Synthesis,anticancer screening,and in silico ADME prediction of novel 2-pyridones as Pim inhibitors

A novel series of 26 substituted N-(2-ethylphenyl)-2-oxo-pyridine-3-carbonitriles have been designed and synthesized via one-pot synthesis of various aromatic aldehydes, different aromatic acetophenones, and 2-cyano-N-(2-ethylphenyl)acetamide 1 . Moreover, cytotoxicity of the target compounds was evaluated by NCI, which selected 14 compounds for one-dose screening. Among them, compound 21 was selected for five-dose screening, which confirmed its potency against most of cancer cell lines. This compound elicited selectivity profile against human cell line WI-38. Cell cycle analysis was carried out, revealed that compound 21 is an apoptosis inducer causing cell cycle arrest at G2/M. Further exploration on the mode of action by evaluating its effect against Pim-1, Pim-2, and Pim-3 demonstrated its inhibitory effect on Pim-1 and Pim-3 rather than Pim-2. Molecular docking showed that compound 21 binds with high affinity to the active site of Pim-1 enzyme through three hydrogen bonds and two arene-H bonds.     

Isoxazole derivatives of silatrane: synthesis,characterization, in silico ADME profile,prediction of potential pharmacological activity and evaluation of antimicrobial action

A new family of mono- ( 3a-h ) and bis- ( 4a-g ) isoxazole-bridged silatranes has been synthesized by the reaction of 3-aminopropylsilatrane ( 1 ) and 3-substituted 5-chloro-methylisoxazoles ( 2a-h ). The structure of the isoxazole-silatrane hybrids is characterized by elemental analysis, FT-IR, UV, NMR (¹H, ¹³C,²⁹Si and ¹⁵N) spectroscopy, high-resolution mass spectrometry, and X-ray diffraction analysis. The in silico ADME (absorption, distribution, metabolism, excretion) assessment reveals that properties of mono-adducts ( 3a-h ) are similar to those of drugs obeyed to the Lipinski's rule. The calculated screening of potential pharmacological activity profiles (in silico PASS program) of isoxazole-silatranes shows that all synthesized compounds (both mono- and bis-substituted) may have high antitumor action, unlike starting isoxazoles. The preliminary screening of the synthesized silatranes for antimicrobial activity against Enterococcus durans, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa indicates that all test samples are active only against gram-positive microorganisms. Silatrane 3f displays minimal inhibitory concentration (MIC 12.5 and 6.2 μg ml⁻¹) against E. durans and B. subtilis as compared with standard drug gentamicin (MIC 25 and 50 μg ml⁻¹).     

Synthesis, biological evaluation and in silico metabolic and toxicity prediction of some flavanone derivatives

Flavones chemically are anthoxanthins, occur either in the free state or as glycosides associated with tannins (flavanoids). Flavanoids (derivatives of flavone) possess various pharmacological activities and due to its xanthine-oxidase enzyme inhibitory effect it also has superoxide-scavenging activities. A series of 2-phenyl-2,3-dihydrochromon-4-one derivatives (flavanone derivatives) were synthesized from chalcones by cyclization method and their activities were evaluated against some gram positive and gram-negative bacteria. IR, NMR and CHN analysis confirmed the structure of the synthesized compounds. The results of the antibacterial studies shows that compounds 2b, 2e, 2f and 2h possess activity against many bacterial strains. Among that the compound (2h) has remarkable activity against all strains viz. 25 microg/ml inhibitory concentration against S. aureus, S. sonnei, E. coli, S. typhimurium and V. cholerae. Compound 2f possess minimum inhibitory concentration of 200 microg/ml against E. coli and S. typhimurium and 25 microg/ml against S. sonnei, S. dysenteriae and V. cholerae. In silico metabolic and toxicity study of the synthesized compounds were performed and the predicted result showed that the compound having hydroxyl functional group undergo sulfate and O-glucuronide conjugation reaction and methoxy derivatives undergo demethylation reaction. The biologically active compounds are free of toxicity in oncogene, teratogen, sensitivity and immunotoxicity.     

Synthesis,docking and ADME prediction of novel 1,2,3-triazole-tethered coumarin derivatives as potential neuroprotective agents

Research on Chemical Intermediates - In an attempt to find potential neuroprotective agents, a series of novel 3-(1-((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl) methoxyimino)...     

K-means clustering analysis,ADME/pharmacokinetic prediction,MEP, and molecular docking studies of potential cytotoxic agents

Structural Chemistry - In this paper, a combined approach based on a k-means algorithm and statistical analysis has been applied successfully to classify 500 cytotoxic agents using 21 molecular...     

Structure-based computational database screening, in vitro assay, and NMR assessment of compounds that target TAR RNA

There has been little prior effort to discover new drugs on the basis of a unique RNA structure. Binding of the viral transactivator Tat to the 5' bulge of the transactivation response (TAR) element is necessary for HIV-1 replication, so TAR RNA is a superb target. A computational approach was developed to screen a large chemical library for binding to a three-dimensional RNA structure. Scoring function development, flexible ligand docking, and limited target flexibility were essential. From the ranked list of compounds predicted to bind TAR, 43 were assayed for inhibition of the Tat-TAR interaction via electrophoretic mobility shift assays. Eleven compounds (between 0.1 and 1 microM) inhibited the Tat-TAR interaction, and some inhibited Tat transactivation in cells. NMR spectra verified specific binding to the 5' bulge and no interaction with other regions of TAR.     

Synthesis and surface and antimicrobial properties of novel cationic surfactants

A series of surfactants with tuned polarity were prepared, including a new class of compounds: gluco-pyridinium surfactants. Pure anomers were obtained by chromatographic separation. The conductivity and surface tension of surfactant solutions in water were measured, and provided interesting information regarding their aggregation behavior. Peculiarities were observed in the premicellar range. Tensidic parameters correlated with antimicrobial activity. A few parameters, mainly the hydrophobicity of the headgroup, may play a role in finding more efficient antimicrobial structures.     

Linked drug-drug conjugates based on triterpene and phenol structures. Rational synthesis,molecular properties,toxicity and bioactivity prediction

One of the tasks of modern medicinal chemistry is to produce new molecules that have interesting and desired biological effects. In addition, the synthetic procedure for obtaining these compounds should be at least partially smart and rational e.g. “Lego” and green approaches. The study focuses on the synthesis of several hybrid type compounds that are expected to be characterized by beneficial bioactivities. In order to hybridize natural triterpene oleanolic acid and phenol structures, the linker-mode concept was selected. The synthetic goal was achieved in two stages. The first concerns the rapid introduction of the halogenoacidic linker to active phenols selected as a result of microwave-ultrasonic (MW-US) assisted O-alkylation with the use of 2-halogenoacetic acid. The next stage of the synthetic studies involves the reaction of phenoxyacetic acid derivatives obtained containing an active carboxylic group with oleanolic acid/oxime units by the methods typical of triterpene chemistry. Novel linked ester- and iminoester-type triterpene derivatives with phenols (thymol, eugenol, paracetamol, nipagins, naphthols, curcumin and genistein) were obtained and characterized. Additionally, based on the analysis of numerous references and selected methods of computational chemistry (Molinspiration Cheminformatics, Osiris Property Explorer and PASS method) the molecular parameters and the preliminary anti-inflammatory and antinociceptive activity characterising these molecules as potential drugs were calculated and predicted.     

Synthesis,antioxidant and antimicrobial properties of novel pyridyl-carbonyl thiazoles as dendrodoine analogs

Marine compound dendrodoine was first obtained from tunicate species ( Dendrodo grossularia ). It has a five-membered ring, namely, it is a heterocycle thiadiazole, which is found rarely in natural sources . Following its biological activities, novel analogs have been investigated recently. Synthesis of the analogs for this study is realized with uncommon thiazole closure, including methylene-carbonyl condensation. Structures are elucidated by NMR ( ¹ , ¹³ C) and HRMS spectrums. As an alkaloid derivative, antioxidant properties were evaluated with DPPH and FRAP assays and antimicrobial effect with microdilution method. Among the series, 3bc-3cf showed higher antioxidant activity than those having 3 or 4-pyridyl substituents. There is lesser activity for 2-pyridyl activity for 2-pyridyl containing group, which may be a result of intramolecular interactions. No activity was observed against gram-negative bacteria at 250 μg/mL. 3ae and 3ce showed activity at 64 μg/mL against S. aureus and 3ae showed activity at 16 μg/mL against S. epidermidis gram-positive bacteria. Chloramphenicol showed activity against all microorganisms at 8–16 μg/mL. Sixteen original dendrodoine analogs have been defined by close/higher activity compared to dendrodoine analogs and Trolox.     

In silico ADME predictions and in vitro antibacterial evaluation of 2-hydroxy benzothiazole-based 1,3,4-oxadiazole derivatives

In the present work, a library of fifteen 2-hydroxy benzothiazole-linked 1,3,4 -oxadiazole derivatives have been synthesized and confirmed using different analytical techniques. All of the synthesized compounds have been tested for antibacterial and in silico pharmacokinetic studies for the first time. From the ADME predictions, compound 4 showed the highest in silico absorption percentage (86.77%), while most of the compounds showed more than 70% absorption. All of the compounds comply with the Lipinski rule of 5, suggesting that the compounds possess good drug likeness properties upon administration. Furthermore, all of the compounds follow the Veber rule, indicating good bioavailability and good intestinal absorption. The antibacterial results exhibited excellent to moderate activity. Compounds 5 , 9 , 12 , 14 , 15 , 16 , and 17 were the most active compounds against the tested bacterial strains. Compound 14 showed comparable MIC 6.25 ±0.2 μg/disc to the standard drug amoxicillin against the tested Gram-positive bacterial strains. Compounds 5 , 14 , 17 exhibited MIC 12.5 ±0.8 μg/disc, which was comparable to the standard drug against E. faecalis . It can be concluded that the synthesized compound could be used as a lead molecule in the development of new antibacterial agents with high efficacy.     

Synthesis of novel 2,4,6-trisubstituted pyrimidine derivatives and their in vitro antimicrobial activity

A series of novel pyrimidines (6a–6i) has been synthesized from corresponding chalcones and isonicotinimidamide.HCl in the presence of potassium carbonate involving Michael addition followed by cycloaddition. All newly synthesised chalcones and pyrimidines were screened for in vitro antimicrobial activity against various Gram positive, Gram negative bacterial and fungal strains. Most of compounds displayed high antimicrobial activity compared to standard drugs Penicillin, Streptomycin and Ampothericin-B.     

Synthesis,crystal structures,and properties of two novel compounds containing triphosphonate groups

Two novel phosphonate compounds (H₂L)·Hphen (1) and [Ca(HL)(H₂O)]_n·3.5nH₂O (2) (L = N(CH₂PO₃H)₃^3?) were synthesized under hydrothermal conditions. Compound 1 features a chain structure in the ac plane, where HL^2? anions are interconnected through sharing hydrogen ions to form a 1D zigzag type. Compound 2 features a layered structure in the ab plane, which has inorganic calcium cores with the organic part of the phosphonate anions being encircling the cores through coordination actions. The free water molecules can form hydrogen bonds with the coordinated water molecules and phosphonate oxygen atoms, which are able to link the adjacent layers to generate a 3D network structure. In addition, the thermal stability and photoluminescence properties were also studied.     

Synthesis, structural investigation and computational modelling of water-binding aquafoldamers

Detailed studies on water-binding aquafoldamers are presented that illustrate the potential use of the elongated larger aquafoldamers for recognizing larger water clusters of diverse topologies. A novel self-trapping dimerization mode involving two tetramer molecules is proposed, which is consistent with the obtained varying experimental evidences.     

Synthesis and photochromic properties of novel yellow developing photochromic compounds

Two 1-thiazolyl-2-thienylcyclopentene derivatives, 1a and 2a, and a 1-thiazolyl-2-vinylcyclopentene derivative 3a have been synthesized in an attempt to obtain photochromic compounds which change the color from colorless to yellow, and have low photocycloreversion quantum yields and high absorption coefficients of the colored isomers. All of these compounds underwent reversible photochromic reactions. Compounds 1a and 2a in toluene solutions changed the color upon 313 nm light irradiation from colorless to orange and pink, in which absorption maxima were observed at 494 nm (ε=10,000 M⁻¹ cm⁻¹) and 525 nm (ε=8500 M⁻¹ cm⁻¹), respectively. On the other hand, the colorless toluene solution of 3a turned yellow upon irradiation with 313 nm light, in which the absorption maximum was observed at 416 nm (ε=17,100 M⁻¹ cm⁻¹). The photocyclization/cycloreversion quantum yields of 3 were 0.19 and 0.0014, respectively. The conversion from the open- to the closed-ring isomer of 3 in the photostationary state under irradiation with 313 nm light was close to 100%.     

Synthesis of indole-based oxadiazoles and their interaction with bacterial peptidoglycan and SARS-CoV-2 main protease: In vitro,molecular docking and in silico ADME/Tox study

In the present study, Indole-based-oxadiazole (1A-17A) compounds were successfully synthesized. The structures of all synthesized compounds were fully characterized by different sophisticated spectroscopic techniques such 1H NMR, 13C NMR, and HREI-MS. Further, the synthesized compounds were explored to investigate their broad-spectrum antibacterial and antibiofilm potential against multidrug resistant Pseudomonas aeruginosa (MDR-PA) and methicillin resistant Staphylococcus aureus (MRSA). The compounds possessed a broad spectrum of antibacterial activity having MIC values of values 1–8 mg/ml against the tested microorganisms. Compound A6 and A7 shows maximum antibacterial activity against MDR-PA, whereas A6, A7 and A11 shows highest activity against MRSA. Furthermore, antibiofilm assay shows that A6, A7 and A11 showed maximum inhibition of biofilm formation and it was found that at 4 mg/ml; A6, A7 and A11 inhibit MRSA biofilm formation by 81.1, 77.5 and 75.9%, respectively; whereas in case of P. aeruginosa; A6 and A7 showed maximum biofilm inhibition and inhibit biofilm formation by 81.5 and 73.7%, respectively. Molecular docking study showed that compounds A6, A7, A8, A10, and A11 had high binding affinity to bacterial peptidoglycan, indicating their potential inhibitory activity against tested bacteria, whereas A6 and A11 were found to be the most effective inhibitors of SARS CoV-2 main protease (3CLpro), with a binding affinity of ? 7.78 kcal/mol. Furthermore, SwissADME and pkCSM-pharmacokinetics online tools was applied to calculate the ADME/Tox profile of the synthesized compounds and the toxicity of these chemicals was found to be low. The Lipinski, Veber, Ghose, and Consensus LogP criteria were also used to predict drug-likeness levels of the compounds. Our findings imply that the synthesized compounds could be a useful for the preventing and treating biofilm-related microbial infection as well as SARS-CoV2 infections.     

In silico and in vitro assessment of androgen receptor antagonists

There is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart from lifestyle, pollutants are also known to negatively affect the reproductive system. In addition to many other compounds that have been shown to alter androgen signaling, several environmental pollutants are known to disrupt androgen signaling via binding to androgen receptor (AR) or indirectly affecting the androgen synthesis. We analyzed here the molecular mechanism of the interaction between the human AR Ligand Binding Domain (hAR-LBD) and two environmental pollutants, linuron (a herbicide) and procymidone (a pesticide), and compared with the steroid agonist dihydrotestosterone (DHT) and well-known hAR antagonists bicalutamide and enzalutamide. Using molecular docking and dynamics simulations, we showed that the co-activator interaction site of the hAR-LBD is disrupted in different ways by different ligands. Binding free energies of the ligands were also ordered in increasing order as follows: linuron, procymidone, DHT, bicalutamide, and enzalutamide. These data were confirmed by in vitro assays. Reporter assay with MDA-kb2 cells showed that linuron, procymidone, bicalutamide and enzalutamide can inhibit androgen mediated activation of luciferase activity. Gene expression analysis further showed that these compounds can inhibit the expression of prostate specific antigen (PSA) and microseminoprotein beta (MSMB) in prostate cell line LNCaP. Comparative analysis showed that procymidone is more potent than linuron in inhibiting AR activity. Furthermore, procymidone at 10 μM dose showed equivalent and higher activity to AR inhibitor enzalutamide and bicalutamide respectively.     

Synthesis, computational modeling, and properties of benzo-appended BODIPYs

A series of new functionalized mono- and dibenzo-appended BODIPY dyes were synthesized from a common tetrahydroisoindole precursor following two different synthetic routes. Route?A involved the assembly of the BODIPY core prior to aromatization, while in Route?B the aromatization step was performed first. In general, Route?A gave higher yields of the target dibenzo-BODIPYs, due to the ease of aromatization of the BODIPYs compared with the corresponding dipyrromethenes, probably due to their higher stability under the oxidative conditions (2,3-dichloro-5,6-dicyano-1,4-benzoquinone in refluxing toluene). However, due to the slow oxidation of highly electron-deficient BODIPY 3?c bearing a meso-C(6)F(5) group, dibenzo-BODIPY 4?c was obtained, in 35?% overall from dipyrromethane, only by Route?B. Computational calculations performed at the 6-31G(d,p) level are in agreement with the experimental results, showing similar relative energies for all reaction intermediates in both routes. In addition, BODIPY 3?c had the highest molecular electrostatic potential (MEPN), confirming its high electron deficiency and consequent resistance toward oxidation. X-ray analyses of eight BODIPYs and several intermediates show that benzannulation further enhances the planarity of these systems. The π-extended BODIPYs show strong red-shifted absorptions and emissions, about 50-60?nm per benzoannulated ring, at 589-658 and 596-680?nm, respectively. In particular, db-BODIPY 4?c bearing a meso-C(6)F(5) group showed the longest λ(max) of absorption and emission, along with the lowest fluorescence quantum yield (0.31 in CH(2)Cl(2)); on the other hand monobenzo-BODIPY 8 showed the highest quantum yield (0.99) of this series. Cellular investigations using human carcinoma HEp2 cells revealed high plasma membrane permeability for all dibenzo-BODIPYs, low dark- and photo-cytotoxicities and intracellular localization in the cell endoplasmic reticulum, in addition to other organelles. Our studies indicate that benzo-appended BODIPYs, in particular the highly stable meso-substituted BODIPYs, are promising fluorophores for bioimaging applications.     

一种苯并咪唑黄原酸酯的合成及其摩擦学性能

由于操作条件及环境保护的要求日益苛刻,环境友好型润滑油添加剂越来越受到人们的关注,润滑油添加剂向着低灰份、多功能、绿色环保方向发展。本文设计合成了三个环保型含氮硫化合物,采用质谱,红外光谱,元素分析对其结构进行了表征。考察了该类添加剂在菜籽油中的溶解性;采用热重分析对其热稳定性进行了评价;并在四球摩擦磨损试验机上考察了所合成的含氮硫化合物在菜籽油中的摩擦学性能。结果表明,该类添加剂在菜籽油中的溶解度都能达到2%,最低热分解温度为129℃,最高达532℃;在菜籽油中的极压值最高达1186N,是菜籽油的2倍,是ZDDP的1.3倍,抗磨性能最好的是B3,极压值最好的是B2。     

Synthesis,spectral, bioactivity,and NLO properties of chalcone metal complexes

A series of metal(II) complexes ML and ML₂ [where M?=?Cu(II), Co(II), Ni(II), Zn(II), Mn(II), Cd(II), and VO(II); L?=?2-hydroxyphenyl-3-(1H-indol-3-yl)-prop-2-en-1-one (HPIP)] have been prepared and characterized by elemental analysis, magnetic susceptibility, molar conductance, IR, UV-Vis, NMR, Mass, and ESR spectral studies. Conductivity measurements reveal that the complexes are non-electrolytes, except VO(II) complex. Spectroscopy and other data show square pyramidal geometry for oxovanadium and octahedral geometry for the other complexes. Redox behavior of the copper(II) and vanadyl complexes has been studied with cyclic voltammetry. Antimicrobial activities against several microorganisms indicate that a few complexes exhibit considerable activity. The nuclease activity shows that the complexes cleave DNA. All synthesized compounds can serve as potential photoactive materials as indicated from their characteristic fluorescence properties. The second harmonic generation efficiency of the ligand is higher than that of urea and KDP.