Design and synthesis of new 7, 8-dimethoxy-α-naphthoflavones as CYP1A1 inhibitors

The flavonoids as inhibitors of CYP1Al exhibit chemopreventive effects against certain procarcinogens and have been considered as the promising cancer preventive agents.A series of novel 7,8-dimethoxy-αnaphthoflavones as the substrate analogs were designed and prepared.The enzyme assay suggested that all of these new flavones were stronger inhibitors of CYP1 Al than the lead compoundα-naphthoflavone. Among the tested ones,3h showed the most potent inhibitory effects.     

Molecular insight into the interaction mechanisms of amino‐2H‐imidazole derivatives with BACE1 protease: A QM/MM and QTAIM study

In this study, we described quantitatively the interactions between two new amino‐2H‐imidazole inhibitors ((R)‐1t and (S)‐1m) and BACE1 using a hybrid quantum mechanics‐molecular mechanical (QM/MM) method together with a quantum theory of atoms In Molecules (QTAIM) analysis. Our computational calculations revealed that the binding affinity of these compounds is mostly related to the amino‐2H‐imidazole core, which interact tightly with the aspartate dyad of the active site. The interactions were stronger when the inhibitors presented a bulky substituent with a hydrogen bond acceptor motif pointing toward Trp76, such as the 3,5‐dimethyl‐4‐methoxyphenyl group of compound (S)‐1m. Furthermore, the QTAIM analysis revealed that many hydrophobic interactions complement cooperatively the hydrogen bond which is not present when compound (R)‐1t is bound to the enzyme. The combined QM/MM‐QTAIM analysis allows identifying the interactions that account for the activity difference between compounds, even at a nanomolar range.     

Exploring beta amyloid cleavage enzyme-1 inhibition and neuroprotective role of benzimidazole analogues as anti-alzheimer agents

Beta amyloid cleavage enzyme-1 (BACE1) is the key enzyme involved in Aβ peptide formation in Alzheimer's disease pathogenesis. We intend to target this enzyme by exploring benzimidazole analogues against BACE1 as potential anti-Alzheimer agents. Docking studies were performed to determine the hydrogen bond interactions between the designed molecules and the target protein's active site. Research indicates the relationship between oxidative stress and Aβ effect in precipitating neurodegeneration; hence, the series was also studied in vitro to ascertain its neuroprotective role by performing the lipid peroxidation assay. In silico absorption, distribution, metabolism, and excretion studies were undertaken to assess the drug-like suitability of the analogues. To judge the effect of the synthesized analogues on central nervous system (CNS), toxicity and memory model studies were conducted on mice. Thus, overall results showcase analogues 11 and 14 as the most promising ones with the dual role of BACE1 inhibition and neuroprotection, along with memory retention.     

Bioassay‐guided isolation of an active compound with protein tyrosine phosphatase 1B inhibitory activity from Sargassum fusiforme by high‐speed counter‐current chromatography

A rapid and efficient method using high‐speed counter‐current chromatography was established for the bioassay‐guided separation of an active compound with protein tyrosine phosphatase 1B inhibitory activity from Sargassum fusiforme. Under the bioassay guidance, the ethyl acetate extract with the best IC₅₀ value of 0.37 ± 0.07 μg/mL exhibited a potential protein tyrosine phosphatase 1B inhibitory activity, which was further separated by high‐speed counter‐current chromatography. The separation was performed with a two‐phase solvent system composed of n‐hexane/methanol/water (5:4:1, v/v). As a result, dibutyl phthalate (19.7 mg) with the purity of 95.3% was obtained from 200 mg of the ethyl acetate extract. Its IC₅₀ was 14.05 ± 0.06 μM, which was further explained by molecular docking. The result of molecular docking showed that dibutyl phthalate enfolded in the catalytic site of protein tyrosine phosphatase 1B. The main force between dibutyl phthalate and protein tyrosine phosphatase 1B was the hydrogen bond interaction with Gln266. In addition, hydrogen bond, van der Waals force and hydrophobic interaction with the amino acids (Ala217, Ile219, and Gly220) were also responsible for the stable protein‐ligand complex.     

Pharmacophore modelling,atom-based 3D-QSAR generation and virtual screening of molecules projected for mPGES-1 inhibitory activity

COX-2 inhibitors exhibit anticancer effects in various cancer models but due to the adverse side effects associated with these inhibitors, targeting molecules downstream of COX-2 (such as mPGES-1) has been suggested. Even after calls for mPGES-1 inhibitor design, to date there are only a few published inhibitors targeting the enzyme and displaying anticancer activity. In the present study, we have deployed both ligand and structure-based drug design approaches to hunt novel drug-like candidates as mPGES-1 inhibitors. Fifty-four compounds with tested mPGES-1 inhibitory value were used to develop a model with four pharmacophoric features. 3D-QSAR studies were undertaken to check the robustness of the model. Statistical parameters such as r² = 0.9924, q² = 0.5761 and F test = 1139.7 indicated significant predictive ability of the proposed model. Our QSAR model exhibits sites where a hydrogen bond donor, hydrophobic group and the aromatic ring can be substituted so as to enhance the efficacy of the inhibitor. Furthermore, we used our validated pharmacophore model as a three-dimensional query to screen the FDA-approved Lopac database. Finally, five compounds were selected as potent mPGES-1 inhibitors on the basis of their docking energy and pharmacokinetic properties such as ADME and Lipinski rule of five.     

Synthesis and antioxidant screening of new 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl amide derivatives and some pyrazole-based heterocycles

Abstract

The high functionality compound namely 2-cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acryloyl chloride (1) was utilized as a building block synthon via reactions with some nitrogen and sulfur nucleophilic reagents. The present work was planned to study the effect of 2-cyano group on the reactivity and stability of C₂–C₃ double bond toward different strong-to-weak nucleophiles, in addition to its facility of nucleophilic addition at C₂–C₃ double bond to construct new heterocyclic derivatives. The proclivity toward some mono-, 1,2-, 1,3-, 1,4-, and 1,5-binucleophiles was investigated. The reaction with 2-cyanoacetohydrazide was mainly dependent on the reaction conditions. Some new heterocycles integrated with pyrazole scaffold were successfully synthesized, such as benzoxazinone, indoline, isoindoline, pyrazolone, chromene, and pyrimidopyrimidine derivatives. Some of the newly synthesized compounds were screened for their antioxidant activity using ABTS method, and the results revealed that some compounds exhibited promising inhibitory antioxidant activity.     

Octyl 1‐(5‐tert‐butyl‐1H‐pyrazol‐3‐yl)‐2‐(4‐chlorophenyl)‐1H‐benzimidazole‐5‐carboxylate: complex sheets built from N—H...N,C—H...N and C—H...O hydrogen bonds

In the title compound, C₂₉H₃₅ClN₄O₂, the bond lengths provide evidence for aromatic delocalization in the pyrazole ring but bond fixation in the fused imidazole ring, and the octyl chain is folded, rather than adopting an all‐trans chain‐extended conformation. A combination of N—H...N, C—H...N and C—H...O hydrogen bonds links the molecules into sheets, in which the hydrogen bonds occupy the central layer with the tert‐butyl and octyl groups arranged on either side, such that the closest contacts between adjacent sheets involve only the octyl groups. Comparisons are made with the supramolecular assembly in some simpler analogues.     

4‐Chloro‐1‐naphthol

Molecules of the title compound, C₁₀H₇ClO, (I), are connected by a single strong O—H...O hydrogen bond into a simple C(2) chain, which runs parallel to the c axis and is additionally stabilized by intermolecular π–π stacking interactions. The significance of this study lies in the comparison drawn between the crystal structure of (I) and those of several of its simple analogues. This comparison shows a close similarity in the packing of the molecules that form π‐stacks along the shortest crystallographic axes. A substantial spatial overlap is observed between adjacent molecules in such a π‐stack, depending mainly on the kind of substituent.     

Design,Synthesis, and Insecticidal Activity of 1,5‐Diphenyl‐1‐pentanone Analogues

Three series of novel 1,5‐diphenyl‐1‐pentanone derivatives were designed and synthesized. Their structures were characterized by IR, ¹H NMR techniques, and elemental analysis. The insecticidal activities of the new compounds were preliminarily evaluated. The bioassay results indicated that the compounds X11 – X30 displayed better aphicidal activity against Aphis gossypii than compounds X1 – X10 and the lead compound (E)‐1,5‐diphenyl‐1‐penten‐1‐one ( A ). The inhibitory rates of compounds X6 and X29 were 100% against Plutella xylostella (L.) at 600 mg·L^?1. Compounds X12 , X13, X19 , X24, X25 , X26 and X27 showed higher insecticidal activity against Tetranychus cinnabarinus (Boisduval) at 600 mg·L^?1 than the lead compound ( A ).     

Synthesis and Bioactivity of Substituted Benzoylguanidine Derivatives as Potent Na+/H+ Exchanger Inhibitors

A novel series of substituted benzoylguanidine derivatives were designed and synthesized in order to evaluate their NHE1 inhibitory activity. Most of them were found to inhibit NHE1‐mediated platelet swelling in a concentration‐dependent manner, and eight compounds showed more potent NHE1 inhibitory activity than Cariporide. Compound 6f with an IC₅₀ value of 1.08×10^?10 mol·L^?1, was 39 times more potent than lead compound CPU‐X‐050420 in vitro tests.     

Discovery of novel IDO1 inhibitors via structure-based virtual screening and biological assays

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the first and rate-limiting step in catabolism of tryptophan via the kynurenine pathway, which plays a pivotal role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for many diseases, such as breast cancer, lung cancer, colon cancer, prostate cancer, etc. In this study, docking-based virtual screening and bioassays were conducted to identify novel inhibitors of IDO1. The cellular assay demonstrated that 24 compounds exhibited potent inhibitory activity against IDO1 at micromolar level, including 8 compounds with IC₅₀ values below 10 μM and the most potent one (compound 1) with IC₅₀ of 1.18?±?0.04 μM. Further lead optimization based on similarity searching strategy led to the discovery of compound 28 as an excellent inhibitor with IC₅₀ of 0.27?±?0.02 μM. Then, the structure–activity relationship of compounds 1, 2, 8 and 14 analogues is discussed. The interaction modes of two compounds against IDO1 were further explored through a Python Based Metal Center Parameter Builder (MCPB.py) molecular dynamics simulation, binding free energy calculation and electrostatic potential analysis. The novel IDO1 inhibitors of compound 1 and its analogues could be considered as promising scaffold for further development of IDO1 inhibitors.

     

Comparative Analysis of Hydration Layer Reorientation Dynamics of Antifreeze Protein and Protein Cytochrome P450

Antifreeze proteins (AFPs) inhibit ice recrystallization by a mechanism remaining largely elusive. Dynamics of AFPs' hydration water and its involvement in the antifreeze activity have not been identified conclusively. We herein, by simulation and theory, examined the water reorientation dynamics in the first hydration layer of an AFP from the spruce budworm, Choristoneura fumiferana, compared with a protein cytochrome P450 (CYP). The increase of potential acceptor water molecules around donor water molecules leads to the acceleration of hydrogen bond exchange between water molecules. Therefore, the jump reorientation of water molecules around the AFP active region is accelerated. Due to the mutual coupling and excitation of hydrogen bond exchange, with the acceleration of hydrogen bond exchange, the rearrangement of the hydrogen bond network and the frame reorientation of water are accelerated. Therefore, the water reorientation dynamics of AFP is faster than that of CYP. The results of this study provide a new physical image of antifreeze protein and a new understanding of the antifreeze mechanism of antifreeze proteins.     

Highly sensitive and selective detection of cytochrome P450 46A1 activity by a ultra-high-performance liquid chromatography–tandem mass spectrometry method

Cytochrome P450 46A1 (CYP46A1) is a key enzyme responsible for metabolizing cholesterol to 24-hydroxycholesterol in the brain, and thus might serve as a therapeutic target for several neurodegenerative disorders including Parkinson's disease, Alzheimer's disease and Huntington's disease. However, an applicable, sensitive and reliable method for the precise measurement of CYP46A1 activities in complex biological samples remains limited. In this study, a novel ultra-high-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) method for highly sensitive and selective determination of 24-hydroxycholesterol was developed to characterize CYP46A1 activity. The mass spectrometric detection was performed using multiple reaction monitoring for 24-hydroxcholesterol at m/z 385.2 → 367.2. The limit of quantification for 24-hydroxycholesterol using this UPLC–MS/MS method was as low as 10 nM, which is lower than those reported previously. The method also showed favorable accuracy and precision. Meanwhile, the short- and long-term stability of this method was fully validated. In addition, the method was successfully applied to investigate the kinetic properties of 24-hydroxycholesterol formation by CYP46A1.     

Metal‐Free meta‐Selective Alkyne Oxyarylation with Pyridine N‐Oxides: Rapid Assembly of Metyrapone Analogues

An efficient metal‐free oxyarylation of electron‐poor alkynes with pyridine N‐oxides has been developed. This transformation affords meta‐substituted pyridines analogous to the drug metyrapone in high regioselectivities. Density functional theory (DFT) calculations provided important insight into the mechanism. Evaluation of the inhibitory properties revealed the most active CYP11B1 inhibitor of these derivatives, with two‐digit nanomolar inhibitory activity akin to that of metyrapone.     

益母草碱类似物设计、合成及其Na+/H+交换器-1抑制活性

以中药益母草中有效成分益母草碱为先导化合物,按生物电子等排原理,设计合成了18个益母草碱类似物.通过MS,1H NMR,13C NMR对化合物结构进行表征.初步的药效研究结果表明部分化合物具有Na+/H+交换器-1 (NHE-1)抑制活性,其中化合物1a和1e的活性显著强于阳性对照药Cariporide.     

Sensing cytochrome P450 1A1 activity by a resorufin-based isoform-specific fluorescent probe

Cytochrome P450 1A1 (CYP1A1), a heme-containing monooxygenase, is of particular importance for human health because of its vital roles in the metabolic activation of pro-carcinogenic compounds to the carcinogens. Deciphering the relevance of CYP1A1 to human diseases and screening of CYP1A1 modulators require reliable tool(s) for probing this key enzyme in complex biological matrices. Herein, a practical and ultrasensitive fluorescence-based assay for real-time sensing CYP1A1 activities in biological systems has been developed, via designing an isoform-specific fluorogenic sensor for CYP1A1 (CHPO). The newly developed fluorogenic substrate for CYP1A1 has been carefully investigated in terms of specificity, sensitivity, precision, quantitative linear range and the anti-interference ability. The excellent selectivity, strong anti-interference ability and fast response kinetics, making the practicability of CHPO-based CYP1A1 activity assay is better than that of most reported CYP1A1 activity assays. Furthermore, CHPO has been successfully used for imaging CYP1A1 activities in living cells and human tissues, as well as for high-throughput screening of CYP1A1 inhibitors using tissue preparations as enzyme sources. Collectively, this study provided a practical fluorogenic sensor for real-time sensing CYP1A1 in complex biological systems, which would strongly facilitate the investigations on the relevance of CYP1A1 to human diseases and promote high-throughput screening of CYP1A1 modulators for biomedical applications.     

The mass spectra of benzamide and thiobenzamide

The mass spectra of benzamide, thiobenzamide and their N-d₂ analogues have been studied In addition to fragmenting by simple bond cleavages the molecular ions dissociate partly from their imide forms. Equilibration or ‘scrambling’ of ortho ring hydrogen atoms with amide hydrogen did not occur in benzamide but such exchange must take place in the thiocompound whose fragmentation behaviour is very complex. Neither labelled compound produced the label-retaining benzoyl (thiobenzoyl) cation which has been the subject of much interest in the mass spectrum of O-d₁ benzoic acid.     

Rapid Total Synthesis of Cyclic Lipodepsipeptides as a Premise to Investigate their Self‐Assembly and Biological Activity

A rapid and efficient total synthesis is reported for the cyclic lipodepsipeptide pseudodesmin A. This member of the Pseudomonas viscosin group is active against Gram‐positive bacteria and features self‐assembling properties. A conserved serine residue within the lactone macrocycle is exploited for initial immobilization on 2‐chlorotrityl chloride resin through ether formation with the side‐chain alcohol. Subsequent elongation proceeds through Fmoc solid‐phase peptide synthesis, including automated incorporation of the enantioselectively synthesized (R)‐3‐hydroxydecanoic acid lipid tail. Following esterification to generate the incipient lactone bond, the macrocycle is formed by on‐resin head‐to‐tail macrolactamization and cleaved from the resin to give the desired compound in good purity. The short and efficient synthesis route allows rapid generation of analogues by facile variation of both the peptide and lipid moieties with good control of epimerization while maximizing automation. Synthesis of the pseudodesmin A enantiomer yields identical self‐assembly and biological activity to that observed for the natural compound, showing that activity is not mediated by chiral interactions. A D ‐Asn8 analogue developed en route retains self‐assembly, but loses activity. The synthesis strategy should be generally applicable for the rapid generation of analogues from various cyclic lipodepsipeptide groups, allowing an investigation of their self‐assembling properties and structure–activity relationships.