of HSO3- with high selectivity and sensitivity (detection limit of 63.15 nM). MIB offers obvious advantages of good water-solubility, fast response time (within 1 min), unique dual lysosome/mitochondria targeting capability and has been applied to the sensing of endogenous and exogenous SO2 in live cells through fluorescent imaging. In addition, the proposed probe has been utilized for the determination of bisulfite in real water, food and herbal medicine samples, showing good recovery (91.45 % − 109.3 %) and precision.

Synthesis of Morpholine-, Piperidine-, and N-Substituted Piperazine-Coupled 2-(Benzimidazol-2-yl)-3-arylquinoxalines as Novel Potent Antitumor Agents.

A novel series of 2-(benzimidazol-2-yl)quinoxalines with three types of pharmacophore groups, namely, piperazine, piperidine, and morpholine moieties, which are part of known antitumor drugs, was designed and synthesized. The compounds have been characterized by NMR and IR spectroscopy, high- and low-resolution mass spectrometry, and X-ray crystallography. 2-(Benzimidazol-2-yl)quinoxalines with N-methylpiperazine substituents showed promising activity against a wide range of cancer lines, without causing hemolysis and showing little cytotoxicity against normal human Wi-38 cells (human fetal lung). A mixture of regioisomers 2-(benzimidazol-2-yl)-3-(4-fluorophenyl)-6(and 7)-(4-methylpiperazin-1-yl)quinoxalines (mri BIQ 13da/14da) showed a highly selective cytotoxic effect against human lung adenocarcinoma (cell line A549) with a half-maximal inhibitory concentration at the level of doxorubicin with a selectivity index of 12. The data obtained by flow cytometry, fluorescence microscopy, and multiparametric fluorescence analysis suggested that the mechanism of the cytotoxic effect of the mri BIQ 13da/14da on A549 cells may be associated with the stopping of the cell cycle in phase S and inhibition of DNA synthesis as well as with the induction of mithochondrial apoptosis. Thus, mri BIQ 13da/14da can be considered as a leading compound deserving further study, optimization, and development as a new anticancer agent.

Acetic Acid Mediated for One-Pot Synthesis of Novel Pyrazolyl s-Triazine Derivatives for the Targeted Therapy of Triple-Negative Breast Tumor Cells (MDA-MB-231) via EGFR/PI3K/AKT/mTOR Signaling Cascades.

Here, we described the synthesis of novel pyrazole-s-triazine derivatives via an easy one-pot procedure for the reaction of β-dicarbonyl compounds (ethylacetoacetate, 5,5-dimethyl-1,3-cyclohexadione or 1,3-cyclohexadionone) with N,N-dimethylformamide dimethylacetal, followed by addition of 2-hydrazinyl-4,6-disubstituted-s-triazine either in ethanol-acetic acid or neat acetic acid to afford a novel pyrazole and pyrazole-fused cycloalkanone systems. The synthetic protocol proved to be efficient, with a shorter reaction time and high chemical yield with broad substrates. The new pyrazolyl-s-triazine derivatives were tested against the following cell lines: MCF-7 (breast cancer); MDA-MB-231 (triple-negative breast cancer); U-87 MG (glioblastoma); A549 (non-small cell lung cancer); PANC-1 (pancreatic cancer); and human dermal fibroblasts (HDFs). The cell viability assay revealed that most of the s-triazine compounds induced cytotoxicity in all the cell lines tested. However, compounds 7d, 7f and 7c, which all have a piperidine or morpholine moiety with one aniline ring or two aniline rings in their structures, were the most effective. Compounds 7f and 7d showed potent EGFR inhibitory activity with IC50 values of 59.24 and 70.3 nM, respectively, compared to Tamoxifen (IC50 value of 69.1 nM). Compound 7c exhibited moderate activity, with IC50 values of 81.6 nM. Interestingly, hybrids 7d and 7f exerted remarkable PI3K/AKT/mTOR inhibitory activity with 0.66/0.82/0.80 and 0.35/0.56/0.66-fold, respectively, by inhibiting their concentrations to 4.39, 37.3, and 69.3 ng/mL in the 7d-treatment, and to 2.39, 25.34 and 57.6 ng/mL in the 7f-treatment compared to the untreated control.

Synthesis, structural investigation and molecular docking studies of pyridinyl tetrahydroisoquinoline, morpholine and piperidine containing schiff's bases

The present work was conducted to synthesize some Schiff's bases derived from pyridinyl tetrahydroisoquinoline, morpholine and piperidine moieties by the condensation reaction of aminobenzaldehyde with various aromatic amines in good to excellent yield. The structures of synthesized compounds were confirmed by 1H NMR, 13C NMR and mass spectra (ESI-MS) data. These compounds also evaluated for their in silico anti-microbial properties by molecular docking studies. Docking studies were carried out by using Argus Lab 4.0.1 software.

New sonochemical reactions of the C60 fullerene with amino alcohols yielding morpholine–C60 adducts

A selective and efficient method for the synthesis of previously unknown mono-adducts of the C60 fullerene with fused morpholine moieties has been developed based on the reaction of C60 with amino alcohols, including biogenic amines (2-aminoethanol, 2-amino-1-phenylethanol, noradrenaline, and adrenaline), in a mixed solvent (toluene/DMF) at room temperature under air and ultrasonication. The radical anion C60 •‒ (g = 2.0004 and ΔH 1/2 = 3.4 G) was detected as a key intermediate by the EPR method upon the synthesis of the C60–morpholine adduct. This intermediate results due to the one-electron transfer from 2-aminoethanol onto the C60 core.

Direct and Sequential Bioactivation of Pemigatinib to a Reactive Iminium Ion Intermediate Culminates in Mechanism‐Based Inactivation of Cytochrome P450 3A

Mechanism‐based inactivation (MBI) is a unique phenomenon in drug metabolism that arises when an enzyme metabolically activates a drug to a chemically reactive intermediate and primes it for irreversible binding, leading to an irrevocable loss of catalytic activity that is only restored upon de novo synthesis of the implicated enzyme. Our laboratory recently established the MBI of cytochrome P450 3A (CYP3A) by the fibroblast growth factor receptor (FGFR) inhibitors erdafitinib and infigratinib. Serendipitously, our preliminary data has also revealed that pemigatinib (PEM) – another clinically approved FGFR1‐3 inhibitor – similarly elicited time‐dependent inhibition of CYP3A. This was rather unexpected as it was previously purported that PEM did not pose any metabolism‐dependent liabilities due to the absence of glutathione‐related conjugates in metabolic profiling experiments conducted in human liver microsomes. Consequently, we posited that PEM is bioactivated by CYP3A to a hard electrophile, thereby allowing it to elude glutathione trapping and detection in the aforementioned reactive metabolite screen. Here, we confirmed that PEM inhibited both CYP3A isoforms in a time‐, concentration‐, and cofactor‐dependent manner consistent with MBI – with KI, kinact, and partition ratio of 8.69 and 11.95 μM, 0.108 and 0.042 min−1, and ~44 and ~47 for CYP3A4 and CYP3A5 respectively, when rivaroxaban was employed as the probe substrate. While the rate of inactivation was diminished by coincubation with an alternative substrate (testosterone) or direct inhibitor of CYP3A (ketoconazole), the inclusion of nucleophilic trapping agents afforded no such protection. Furthermore, the lack of catalytic activity recovery following dialysis and oxidation with potassium ferricyanide coupled with the absence of a spectrally resolvable peak in the Soret region collectively implied that the underlying mechanism of inactivation was not elicited via the formation of pseudoirreversible metabolite‐intermediate complexes. Utilizing cyanide trapping and high‐resolution mass spectrometry, we illuminated the direct and sequential oxidative bioactivation of PEM and its major O‐desmethylated metabolite at its distal morpholine moiety to a reactive iminium ion intermediate that could covalently modify the CYP3A apoprotein and/or prosthetic heme and culminate in its MBI. Finally, structural determinants gleaned from our in silicocovalent docking simulations suggested that the discrepancies in MBI potencies between both CYP3A isoforms might be alluded to the propensity for PEM to interact more favourably with an accessible active‐site serine residue in position 312 of CYP3A4 as compared to CYP3A5. Further physiologically based pharmacokinetic modelling studies are currently underway to better discern the clinical implications of our findings.

Investigation of N-Substituted Morpholine Structures in an Amphiphilic PDMS-Based Antifouling and Fouling-Release Coating.

Biofouling is a major disruptive process affecting the fuel efficiency and durability of maritime vessel coatings. Previous research has shown that amphiphilic coatings consisting of a siloxane backbone functionalized with hydrophilic moieties are effective marine antifouling and fouling-release materials. Poly(ethylene glycol) (PEG) has been the primary hydrophilic component used in such systems. Recently, the morpholine group has emerged as a promising compact alternative in antifouling membranes but is yet to be studied against marine foulants. In this work, the use of morpholine moieties to generate amphiphilicity in a poly(dimethylsiloxane) (PDMS)-based antifouling and fouling-release coating was explored. Two separate coating sets were investigated. The first set examined the incorporation of an N-substituted morpholine amine, and while these coatings showed promising fouling-release properties for Ulva linza, they had unusually high settlement of spores compared to controls. Based on those results, a second set of materials was synthesized using an N-substituted morpholine amide to probe the source of the high settlement and was found to significantly improve antifouling performance. Both coating sets included PEG controls with varying lengths to compare the viability of the morpholine structures as alternative hydrophilic groups. Surfaces were evaluated through a combination of bubble contact angle goniometry, profilometry, X-ray photoelectron spectroscopy (XPS), and marine bioassays against two soft fouling species, U. linza and Navicula incerta, known to have different adhesion characteristics.

Experimental and computational investigation of 3,5-di-tert-butyl-2-(((3-((2-morpholinoethyl)(pyridin-2-ylmethyl) amino)propyl)imino) methyl)phenol and related reduced form as an inhibitor for C-steel

The effect of new compounds containing morpholine moiety including: 3,5-di-tert-butyl-2-(((3-((2-morpholinoethyl)(pyridine-2-ylmethyl)amino)propyl)imino)methyl)phenol (L1) and its reduced form, 3,5-di-tert-butyl-2-(((3-((2-morpholinoethyl)(pyridine-2-ylmethyl)amino)propyl)amino) methyl)phenol (L2) on the corrosion inhibiting of C-steel in 1.0 M HCl and 3.5 wt% NaCl was tested by experimental and computational techniques. The concentration of inhibitor varied in the range of 0.2–2.0 mM. The corrosion behavior of C-steel was investigated using electrochemical techniques, including open circuit potential (OCP), potentiodynamic polarization (Tafel), electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM) inhibitor-free and inhibitor-containing solutions. From the Tafel diagram, the icorr of the C-steel electrode in the 1.0 M hydrochloric acid solution represents the highest value among the other inhibitor-containing solutions. The icorr for C-steel in L1 containing solution decreases gradually from 1.43 × 10−4 to 0.91 × 10−4 A/cm2, with the concentration of L1 increasing from 0.2 to 2.0 mM. Along with the increase of the L2 concentration from 0.2 to 2.0 mM, the icorr is reduced by about 41%. EIS studies demonstrated that the capacitance of the double layer increased by the addition of inhibitors and increasing the resistance of charge transfer, suggesting an improvement of the corrosion protection in inhibitor-containing acidic solution. SEM images confirmed the corrosion results in which inhibitor-containing solution protects the C-steel surface against the attack of species. The results showed that in all solutions containing equivalent concentrations of inhibitors, the reduced form of L1 had a better inhibition efficiency than the L1 inhibitor. Inhibitors, L1 and its reduced form exhibit Langmuir adsorption isotherm, in which monolayer adsorption of inhibitors is carried out on the C-steel electrode. The properties of the studied molecules to be corrosion inhibitors were examined with the Gaussian software program. The calculations of the molecules were made in different methods and basis sets.

Design, synthesis and biological evaluation of novel dual-targeting fluorescent probes for detection of Fe3+ in the lysosomes of hepatocytes mediated by galactose-morpholine moieties

In this work, novel dual-targeting probes composed of galactose and morpholine were designed and synthesized for monitoring Fe3+ levels in the lysosome of hepatocyte. MP-Gal-1, MP-Gal-2 and MP-Gal-3 showed good selectivity and sensitivities toward Fe3+ with the detection limits of 9.40 × 10−8 M, 7.68 × 10−8 M and 7.10 × 10−8 M, respectively. 1:2 stoichiometry is the most likely recognition mode between probe and Fe3+. Low toxic MP-Gal-1, MP-Gal-2 and MP-Gal-3 exhibited favorable hepatic targeting effect in both cell and tissue levels, which was because the galactose group of probe could be recognized by ASGPR overexpressed on the hepatocytes. The hepatocyte-targeting capacity followed MP-Gal-1 < MP-Gal-2 < MP-Gal-3 trend, which was attributed to the galactose cluster effect. MP-Gal-1, MP-Gal-2 and MP-Gal-3 also displayed good lysosomes-targeting capacities, because the basic morpholine moiety of probes could be easily attracted by the acidic lysosome. Therefore, MP-Gal-1, MP-Gal-2 and MP-Gal-3 have good dual targeting capacities (liver and lysosome) and could be used to detect lysosomal Fe3+ in the liver, which is great significant for precise diagnosis and treatment of liver lysosomal iron-related diseases.

Direct and Sequential Bioactivation of Pemigatinib to Reactive Iminium Ion Intermediates Culminates in Mechanism-Based Inactivation of Cytochrome P450 3A.

We recently established the mechanism-based inactivation (MBI) of cytochrome P450 3A (CYP3A) by the fibroblast growth factor receptor (FGFR) inhibitors erdafitinib and infigratinib. Serendipitously, our preliminary data have also revealed that pemigatinib (PEM), another clinically approved FGFR1-3 inhibitor, similarly elicited time-dependent inhibition of CYP3A. This was rather unexpected, as it was previously purported that PEM did not pose any metabolism-dependent liabilities due to the absence of glutathione-related conjugates in metabolic profiling experiments conducted in human liver microsomes. Here, we confirmed that PEM inhibited both CYP3A isoforms in a time-, concentration-, and cofactor-dependent manner consistent with MBI, with inactivator concentration at half-maximum rate constant, maximum inactivation rate constant, and partition ratio of 8.69 and 11.95 μM, 0.108 and 0.042 min-1, and approximately 44 and approximately 47 for CYP3A4 and CYP3A5, respectively. Although the rate of inactivation was diminished by coincubation with an alternative substrate or direct inhibitor of CYP3A, the inclusion of nucleophilic trapping agents afforded no such protection. Furthermore, the lack of catalytic activity recovery following dialysis and oxidation with potassium ferricyanide coupled with the absence of a spectrally resolvable peak in the Soret region collectively implied that the underlying mechanism of inactivation was not elicited via the formation of pseudo-irreversible metabolite-intermediate complexes. Finally, utilizing cyanide trapping and high-resolution mass spectrometry, we illuminated the direct and sequential oxidative bioactivation of PEM and its major O-desmethylated metabolite at its distal morpholine moiety to reactive iminium ion hard electrophilic species that could covalently inactivate CYP3A via MBI. SIGNIFICANCE STATEMENT: This study reports for the first time the covalent MBI of CYP3A by PEM and deciphered its bioactivation pathway involving the metabolic activation of PEM and its major O-desmethylated metabolite to reactive iminium ion intermediates. Following which, a unique covalent docking methodology was harnessed to unravel the structural and molecular determinants underpinning its inactivation. Findings from this study lay the foundation for future investigation of clinically relevant drug-drug interactions between PEM and concomitant substrates of CYP3A.

Linezolid Metabolism Is Catalyzed by Cytochrome P450 2J2, 4F2, and 1B1.

The oxazolidinone antibacterial linezolid has been in clinical use for over 20 years, yet knowledge of the contributions of specific cytochrome (CYP) 450 enzymes to the metabolic clearance of this drug were mostly unknown. In this investigation, it was revealed that three P450 enzymes that had not been previously explored in linezolid metabolism, CYP2J2, CYP4F2, and CYP1B1, catalyzed the 2-hydroxylation and de-ethyleneation of the morpholine moiety of linezolid. The intrinsic clearance for linezolid metabolism in pooled human liver microsomes was low at 0.51 μL/min/mg protein, consistent with its in vivo clearance in humans, and the KM was high (>200 μM). In recombinant human P450 enzymes, a rank order of intrinsic clearance values for linezolid 2-hydroxylation were CYP2J2 ≫ CYP4F2 > CYP2C8 > CYP1B1 ≈ CYP2D6 ≈ CYP3A4 > CYP1A1 > CYP3A5, with nine other P450 enzymes showing no linezolid metabolism. The effect of selective inhibitors for these eight P450 enzymes on linezolid metabolism in pooled human liver microsomes was evaluated to provide estimates of the relative fractional contributions of these enzymes to linezolid metabolism. These experiments suggest that CYP2J2 and CYP4F2 contribute about 50% each to linezolid hepatic metabolism. It is proposed that the oxidative metabolic clearance of linezolid is primarily catalyzed by these two unusual P450 enzymes and that this explains the lack of observation of meaningful effects of common perpetrators of drug interactions on linezolid pharmacokinetics. SIGNIFICANCE STATEMENT: Linezolid is an important antibacterial drug, but the enzymes involved in its oxidative metabolism were unknown. In this study, evidence is shown that supports an important role for two enzymes not frequently associated with the metabolism of drugs: cytochrome P450 2J2 and cytochrome P450 4F2. These observations offer insight to understand the results of clinical drug-drug interaction studies conducted on linezolid.