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Cyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25-6981 by the quinolone system and to restrict the conformational flexibility of the aminopropanol substructure in a cyclopentane system. The designed ligands were synthesized in an eight-step sequence starting with terephthalaldehyde (5). Key steps pf the synthesis were the intramolecular Friedel-Crafts acylation of propionic acids 10 to yield the cyclopenta[g]quinolinediones 11 and the Mannich reaction of diketone 11a followed by conjugate addition at the α,β-unsaturated ketone 12a. Although the quinolones 13a, 15a, and 16a contain an H-bond donor group (secondary lactam) as ifenprodil and Ro 25-6981, they show only moderate GluN2B affinity (K i  > 410 nM). However, the introduction of lipophilic substituents at the quinolone N-atom resulted in more than 10-fold increased GluN2B affinity of the benzyl and benzyloxymethyl derivatives cis-13c (K o  = 36 nM) and 13e (K o  = 27 nM). All compounds are selective over the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The benzyl derivative 13c showed six- and threefold selectivity over σ 1 and σ 2 receptors, respectively., (© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Antibiotic resistance is becoming increasingly severe. The development of small molecular antimicrobial peptides is regarded as a promising design strategy for antibiotics. Here, a series of bisphenol derivatives with amphiphilic structures were designed and synthesized as antibacterial agents by imitating the design strategy of antimicrobial peptides. After a series of structural optimizations, lead compound 43 was identified, which exhibited excellent antibacterial activity against Gram-positive bacterial strains (MICs = 0.78-1.56 μg/mL), poor hemolytic activity (HC 50  > 200 μg/mL), and low cytotoxicity (CC 50  > 100 μg/mL). Further biological evaluation results indicated that 43 exerted antibacterial effects by directly destroying bacterial cell membranes and displayed rapid bactericidal properties (within 0.5-1 h), leading to a very low probability of drug resistance. Moreover, in a murine model of corneal infection, 43 exhibited a strong in vivo antibacterial efficacy. These findings indicate that 43 is a promising candidate compound for the treatment of bacterial infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

A series of derivatives of salidroside with mirror isomer glucose and different phenyl moieties were synthesized by Schmidt glycosylation in satisfactory yields, and their antioxidant and anti-inflammatory activities were evaluated by using LPS-induced RAW264.7 cells. One of the synthesized derivatives ʟ-Sal-4, bearing ʟ-glycosyl and -OMe modification at the phenyl ring, exhibited high activity in inhibiting the production of pro-inflammatory cytokines and oxidative stress biomarker MDA as well as in enhancing the activity of SOD enzyme, compared with the natural product and its corresponding ᴅ-enantiomer. Further proteomic analysis suggested that ʟ-Sal-4 exerted its anti-inflammatory activity through metabolic reprogramming. The in vitro activity showed that ʟ-Sal-4 is a potent antioxidant and anti-inflammatory agent. Our finding indicated that the ʟ-glucose-derived salidroside might be a promising lead compound in the development of salidroside derivatives as therapeutic agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Structurally diverse zinc(II) complexes with tripodal tetradentate phenolic-amines of variable substituents in the phenol and amine moieties were synthesized and thoroughly characterized. The two dinuclear [Zn 2 (L 1 ) 2 ](ClO 4 ) 2 ·MeOH (1), [Zn 2 (L 2 ) 2 ](ClO 4 ) 2 (2), and four mononuclear [Zn(L 3 )(H 2 O)]·MeOH (3), [Zn(L 4 )] (4), [Zn(L 5 )] (5) and [Zn(L 6 )] (6) complexes revealed distorted octahedral, trigonal-bipyramidal or tetrahedral geometries. The free HL1 and H2L3-6 ligands, and complexes 1-6 were evaluated for in vitro cytotoxicity against human cancer cell lines (A2780, A2780R, PC-3 and 22Rv1) and normal healthy MRC-5 cells. Overall results revealed high-to-moderate cytotoxicity (with the best IC 50 values for complex 6 ranging from 2.4 to 4.5 μM), which is however, significantly higher than that of the reference drug cisplatin. The moderately active complexes 1-4 showed considerable selectivity on A2780 cells (IC 50 ≈ 16.3-19.5 μM) over MRC-5 ones (with IC 50 >50 μM for 1, 2 and 4, and with IC 50 >25 μM for 3). The complexes 1, 2, and 6 and the ligand H2L6 were chosen for subsequent deeper biological evaluations. Their time-resolved cellular uptake and other cellular effects in A2780 cells were studied, such as cell cycle profile, intracellular ROS production, induction of apoptosis and activation of caspases 3/7. Complexes 1 and 2 caused significant G0/G1 cell cycle arrest in A2780 cells and antioxidant effects at normal conditions. They showed only limited effects on cellular processes connected with cytotoxicity, i.e. induction of apoptosis, depletion of mitochondrial membrane potential, and autophagy. These findings can be at least partly attributed to the low ability of the complexes to enter the A2780 cells and the depression of metabolic activity of the target cancer cells.

Polyphenols from agro-food waste represent a valuable source of bioactive molecules that can be recovered to be used for their functional properties. Another option is to use them as starting material to generate molecules with new and better properties through semi-synthesis. A proanthocyanidin-rich (PACs) extract from avocado peels was used to prepare several semi-synthetic derivatives of epicatechin by acid cleavage in the presence of phenol and thiol nucleophiles. The adducts formed by this reaction were successfully purified using one-step centrifugal partition chromatography (CPC) and identified by chromatographic and spectroscopic methods. The nine derivatives showed a concentration-dependent free radical scavenging activity in the DPPH assay. All compounds were also tested against a panel of pathogenic bacterial strains formed by Listeria monocytogenes (ATCC 7644 and 19115), Staphylococcus aureus (ATCC 9144), Escherichia coli (ATCC 11775 and 25922), and Salmonella enterica (ATCC 13076). In addition, adducts were tested against two no-pathogenic strains, Limosilactobacillus fermentum UCO-979C and Lacticaseibacillus rhamnosus UCO-25A. Overall, thiol-derived adducts displayed antimicrobial properties and, in some specific cases, inhibited biofilm formation, particularly in Listeria monocytogenes (ATCC 7644). Interestingly, phenolic adducts were inactive against all the strains and could not inhibit its biofilm formation. Moreover, depending on the structure, in specific cases, biofilm formation was strongly promoted. These findings contribute to demonstrating that CPC is a powerful tool to isolate new semi-synthetic molecules using avocado peels as starting material for PACc extraction. These compounds represent new lead molecules with antioxidant and antimicrobial activity.

Background: SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors., Methods: Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation in vivo was studied in nude mice after oral administration of LXQ-217., Results: An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3 K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs., Conclusions: Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug., (© 2024 Wiley‐VHCA AG, Zurich, Switzerland.)

Catalytic activation of unstrained and nonpolar C-C bonds remains a largely unmet challenge. Here, we describe our detailed efforts in developing a rhodium-catalyzed hydrogenolysis of unstrained C(aryl)-C(alkyl) bonds in 2,2'-methylenediphenols aided by removable directing groups. Good yields of the monophenol products are obtained with tolerating a wide range of functional groups. In addition, the reaction is scalable, and the catalyst loading can be reduced to as low as 0.5 mol %. Moreover, this method proves to be effective to cleave C(aryl)-C(alkyl) linkages in both models of phenolic resins and commercial novolacs resins. Finally, detailed experimental and computational mechanistic studies show that with C-H activation being a competitive but reversible off-cycle reaction, this transformation goes through a directed C(aryl)-C(alkyl) oxidative addition pathway.

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents., Competing Interests: Declaration of interests The authors declare the following competing financial interest(s): S.J.F. and T.S.S. are inventors of licensed patent applications claiming central nervous system-penetrating prodrugs of nuclear receptor modulators and their uses, including drugs acting on the thyroid hormone receptors. T.S.S., D.B., and B.E. are co-founders of Autobahn Therapeutics, and T.S.S. is a Senior Advisor to Autobahn Therapeutics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Helicobacter pylori urease remains a validated drug target for the eradication of pervasive chronic stomach infection that leads to severe human health diseases such as gastritis and stomach cancer. The increased failure of current treatment protocols because of resistance to broadband antibiotics, severe side effects and low compliance underscore the need for a targeted eradication therapy. Therefore, in the present research, we have developed a new series of acetylphenol-based acyl thioureas that can potentially provide a new template for drug candidates to inhibit urease enzyme. Newly synthesized compounds 7a-j were evaluated for urease inhibitory strength using thiourea as a positive control. In vitro inhibitory results revealed that all the tested compounds were significantly potent than the standard drug. The most active lead 7f competitively inhibited the enzyme and displayed an IC 50 value of 0.054 ± 0.002 μM, a ~413-fold strong inhibitory potential than thiourea (IC 50  = 22.3 ± 0.031 μM). Various insightful structure-activity relationships were developed showing the key structural requirements for potent inhibitory effects. Molecular docking analysis of 7f inside the active pocket of urease suggested several important interactions with amino acid residues such as ILE411, MET637, ARG439, GLN635, ALA636 and ALA440. Finally, pharmacokinetic properties suggested that the tested derivatives are safe to develop as low-molecular-weight drugs to treat ureolytic bacterial infections., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Bakuchiol, a prenylated phenolic monoterpene derived from the fruit of Psoralen corylifolia L. (Buguzhi), is widely used to treat tumors, viruses, inflammation, and bacterial infections. In this study, we designed and synthesized 30 bakuchiol derivatives to identify new anti-inflammatory drugs. The anti-inflammatory activities of the derivatives were screened using lipopolysaccharide-induced RAW264.7 cells. To evaluate the anti-inflammatory activity of the compounds, we measured nitric oxide (NO), interleukin-6, and tumor necrosis factor-α production. Based on the screening results, compound 7a displayed more pronounced activity than bakuchiol and celecoxib. Furthermore, the mechanistic studies indicated that 7a inhibited pro-inflammatory cytokine release, which was correlated with activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway and blockade of the nuclear factor-κB/mitogen-activated protein kinase signaling pathway. The in vivo anti-inflammatory activity in zebrafish indicated that 7a inhibited NO and reactive oxygen species production in a dose-dependent manner. These results indicate that 7a is a potential candidate for development as an anti-inflammatory agent.

Botrytis cinerea is a ubiquitous fungus that affects hundreds of plants, resulting in economic losses to the horticulture and fruit industry. The search for new antifungal agents is a matter of current interest. Thus, in this work a series of geranylated phenols in which the side alkyl chain has been hydrated have been synthesized, and their activity against B. cinerea has been evaluated. The coupling of phenol and geraniol has been accomplished under microwave irradiation obtaining the highest reaction yields in the shortest reaction times. Hydration of the side chain was carried out in dioxane with p -toluenesulfonic acid polymer-bound as the catalyst. All synthesized compounds were tested against B. cinerea using the growth inhibition assay and EC 50 values were determined. The results show that activity depends on the number and nature of functional groups in the phenol ring and hydration degree of the geranyl chain. The most active compound is 1,4-dihydroquinone with one hydroxyl group attached at the end of the alkyl chain. Results from a molecular docking study suggest that hydroxyl groups in the phenol ring and alkyl chain are important in the binding of compounds to the active site, and that the experimental antifungal activity correlates with the number of H-bond that can be formed in the binding site.

The synthesis of inhibitors for oxidative stress-associated destructive processes based on 2 H -imidazole-derived phenolic compounds affording the bifunctional 2 H -imidazole-derived phenolic compounds in good-to-excellent yields was reported. In particular, a series of bifunctional organic molecules of the 5-aryl-2 H -imidazole family of various architectures bearing both electron-donating and electron-withdrawing substituents in the aryl fragment along with the different arrangements of the hydroxy groups in the polyphenol moiety, namely derivatives of phloroglucinol, pyrogallol, hydroxyquinol, including previously unknown water-soluble molecules, were studied. The structural and antioxidant properties of these bifunctional 5-aryl-2 H -imidazoles were comprehensively studied. The redox transformations of the synthesized compounds were carried out. The integrated approach based on single and mixed mechanisms of antioxidant action, namely the AOC, ARC, Folin, and DPPH assays, were applied to estimate antioxidant activities. The relationship "structure-antioxidant properties" was established for each of the antioxidant action mechanisms. The conjugation effect was shown to result in a decrease in the mobility of the hydrogen atom, thus complicating the process of electron transfer in nearly all cases. On the contrary, the conjugation in imidazolyl substituted phloroglucinols was found to enhance their activity through the hydrogen transfer mechanism. Imidazole-derived polyphenolic compounds bearing the most electron-withdrawing functionality, namely the nitro group, were established to possess the higher values for both antioxidant and antiradical capacities. It was demonstrated that in the case of phloroglucinol derivatives, the conjugation effect resulted in a significant increase in the antiradical capacity (ARC) for a whole family of the considered 2 H -imidazole-derived phenolic compounds in comparison with the corresponding unsubstituted phenols. Particularly, conjugation of the polyphenolic subunit with 2,2-dimethyl-5-(4-nitrophenyl)-2 H -imidazol-4-yl fragment was shown to increase ARC from 2.26 to 5.16 (10 4 mol-eq/L). This means that the considered family of compounds is capable of exhibiting an antioxidant activity via transferring a hydrogen atom, exceeding the activity of known natural polyphenolic compounds.

Alkenyl phenols are utilized by nature in the construction of one of the most important biopolymers, lignin. Using similar building blocks, an array of distinct structures can be formed by selective dimerization of the starting phenols to form lignans, neolignans, oxyneolignans, and norlignans. Given the multitude of possible outcomes, many methods have been reported to affect the desired bond formations and access these biologically relevant scaffolds. The most biomimetic of these methods, discussed here, involve the unprotected phenols undergoing oxidative bond formation that proceeds via dehydrogenative coupling. This review aims to place the known literature in context, highlight the progress made toward the synthesis of these important molecules, and recognize the gaps and limitations that still exist.

Three barbiturate squaraine dyes derived from indolenine or benzothiazole, with different barbituric acid derivatives were prepared, characterized and photophysically evaluated by standard spectroscopic methods. As expectable for squaraines, these dyes showed narrow and intense absorption and emission bands in the Vis/NIR region. The interaction of synthesized dyes with bovine and human serum albumins (BSA and HSA) was also evaluated in phosphate buffer (PB). The results revealed that upon the addition of BSA or HSA the complex dye-protein emit more fluorescence, and the emission intensity is directly proportional to the concentration of protein used (0-3.5 µM). The titration tests allowed to calculate the binding constants, in an order of magnitude of 10 4 -10 6 M, as well as the limits of detection and quantification in the nanomolar tens range. All dyes showed a good response to the interaction with both proteins, but the most pronounced envisioning their use as protein labeling was observed for the squaraine dye derived from the indolenine with a 1,3-dimethylbarbituric acid moiety. The molecular docking studies revealed the existence of a binding between the compounds and four sites on the HSA molecule, where one of these four locations is a new binding site with which this series of dye interacts., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Phenols are widespread in nature, being the major components of several plants and essential oils. Natural phenols' anti-microbial, anti-bacterial, anti-oxidant, pharmacological and nutritional properties are, nowadays, well established. Hence, given their peculiar biological role, numerous studies are currently ongoing to overcome their limitations, as well as to enhance their activity. In this review, the functionalization of selected natural phenols is critically examined, mainly highlighting their improved bioactivity after the proper chemical transformations. In particular, functionalization of the most abundant naturally occurring monophenols, diphenols, lipidic phenols, phenolic acids, polyphenols and curcumin derivatives is explored.

Burkholderia gladioli is a Gram-negative bacterium that biosynthesizes a cocktail of potent antimicrobial compounds, including the antifungal phenolic glycoside sinapigladioside. Herein, we report the total synthesis of the proposed structures of gladiosides I and II, two structurally related phenolic glycosides previously isolated from B. gladioli OR1 cultures. Importantly, the physical and analytical data of the synthetic compounds were in significant discrepancies with the natural products suggesting a misassignment of the originally proposed structures. Furthermore, we have uncovered an acid-catalyzed fragmentation mechanism converting the α,β-unsaturated methyl carbamate-containing gladioside II into the aldehyde-containing gladioside I. Our results lay the foundation for the expeditious synthesis of derivatives of these Burkholderia-derived phenolic glycosides, which would enable to decipher their biological roles and potential pharmacological properties., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A series of novel substituted phenyl 1, 3-thiazolidin-4-one sulfonyl derivatives 5 (a-t) were synthesized and screened for their in-vitro anti-microbial and anti-viral activity. The result of the anti-microbial assay demonstrated compounds 5d, 5f, 5g, 5h, 5i, 5j showed prominent inhibitory activity against all the tested Gram-positive and Gram-negative bacterial strains, while compounds 5g, 5j, 5o, 5p, 5q showed significant activity against the entire set of fungal strains as compared to standard drug Ampicillin and Clotrimazole, respectively. The antimicrobial study revealed that compounds having electron-withdrawing groups showed significant antimicrobial potency. The most active antibacterial compound 5j showed potent inhibition of S. aureus DNA Gyrase enzyme as a possible mechanism of action for antimicrobial activity. Moreover, the antiviral testing of selected compounds showed considerable activity against Herpes simplex virus-1(KOS), Herpes simplex virus-2 (G), Herpes simplex virus-1(TK - KOS ACV r ), Vaccinia virus, Human Coronavirus (229E), Reovirus-1, Sindbis virus, Coxsackie virus B4, Yellow Fever virus and Influenza A, B virus. Compounds 5h exhibited low anti-viral activity against HIV-1(strain IIIB) and HIV-2 (strain ROD). The study clearly outlined that synthesized compounds endowed with good antimicrobial property together with considerable antiviral activity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Two new bismuth(III) complexes, [BiL 1 Cl 2 ] (1) and [BiL 2 Cl 2 ] (2), in which L 1 is (2-hydroxy-4-6-di-tert-butylbenzyl-2-pyridylmethyl)amine and L 2 is 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol, were synthesized and characterized by elemental and conductivity analyses, atomic absorption spectrometry, infrared and 1 H NMR spectroscopies. The molecular structure of 1 reveals that the NN'O ligand forms a 1:1 complex with bismuth through coordination via the nitrogen of the aliphatic amine, the nitrogen of the pyridine ring and the oxygen of the phenolate. The coordination sphere is completed with two chloride anions in a distorted square pyramidal geometry. Bismuth exhibits the same coordination mode in compound 2. The cytotoxic activity of 1 and 2 was investigated in a chronic myelogenous leukemia cell line. The complexes are approximately three times more potent than the corresponding free ligands, with the IC 50 values 0.30 and 0.38 μM for complex 1 and 2, respectively. To address the cellular mechanisms underlying cell demise, apoptosis was quantified by flow cytometry analysis. From 0.1 μM, both complexes induce apoptosis and there is a remarkable concentration-dependent increase in the population of cells in apoptosis. The complexes were also evaluated against Gram-positive and Gram-negative bacteria. Both inhibited the bacterial growth in a concentration-dependent way, with remarkable activity in some of the tested strains, for example, complex 2 was more active than its free ligand against all bacterial strains and approximately fourteen times more potent against S. dysenteriae and S. typhimurium., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The cationic Ru-H complex [(C 6 H 6 )(PCy 3 )(CO)RuH] + BF 4 - ( 1 ) was found to be an effective catalyst for the dehydrative C-H coupling reaction of phenols and aldehydes to form 2-alkylphenol products. The coupling reaction of phenols with branched aldehydes selectively formed 1,1-disubstituted benzofurans, while the coupling reaction with salicylaldehydes yielded xanthene derivatives. A normal deuterium isotope effect was observed from the coupling reaction of 3-methoxyphenol with benzaldehyde and 2-propanol/2-propanol- d 8 ( k H / k D = 2.3 ± 0.3). The carbon isotope effect was observed on the benzylic carbon of the alkylation product from the coupling reaction of 3-methoxyphenol with 4-methoxybenzaldehyde (C(3) 1.021(3)) and on both benzylic and ortho -arene carbons from the coupling reaction with 4-trifluorobenzaldehdye (C(2) 1.017(3), C(3) 1.011(2)). The Hammett plot from the coupling reaction of 3-methoxyphenol with para -substituted benzaldehydes p -X-C 6 H 4 CHO (X = OMe, Me, H, F, Cl, CF 3 ) displayed a V-shaped linear slope. Catalytically relevant Ru-H complexes were observed by NMR from a stoichiometric reaction mixture of 1 , 3-methoxyphenol, benzaldehyde, and 2-propanol in CD 2 Cl 2 . The DFT calculations provided a detailed catalysis mechanism featuring an electrophilic aromatic substitution of the aldehyde followed by the hydrogenolysis of the hydroxy group. The calculations also revealed a mechanistic rationale for the strong electronic effect of the benzaldehdye substrates p -X-C 6 H 4 CHO (X = OMe, CF 3 ) in controlling the turnover-limiting step. The catalytic C-H coupling method provides an efficient synthetic protocol for 2-alkylphenols, 1,1-disubstituted benzofurans, and xanthene derivatives without employing any reactive reagents or forming wasteful byproducts.

Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure-activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years., Competing Interests: The authors declare no conflict of interest.

A series of novel dopamine analogs incorporating urea and sulfonamide functional groups was synthesized from 3,4-dimethoxyphenethylamine. The reaction of 3,4-dimethoxyphenethylamine with N,N-dimethylcarbamoyl chloride, followed by the sulfonyl chlorination of the urea derivative, gave benzene-1-sulfonyl chloride 9, which was reacted with NH 3 (aq) or N-alkyl amines to give related sulfonamides. The O-demethylation reaction of the subsequent compounds with BBr 3 afforded four novel phenolic dopamine analogs including sulfonamide and urea in the same structure. The anticholinergic and antioxidant effects of the synthesized compounds were examined. Compound 13 exhibited inhibition at the micromolar level for both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The IC 50 value of 13 was calculated as 298 ± 43 µM for AChE and 321 ± 29 µM for BChE. The antioxidant and antiradical effects of the molecules were investigated by five different methods. Among the synthesized compounds 10-18, the best antioxidant and antiradical activities belong to the phenolic compounds 15-18. Compounds 16 and 18 have a higher reducing power than the standards used, that is, butylated hydroxytoluene, butylated hydroxyanisole, Trolox, and α-tocopherol, for Fe 3+ -Fe 2+ and Cu 2+ -Cu + reducing activities. For the DPPH• radical scavenging method, compounds 16-18 have a much better scavenging power than the standard molecules. In addition, it has been determined by the induced-fit docking method that compound 13 is well-fitted in the active site of the enzymes. ADME studies reveal that the pharmacokinetic and physicochemical properties of all synthesized compounds are within an acceptable range., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Despite the serious public health problem represented by the diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses, there are still no specific licensed antivirals available for their treatment. Here, we examined the potential anti-arbovirus activity of ten di-halogenated compounds derived from L-tyrosine with modifications in amine and carboxyl groups. The activity of compounds on VERO cell line infection and the possible mechanism of action of the most promising compounds were evaluated. Finally, molecular docking between the compounds and viral and cellular proteins was evaluated in silico with Autodock Vina ® , and the molecular dynamic with Gromacs ® . Only two compounds (TDC-2M-ME and TDB-2M-ME) inhibited both ZIKV and CHIKV. Within the possible mechanism, in CHIKV, the two compounds decreased the number of genome copies and in the pre-treatment strategy the infectious viral particles. In the ZIKV model, only TDB-2M-ME inhibited the viral protein and demonstrate a virucidal effect. Moreover, in the U937 cell line infected with CHIKV, both compounds inhibited the viral protein and TDB-2M-ME inhibited the viral genome too. Finally, the in silico results showed a favorable binding energy between the compounds and the helicases of both viral models, the NSP3 of CHIKV and cellular proteins DDC and β2 adrenoreceptor.

Several synthetic approaches (aminomethylation, alkylation, condensation, etc.) have been used to synthesize derivatives based on the sesamol (1), natural phenol. The set of methods, including the study of antioxidant activity (AOA) by the ability to inhibit the initiated oxidation of animal lipids, radical scavenging activity, Fe 2+ -chelation ability, as well as a comparative assessment of membrane-protective activity under the conditions of H 2 O 2 -induced hemolysis of mice red blood cells (RBCs), was used to analyze the antioxidant potential of the synthesized compounds. The synthesized derivatives have demonstrated different activity in the listed test systems, and we have identified compounds which appear to be most promising for a detailed study of their pharmacological properties., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

Introduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance., Methods: Three semi-synthetic series of compounds ( C1-4 , P1-4 , and G1-4 ) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. ( p -coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities., Results: Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC 50 : 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC 50 : 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC 50 values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites., Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study., Competing Interests: The authors reported no conflicts of interest for this work., (© 2021 Abdelgawad et al.)

Twenty-three natural jamunone analogues along with a series of jamunone-based derivatives were synthesized and evaluated for their inhibitory effects against breast cancer (BC) MDA-MB-231 and MCF-7 cells. The preliminary structure-activity relationship revealed that the length of aliphatic side chain and free phenolic hydroxyl group at the scaffold played a vital role in anti-BC activities and the methyl group on chromanone affected the selectivity of molecules against MDA-MB-231 and MCF-7 cells. Among them, jamunone M (JM) was screened as the most effective anti-triple-negative breast cancer (anti-TNBC) candidate with a high selectivity against BC cells over normal human cells. Mechanistic investigations indicated that JM could induce mitochondria-mediated apoptosis and cause G0/G1 phase arrest in BC cells. Furthermore, JM significantly restrained tumor growth in MDA-MB-231 xenograft mice without apparent toxicity. Interestingly, JM could downregulate phosphatidylinositide 3-kinase (PI3K)/Akt pathway by suppressing protein-tyrosine phosphatase 1B (PTP1B) expression. These findings revealed the potential of JM as an appealing therapeutic drug candidate for TNBC.

The electrophotocatalytic heterofunctionalization of arenes is described. Using 2,3-dichloro-5,6-dicyanoquinone (DDQ) under a mild electrochemical potential with visible-light irradiation, arenes undergo oxidant-free hydroxylation, alkoxylation, and amination with high chemoselectivity. In addition to batch reactions, an electrophotocatalytic recirculating flow process is demonstrated, enabling the conversion of benzene to phenol on a gram scale., (© 2021 Wiley-VCH GmbH.)

Phenolics are ubiquitous in nature and have gained immense research attention because of their unique physiochemical properties and widespread industrial use. In recent decades, their accessibility, versatile reactivity, and relative biocompatibility have catalysed research in phenolic-enabled nanotechnology (PEN) particularly for biomedical applications which have been a major benefactor of this emergence, as largely demonstrated by polydopamine and polyphenols. Therefore, it is imperative to overveiw the fundamental mechanisms and synthetic strategies of PEN for state-of-the-art biomedical applications and provide a timely and comprehensive summary. In this review, we will focus on the principles and strategies involved in PEN and summarize the use of the PEN synthetic toolkit for particle engineering and the bottom-up synthesis of nanohybrid materials. Specifically, we will discuss the attractive forces between phenolics and complementary structural motifs in confined particle systems to synthesize high-quality products with controllable size, shape, composition, as well as surface chemistry and function. Additionally, phenolic's numerous applications in biosensing, bioimaging, and disease treatment will be highlighted. This review aims to provide guidelines for new scientists in the field and serve as an up-to-date compilation of what has been achieved in this area, while offering expert perspectives on PEN's use in translational research.

A mononuclear copper(II) complex, [CuL] (1), and a phenolato-bridged trinuclear zinc(II) complex, [Zn3Cl2L2(DMF)2] (2), where L is the deprotonated form of N,N'-bis(4-bromosalicylidene)propane-1,3-diamine (H2L), have been prepared and characterized by elemental analyses, IR and UV-Vis spectroscopy, and single crystal X-ray diffraction. The Cu atom in complex 1 is in square planar coordination, while the terminal and central Zn atoms in complex 2 are in square pyramidal and octahedral coordination, respectively. The antibacterial activities of the complexes have been tested on the bacteria Staphylococcus aureus and Escherichia coli, and the yeast Candida parapsilosis.

Covering: 2005 up to 2020Olive bioactive secoiridoids are recognized as natural antioxidants with multiple beneficial effects on human health. Nevertheless, the study of their biological activity has also disclosed some critical aspects associated with their application. Firstly, only a few of them can be extracted in large amounts from their natural matrix, namely olive leaves, drupes, oil and olive mill wastewater. Secondly, their application as preventive agents and drugs is limited by their low membrane permeability. Thirdly, the study of their biological fate after administration is complicated by the absence of pure analytical standards. Accordingly, efficient synthetic methods to obtain natural and non-natural bioactive phenol derivatives have been developed. Among them, semi-synthetic protocols represent efficient and economical alternatives to total synthesis, combining efficient extraction protocols with efficient catalytic conversions to achieve reasonable amounts of active molecules. The aim of this review is to summarize the semi-synthetic protocols published in the last fifteen years, covering 2005 up to 2020, which can produce natural olive bioactive phenols scarcely available by extractive procedures, and new biophenol derivatives with enhanced biological activity. Moreover, the semi-synthetic protocols to produce olive bioactive phenol derivatives as analytical standards are also discussed. A critical analysis of the advantages offered by semi-synthesis compared to classical extraction methods or total synthesis protocols is also performed.

The present review is aimed at highlighting outlooks for cyclophanic 1,3-diketones as a new type of versatile ligands and building blocks of the nanomaterial for sensing and bioimaging. Thus, the main synthetic routes for achieving the structural diversity of cyclophanic 1,3-diketones are discussed. The structural diversity is demonstrated by variation of both cyclophanic backbones (calix[4]arene, calix[4]resorcinarene and thiacalix[4]arene) and embedding of different substituents onto lower or upper macrocyclic rims. The structural features of the cyclophanic 1,3-diketones are correlated with their ability to form lanthanide complexes exhibiting both lanthanide-centered luminescence and magnetic relaxivity parameters convenient for contrast effect in magnetic resonance imaging (MRI). The revealed structure-property relationships and the applicability of facile one-pot transformation of the complexes to hydrophilic nanoparticles demonstrates the advantages of 1,3-diketone calix[4]arene ligands and their complexes in developing of nanomaterials for sensing and bioimaging.

The maintenance of sufficient but nontoxic pools of metal micronutrients is accomplished through diverse homeostasis mechanisms in fungi. Siderophores play a well established role for iron homeostasis; however, no copper-binding analogs have been found in fungi. Here we demonstrate that, in Aspergillus fumigatus , xanthocillin and other isocyanides derived from the xan biosynthetic gene cluster (BGC) bind copper, impact cellular copper content, and have significant metal-dependent antimicrobial properties. xan BGC-derived isocyanides are secreted and bind copper as visualized by a chrome azurol S (CAS) assay, and inductively coupled plasma mass spectrometry analysis of A. fumigatus intracellular copper pools demonstrated a role for xan cluster metabolites in the accumulation of copper. A. fumigatus coculture with a variety of human pathogenic fungi and bacteria established copper-dependent antimicrobial properties of xan BGC metabolites, including inhibition of laccase activity. Remediation of xanthocillin-treated Pseudomonas aeruginosa growth by copper supported the copper-chelating properties of xan BGC isocyanide products. The existence of the xan BGC in several filamentous fungi suggests a heretofore unknown role of eukaryotic natural products in copper homeostasis and mediation of interactions with competing microbes., Competing Interests: The authors declare no competing interest.

Major lignans of sesame sesamin and sesamolin are benzodioxol--substituted furofurans. Sesamol, sesaminol, its epimers, and episesamin are transformation products found in processed products. Synthetic routes to all lignans are known but only sesamol is synthesized industrially. Biosynthesis of furofuran lignans begins with the dimerization of coniferyl alcohol, followed by the formation of dioxoles, oxidation, and glycosylation. Most genes of the lignan pathway in sesame have been identified but the inheritance of lignan content is poorly understood. Health-promoting properties make lignans attractive components of functional food. Lignans enhance the efficiency of insecticides and possess antifeedant activity, but their biological function in plants remains hypothetical. In this work, extensive literature including historical texts is reviewed, controversial issues are critically examined, and errors perpetuated in literature are corrected. The following aspects are covered: chemical properties and transformations of lignans; analysis, purification, and total synthesis; occurrence in Seseamum indicum and related plants; biosynthesis and genetics; biological activities; health-promoting properties; and biological functions. Finally, the improvement of lignan content in sesame seeds by breeding and biotechnology and the potential of hairy roots for manufacturing lignans in vitro are outlined., Competing Interests: The authors declare no conflict of interest.

In this paper, the synthesis of different bisglucosides is investigated through the reaction of two acetylated glucose units with a diol (or diphenol) in order to develop a versatile molecular platform for the future development of bio-based polymers. A panel of five diols and one diphenol is initially used in order to examine the influence of their chemical skeleton on the reaction yield and both nature and proportion of formed species. Reaction products are identified using 1 H and 13 C NMR spectroscopies completed by MALDI-TOF MS technique. The nucleophilicity of these dihydroxy compounds is identified as being the main factor that governs the reaction characteristics. In particular, the best selectivity is obtained with the use of hydroquinone. Inversely, by-products (oligomers, deacetylated compounds) are observed with the diols defined by higher nucleophilicity despite the choice of stereoselective pathway using acyl protecting groups., (Copyright © 2020. Published by Elsevier Ltd.)

Perfluorinated tetrathiacalix[4]arene was obtained by heating perfluoro- m -xylene with thiourea or 2,5-difluoro-4,6-bis(trifluoromethyl)benzene-1,3-dithiol at 90 °C. Interaction of perfluoro- m -xylene with resorcinol or orcinol under mild conditions and subsequent heating of the mixture with 2,5-difluoro-4,6-bis(trifluoromethyl)benzene-1,3-dithiol leads to polyfluorinated dioxadithiacalix[4]arenes. Triphenyl and pentaphenyl ethers formed by the interaction of perfluoro- m -xylene with resorcinol under heating with thiourea gives polyfluorinated oxathiacalixarenes containing six and five aromatic nuclei, respectively.

Calixarenes, with potential functionalization on the upper and lower rim, have been explored in recent years for the design and construction of anticancer agents in the field of drugs and pharmaceuticals. Herein, optimization of bis [N-(2-hydroxyethyl) aminocarbonylmethoxyl substituted calix [4] arene (CLX-4) using structure-based drug design and traditional medicinal chemistry led to the discovery of series of calix [4]arene carbonyl amide derivatives 5a-5t. Evaluation of the cytotoxicity of 5a-5t employing MTT assay in MCF-7, MDA-MB-231 (human breast cancer cells), HT29 (human colon carcinoma cells), HepG2 (human hepatocellular carcinoma cells), A549 (human lung adenocarcinoma cells) and HUVEC (Human Umbilical Vein Endothelial) cells demonstrated that the most promising compound 5h displayed the most superior inhibitory effect against A549 and MDA-MB-231 cells, which were 3.2 times and 6.8 times of CLX-4, respectively. In addition, the cell inhibition rate (at 10 μM) against normal HUVEC cells in vitro was only 9.6%, indicating the safty of compound 5h. Moreover, compound 5h could inhibit the migration of MDA-MB-231 cell in wound healing assay. Further mechanism studies significantly indicated that compound 5h could block MDA-MB-231 cell cycle arrest in G0/G1 phase by down regulating cyclin D1 and CDK4, and induce apoptosis by up-regulation of Bax, down-regulation of Caspase-3, PARP and Bcl-2 proteins, resulting in the reduction of DNA synthesis and cell division arrest. This work provides worthy of further exploration for the promising calixarene-based anticancer drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Antioxidants is a kind of substances that can effectively inhibit the oxidation reaction of free radicals. There are many chemical components with antioxidant activity in natural products. Sesamol is one of the natural products with antioxidant activity, and it is often used as an antioxidant in food, medicine and other fields. In the present study, sesame was used as the extraction raw material for the extraction and separated of sesamol with antioxidant activity. On this basis, a total 10 of sesamol derivatives were synthesized by two steps reaction with sesamol as starting material. The antioxidant activity of these sesamol derivatives were tested, and the test results showed that these sesamol derivatives had a good antioxidant activity, among them, compound 4d had the best antioxidant activity. Sesamol derivatives can be used as an antioxidant in food, medicine and other fields and it needs a further study., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Small molecules can be physicochemically targeted to the mitochondrial matrix using the lipophilic alkyltriphenylphosphonium (TPP) group. Once in the mitochondria the TPP conjugate can detect or influence processes within the mitochondrial matrix directly. Alternatively, the conjugate can behave as a prodrug, which is activated by release from the TPP group either using an internal or external instruction. Small molecules can be designed that can be used in any cell line, tissue, or whole organism, allow for temporal control, and can be applied in a reversible dose-dependent fashion. An example is the detection and quantification of hydrogen peroxide in mitochondria of whole living organisms by MitoB. Hydrogen peroxide produced within the mitochondrial matrix is involved in signaling and implicated in the oxidative damage associated with aging and a wide range of conditions including cardiovascular disease, neurodegeneration, and cancer. MitoB accumulates in mitochondria and is converted into the exomarker, MitoP, by hydrogen peroxide in the mitochondrial matrix. The hydrogen peroxide concentration is determined from the ratio of MitoP to MitoB after a period of incubation, and this ratio is determined by mass spectrometry using d15-MitoP and d15-MitoB as internal standards. Here we discuss the targeting of small molecules to the mitochondrial matrix using TPP, and describe the synthesis of MitoB and MitoP and the deuterated standards necessary for quantification of hydrogen peroxide in the mitochondrial matrix of whole living organisms.

Salidroside [(2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-hydroxyphenethoxy)tetrahy-dro-2H-pyran-3,4,5-triol] is an antioxidant, anti-inflammatory and neuroprotective agent, but its drug-like properties are unoptimized and its mechanism of actions is uncertain. We synthesized twenty-six novel derivatives of salidroside and examined them in CoCl 2 -treated PC12 cells using MTT assay. pOBz, synthesized by esterifying the phenolic hydroxyl group of salidroside with benzoyl chloride, was one of five derivatives that were more cytoprotective than salidroside, with an EC 50 of 0.038 μM versus 0.30 μM for salidroside. pOBz was also more lipophilic, with log P of 1.44 versus -0.89 for salidroside. Reverse virtual docking predicted that pOBz would bind strongly with monoamine oxidase (MAO) B by occupying its entrance and substrate cavities, and by interacting with the inter-cavity gating residue Ile199 and Tyr435 of the substrate cavity. Enzymatic studies confirmed that pOBz competitively inhibited the activity of purified human MAO-B (K i  = 0.041 μM versus K i  = 0.92 μM for salidroside), and pOBz was highly selective for MAO-B over MAO-A. In vivo, pOBz inhibited cerebral MAO activity after middle cerebral artery occlusion with reperfusion in rats, and it reduced cerebral infarct volume, improved neurological function and NeuN expression, and inhibited complement C3 expression and apoptosis. Our results suggest that pOBz is a structurally novel type of competitive and selective MAO-B inhibitor, with potent neuroprotective properties after cerebral ischemia-reperfusion injury in rats., Competing Interests: Declaration of competing interest The authors declare that no competing financial interests or conflicts of interest are associated with this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The inhibition of δ- and η-class carbonic anhydrases (CAs; EC 4.2.1.1) was poorly investigated so far. Only one δ-CA, TweCA from the diatom Thalassiosira weissflogii, and one η-CA, PfCA, from Plasmodium falciparum , have been cloned and characterised to date. To enrich δ- and η-CAs inhibition profiles, a panel of 22 phenols was investigated for TweCA and PfCA inhibition. Some derivatives showed effective, sub-micromolar inhibition of TweCA (K I s 0.81-65.4 µM) and PfCA (K I s 0.62-78.7 µM). A subset of compounds demonstrated a significant selectivity for the target CAs over the human physiologically relevant ones. This study promotes the identification of new potent and selective inhibitors of TweCA and PfCA , which could be considered as leads for finding molecular probes in the study of carbon fixation processes (in which TweCA and orthologue enzymes are involved) or drug candidates in the treatment of malaria.

: The influence of chirality in calixarene threading has been studied by exploiting the "superweak anion approach". In particular, the formation of chiral pseudo[2]rotaxanes bearing a classical stereogenic center in their axle and/or wheel components has been considered. Two kind of pseudo[2]rotaxane stereoadducts, the " endo -chiral" and " exo -chiral" ones, having the stereogenic center of a cationic axle inside or outside, respectively, the calix-cavity of a chiral calixarene were preferentially formed with specifically designed chiral axles by a fine exploitation of the so-called " endo -alkyl rule" and a newly defined "endo-α-methyl-benzyl rule" ( threading of a hexaalkoxycalix [ 6 ] arene with a directional ( α -methyl-benzyl) benzylammonium axle occurs with an endo - α -methyl-benzyl preference ). The obtained pseudorotaxanes were studied in solution by 1D and 2D NMR, and in the gas-phase by means of the enantiomer-labeled (EL) mass spectrometry method, by combining enantiopure hosts with pseudoracemates of one deuterated and one unlabeled chiral axle enantiomer. In both instances, there was not a clear enantiodiscrimination in the threading process with the studied host/guest systems. Possible rationales are given to explain the scarce reciprocal influence between the guest and host chiral centers., Competing Interests: The authors declare no conflict of interest.

The highly rigid and planar scaffolds with π-conjugated systems have been widely considered to be indispensable for β-amyloid (Aβ) binding ligands. In this study, a library of diphenoxy compounds with different types of more flexible linkers as Aβ ligands were synthesized and evaluated. Most of them displayed good affinity ( K i < 100 nM) for Aβ 1-42 aggregates, and some ligands even showed values of K i less than 10 nM. Structure-activity relationship analysis revealed that modification on the linkers or substituents tolerated great flexibility, which challenged the long-held belief that rigid and planar structures are exclusively favored for Aβ binding. Three ligands were labeled by iodine-125, and they exhibited good properties in vitro and in vivo, which further supported that this flexible scaffold was potential and promising for the development of Aβ imaging agents.

Disulfide bond formation is a critical post-translational modification of newly synthesized polypeptides in the oxidizing environment of the endoplasmic reticulum and is mediated by protein disulfide isomerase (PDIA1). In this study, we report a series of α-aminobenzylphenol analogues as potent PDI inhibitors. The lead compound, AS15 , is a covalent nanomolar inhibitor of PDI, and the combination of AS15 analogues with glutathione synthesis inhibitor buthionine sulfoximine (BSO) leads to synergistic cell growth inhibition. Using nascent RNA sequencing, we show that an AS15 analogue triggers the unfolded protein response in glioblastoma cells. A BODIPY-labeled analogue binds proteins including PDIA1, suggesting that the compounds are cell-permeable and reach the intended target. Taken together, these findings demonstrate an extensive biochemical characterization of a novel series of highly potent reactive small molecules that covalently bind to PDI.

This study focuses on the synthesis of propyl-phenyl acetate via esterification reaction in the presence of immobilized Candida antartica lipase-B (CAL-B). In this work, the effect of relevant factors (kinetics and thermodynamic) on total percent conversion and process optimization was studied. The reaction was performed in heptane medium with 1:2 molar ratio of benzoic acid: n-propanol with 0.6% (w/v) biocatalyst loading at 40 °C to attain a maximum conversion of 96.1% within 40 min of reaction time. Effect of increase in temperature on ∆G values indicates that lipase is more promising at moderate temperature (40 °C). A second-order kinetic model was proposed to evaluate apparent kinetic constants that indicate a good agreement between the experimental and theoretical data (0.94 ≤ R 2  ≤ 0.99) with high initial reaction rate (113.5 mM/min). Finally, the catalyst CAL-B was successfully reused eight times without any significant decrease in relative activity.

A new synthetic pathway to four substituted imidazoles from readily available 2-((4-aryl(thienyl)-5 H -1,2,3-dithiazol-5-ylidene)amino)phenols has been developed. Benzo[ d ]oxazol-2-yl(aryl(thienyl))methanimines were proved as key intermediates in their synthesis. The formation of an imidazole ring from two methanimine derivatives likely includes the opening of one benzoxazole ring followed by ring closure by intermolecular nucleophilic attack of the N -methanimine atom to a carbon atom of another methanimine.

The entrapment of squaraine (SQ) within a molecular container to form rotaxane has been shown to improve the dye stability and the fluorescence proficiency inside the mitochondria. The macrocycle provides shelter and protects the near-infrared (NIR) SQ chromophore from nucleophilic attacks made by the exposed thiol of Cys-containing mitochondrial proteins and mitochondrial glutathione. Herein a microwave-assisted template-directed clipping reaction on low-loading 2-chlorotrityl chloride resin is used to develop an NIR unsymmetrical squaraine rotaxane in high quantum yield.

Diorcinols and related prenylated diaryl ethers were reported to exhibit activity against methicillin-resistant clinical isolates of Staphylococcus aureus (MRSA). Within these lines, we report the first total synthesis of diorcinol D, I, J, the proposed structure of verticilatin and recently isolated antibacterial diaryl ether by using an efficient and highly divergent synthetic strategy. These total syntheses furnish the diaryl ethers in only five to seven steps employing a Pd-catalyzed diaryl ether coupling as the key step. The total synthesis led to the structural revision of the natural product verticilatin, which has been isolated from a plant pathogenic fungus. Furthermore, these structures were tested in order to determine their antibacterial activities against different MRSA strains as well as further Gram-positive and -negative bacteria., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Background: Prostate cancer (PCa) is the most common malignancy in men and in the absence of any effective treatments available., Methods: For the development of potential anticancer agents, 24 kinds of naftopidil-based arylpiperazine derivatives containing the bromophenol moiety were synthesized and characterized by using spectroscopic methods. Their pharmacological activities were evaluated against human PCa cell lines (PC-3 and LNCaP) and a 1 -adrenergic receptors (a 1 -ARs; α 1a , α 1b , and α 1d -ARs). The structure-activity relationship of these designed arylpiperazine derivatives was rationally explored and discussed., Results: Among these derivatives, 3c, 3d, 3h, 3k, 3o, and 3s exhibited the most potent activity against the tested cancer cells, and some derivatives with potent anticancer activities exhibited better a 1 -AR subtype selectivity than others did (selectivity ratio > 10)., Conclusion: This work provided a potential lead compound for the further development of anticancer agents for PCa therapy.

Therapeutic interventions with aldose reductase inhibitors appear to be a promising approach to major pathological conditions (i.e. neuropathy/angiopathy related to chronic hyperglycemia, chronic inflammation and cancer). Until now, the most potent aldose reductase inhibitors have been carboxylic acid derivatives, which poorly permeate biological membranes. In this work, continuing our previous works, we promote the bioisosteric replacement of the carboxylic acid moiety to make equally potent yet more druggable inhibitors., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Sesamol is a phenolic derivative. Its antioxidant activity is low than that of Trolox and depends on benzodioxole moiety. Thus, a molecular modification strategy through alkylation, inspired by natural and synthetic antioxidants, was studied by molecular modeling at the DFT/B3LYP level of theory by comparing the 6-31+G(d,p) and 6-311++G(2d,2p) basis sets. All proposed derivatives were compared to classical related antioxidants such as Trolox, t -butylated hydroxytoluene (BHT) and t -butylated hydroxyanisole (BHA). According to our results, molecular orbitals, single electron or hydrogen-atom transfers, spin density distributions, and alkyl substitutions at the ortho positions related to phenol moiety were found to be more effective than any other positions. The trimethylated derivative was more potent than Trolox. t -Butylated derivatives were stronger than all other alkylated derivatives and may be new alternative forms of modified antioxidants from natural products with applications in the chemical, pharmaceutical, and food industries.

An imidazolium ionic-liquid-modified phenolic resin (ILPR) was synthesized using 3-aminophenol as a functional monomer, glyoxylic acid as a green cross-linker, and polyethylene glycol 6000 as a porogen. The obtained ILPR showed better extraction of benzoylurea plant hormones thidiazuron and forchlorfenuron than the unmodified phenolic resin because the imidazolium IL provides more interaction modes with the analytes. ILPR, as a tailored adsorbent for solid-phase extraction, was coupled with high-performance liquid chromatography (ILPR‒SPE‒HPLC) for the simultaneous determination of thidiazuron and forchlorfenuron in cucumbers. Good linearity of the ILPR‒SPE‒HPLC method was obtained, ranging from 0.0100 to 5.00 μg g -1 with a correlation coefficient (r) ≥ 0.9999. The recoveries of spiked samples ranged from 91.4% to 100.7% with a relative standard deviation of ≤ 6.0%., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)