Synthesis, antiepileptic effects, and structure-activity relationships of α-asarone derivatives: In vitro and in vivo neuroprotective effect of selected derivatives.

In the present study, we compared the antiepileptic effects of α-asarone derivatives to explore their structure-activity relationships using the PTZ-induced seizure model. Our research revealed that electron-donating methoxy groups in the 3,4,5-position on phenyl ring increased antiepileptic potency but the placement of other groups at different positions decreased activity. Besides, in allyl moiety, the optimal activity was reached with either an allyl or a 1-butenyl group in conjugation with the benzene ring. The compounds 5 and 19 exerted better neuroprotective effects against epilepsy in vitro (cell) and in vivo (mouse) models. This study provides valuable data for further exploration and application of these compounds as potential anti-seizure medicines.

Synthesis of fluorescent G-quadruplex DNA binding ligands for the comparison of terminal group effects in molecular interaction: Phenol versus methoxybenzene.

A number of new fluorescent nucleic acid binding ligands were synthesized by utilizing the non-specific thiazole orange dye as the basic scaffold for molecular design. Under simple synthetic conditions, the molecular scaffold of thiazole orange bridged with a terminal side-group (phenol or methoxybenzene) becomes more flexible because the newly added ethylene bridge is relatively less rigid than the methylene of thiazole orange. It was found that these molecules showed better selectivity towards G-quadruplex DNA structure in molecular interactions with different type of nucleic acids. The difference in terms of induced DNA-ligand interaction signal, selectivity, and binding affinity of the ligands with the representative nucleic acids including single-stranded DNA, double-stranded DNA, telomere and promoter G4-DNA and ribosomal RNA were investigated. The position of the terminal methoxyl groups was found showing strong influence both on binding affinity and fluorescent discrimination among 19 nucleic acids tested. The ligand with a methoxyl group substituted at the meta-position of the styryl moiety exhibited the best fluorescent recognition performance towards telo21 G4-DNA. A good linear relationship between the induced fluorescent binding signal and the concentration of telo21 was obtained. The comparison of ligand-DNA interaction properties including equilibrium binding constants, molecular docking, G4-conformation change and stabilization ability for G4-structures was also conducted. Two cancer cell lines (human prostate cancer cell (PC3) and human hepatoma cell (hepG2)) were selected to explore the inhibitory effect of the ligands on the cancer cell growth. The IC50 values obtained in the MTT assay for the two cancer cells were found in the range of 3.4-10.8 µM.

Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation.

Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC50 values of 6.5-11.2 µM. X-ray crystal structures and early assessment of DMPK/ADME-Tox parameters allowed us to initiate structure-based drug design approach and understand the liabilities (such as potential metabolic and aqueous solubility issues) as well as identify the opportunities for improvement of this aminobenzosuberone series. It also suggested that compound 7c should be regarded as an attractive chemical tool to investigate the different biological roles of this multifunctional PfA-M1 protein.

Synthesis, antitumor activity, and molecular docking study of 2-cyclopentyloxyanisole derivatives: mechanistic study of enzyme inhibition.

A series of 24 compounds was synthesised based on a 2-cyclopentyloxyanisole scaffold 3-14 and their in vitro antitumor activity was evaluated. Compounds 4a, 4b, 6b, 7b, 13, and 14 had the most potent antitumor activity (IC50 range: 5.13-17.95 µM), compared to those of the reference drugs celecoxib, afatinib, and doxorubicin. The most active derivatives 4a, 4b, 7b, and 13 were evaluated for their inhibitory activity against COX-2, PDE4B, and TNF-α. Compounds 4a and 13 potently inhibited TNF-α (IC50 values: 2.01 and 6.72 µM, respectively) compared with celecoxib (IC50=6.44 µM). Compounds 4b and 13 potently inhibited COX-2 (IC50 values: 1.08 and 1.88 µM, respectively) comparable to that of celecoxib (IC50=0.68 µM). Compounds 4a, 7b, and 13 inhibited PDE4B (IC50 values: 5.62, 5.65, and 3.98 µM, respectively) compared with the reference drug roflumilast (IC50=1.55 µM). The molecular docking of compounds 4b and 13 with the COX-2 and PDE4B binding pockets was studied.HighlightsAntitumor activity of new synthesized cyclopentyloxyanisole scaffold was evaluated.The powerful antitumor 4a, 4b, 6b, 7b & 13 were assessed as COX-2, PDE4B & TNF-α inhibitors.Compounds 4a, 7b, and 13 exhibited COX-2, PDE4B, and TNF-α inhibition.Compounds 4b and 13 showed strong interactions at the COX-2 and PDE4B binding pockets.

Dehydrodieugenol B derivatives as antiparasitic agents: Synthesis and biological activity against Trypanosoma cruzi.

Chagas disease is a neglected protozoan disease that affects more than eight million people in developing countries. Due to the limited number and toxicity profiles of therapies in current use, new drugs are urgently needed. In previous studies, we reported the isolation of two related antitrypanosomal neolignans from Nectandra leucantha (Lauraceae). In this work, a semi-synthetic library of twenty-three neolignan derivatives was prepared to explore synthetically accessible structure activity relationships (SAR) against Trypanosoma cruzi. Five compounds demonstrated activity against trypomastigotes (IC50 values from 8 to 64 µM) and eight showed activity against intracellular amastigotes (IC50 values from 7 to 16 µM). Eighteen derivatives demonstrated no mammalian cytotoxicity up to 200 µM. The phenolic acetate derivative of natural dehydrodieugenol B was effective against both parasite forms and eliminated 100% of amastigotes inside macrophages. This compound caused rapid and intense depolarization of the mitochondrial membrane potential, with decreased levels of intracellular reactive oxygen species being observed. Fluorescence assays demonstrated that this derivative affected neither the permeability nor the electric potential of the parasitic plasma membrane, an effect also corroborated by scanning electron microscopy studies. Structure-activity relationship studies (SARs) demonstrated that the presence of at least one allyl side chain on the biaryl ether core was important for antitrypanosomal activity, and that the free phenol is not essential. This set of neolignan derivatives represents a promising starting point for future Chagas disease drug discovery studies.

Methyl Chavicol and Its Synthetic Analogue as Possible Antioxidant and Antilipase Agents Based on the In Vitro and In Silico Assays.

This study investigated the in vitro and in silico biological properties of the methyl chavicol (MC) and its analogue 2-[(4-methoxyphenyl)methyl]oxirane (MPMO), emphasizing the antioxidant and antilipase effects. MPMO was synthesized from MC that reacted with meta-chloroperbenzoic acid and, after separation and purification, was identified by 1H and 13C NMR and GC-MS. The antioxidant activity was investigated by DPPH, cooxidation ß-carotene/linoleic acid, and thiobarbituric acid assays. With the use of colorimetric determination, the antilipase effect on the pancreatic lipase was tested, while the molecular interaction profiles were evaluated by docking molecular study. MC (IC50 = 312.50 ± 2.28 µg/mL) and MPMO (IC50 = 8.29 ± 0.80 µg/mL) inhibited the DPPH free radical. The inhibition of lipid peroxidation (%) was 73.08 ± 4.79 and 36.16 ± 4.11 to MC and MPMO, respectively. The malonaldehyde content was significantly reduced in the presence of MC and MPMO. MC and MPMO inhibited the pancreatic lipase in 58.12 and 26.93%, respectively. MC and MPMO (-6.1 kcal·mol-1) produced a binding affinity value lower than did diundecylphosphatidylcholine (-5.6 kcal·mol-1). These findings show that MC and MPMO present antioxidant and antilipase activities, which may be promising molecular targets for the treatment of diseases associated with oxidative damage and lipid metabolism.

Lichen Acids May Be Used as A Potential Drug For Cancer Therapy; by Inhibiting Mitochondrial Thioredoxin Reductase Purified From Rat Lung.

BACKGROUND: Thioredoxin reductase (E.C 1.6.4.5.; TrxR) is a widely distributed flavoprotein that catalyzes the NADPH-dependent reduction of thioredoxin (Trx) in many cellular events such as DNA synthesis, DNA repair, angiogenesis, antioxidative defense, and regulating apoptosis. Although TrxR is indispensible in protecting cells against oxidative stress, the overexpression of TrxR is seen in many aggressive tumors. Therefore, targeted inhibition of TrxR has been accepted as a new approach for chemotherapy. OBJECTIVE: In this study, in vitro inhibition effect of the lichen acids (diffractaic, evernic, lobaric, lecanoric, and vulpinic acid) on mitochondrial TrxR purified from rat lung was investigated. METHOD: It was the first time the enzyme was purified from rat lungs by using 2', 5'-ADP Sepharose 4B affinity chromatography. The purity of the enzyme was checked with SDS-PAGE. In vitro inhibition effect of the lichen acids was investigated spectrophotometrically. To emphasize the importance of the obtained data, the commercial anticancer drugs cisplatin and doxorubicin were used as positive controls. RESULTS: Molecular mass of the enzyme was calculated as approximately 52.4 kDa. The enzyme was purified with a 63.6% yield, 208.3 fold, and 0.5 EU/mg proteins specific activity. The IC50 values of five lichen acids were significantly lower than IC50 values of anticancer drugs. CONCLUSION: All of the lichen acids, especially lecanoric and vulpinic acid, exhibited much stronger inhibitory effect on TrxR than the anticancer drugs cisplatin and doxorubicin. These lichen acids have pharmacological potential as effective natural antioxidants, antimicrobials, and anticancer agents.

Difluoromethyl Bioisostere: Examining the "Lipophilic Hydrogen Bond Donor" Concept.

There is a growing interest in organic compounds containing the difluoromethyl group, as it is considered a lipophilic hydrogen bond donor that may act as a bioisostere of hydroxyl, thiol, or amine groups. A series of difluoromethyl anisoles and thioanisoles was prepared and their druglike properties, hydrogen bonding, and lipophilicity were studied. The hydrogen bond acidity parameters A (0.085-0.126) were determined using Abraham's solute 1H NMR analysis. It was found that the difluoromethyl group acts as a hydrogen bond donor on a scale similar to that of thiophenol, aniline, and amine groups but not as that of hydroxyl. Although difluoromethyl is considered a lipophilicity enhancing group, the range of the experimental Δlog P(water-octanol) values (log P(XCF2H) - log P(XCH3)) spanned from -0.1 to +0.4. For both parameters, a linear correlation was found between the measured values and Hammett σ constants. These results may aid in the rational design of drugs containing the difluoromethyl moiety.

Asymmetric mono- and dinuclear GaIII and ZnII complexes as models for purple acid phosphatases.

Derivatives of the known dinucleating ligands HL1 (2,6-bis{[bis(pyridin-2-ylmethyl)amino]methyl}-4-methylphenol) and H2L2 (2-{[bis(pyridin-2-ylmethyl)amino]methyl}-6-{[(2-hydroxybenzyl)(pyridine-2-ylmethyl)amino]methyl}-4-methylphenol) with two pivaloylamido hydrogen bond donor substituents, H3L3 and H3L5, have been prepared. The mono-, homo- and heterodinuclear ZnII and GaIII complexes of these ligands have been prepared and characterized. The solution equilibria are discussed on the basis of extensive NMR spectroscopic, mass spectrometric and pH-dependent UV-vis spectroscopic titrations. The phosphoester hydrolysis activity of the complexes has been studied as a function of pH and substrate concentration and analyzed using Michaelis-Menten kinetics. It emerges that the mixed metal (mixed valent) complex of the ligand with an asymmetric disposition of the hydrogen bonding substituents (H3L3) is a functional model for the mixed valent, dinuclear metallohydrolase purple acid phosphatase. This complex combines the essential structural features of the active site of PAP and is the first heterodinuclear model complex mimicking the essential function of PAPs, i.e. the hydrolysis of phosphomonoesters.

5-Carba-pterocarpens: A new scaffold with anti-HCV activity.

The synthesis of a series of 5-carba-pterocarpens derivatives involving the cyclization of α-aryl-α-tetralones is described. Several compounds demonstrated potent activity and selectivity in vitro against HCV replicon reporter cells. The best profile in Huh7/Rep-Feo1b replicon reporter cells was observed with 2h (EC50 = 5.5 µM/SI = 20), while 2e was the most active in Huh7.5-FGR-JC1-Rluc2A replicon reporter cells (EC50 = 1.5 µM/SI = 70). Hydroxy groups at A- and D-rings are essential for anti-HCV activity, and substitutions in the A-ring at positions 3 and 4 resulted in enhanced activity of the compounds.

Synthesis of Substituted Tetralins and Benzosuberans via BF3·OEt2-Mediated Formal (4 + 2) and (5 + 2) Stereocontrolled Cycloaddition of 4-Alkenols with Veratrol.

BF3·OEt2-mediated one-pot formal (4 + 2) and (5 + 2) stereocontrolled cycloaddition of 4-alkenols 3 and 4 with veratrol affords the respective substituted tetralins 5 and benzosuberans 6 in good yields. The cascade protocol combines a facile double Friedel-Crafts benzannulation of 4-alkenols 3 and 4 (having two electrophilic sites) and veratrol (7a) (having two nucleophilic sites). A plausible mechanism was studied and proposed.

Synthesis of 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene Derivatives and Evaluations of Their Carbonic Anhydrase Isoenzymes Inhibitory Effects.

Rearrangement of 1,6-bis(3,4-dimethoxyphenyl)hexane-1,6-dione (8) gave two isomeric products having cyclopentene moiety. Starting from the major product (3,4-dimethoxyphenyl)[2-(3,4-dimethoxyphenyl)cyclopent-1-en-1-yl]methanone (11), eight new compounds (16-23) were obtained by the reactions such as reduction (by catalytic hydrogenation and NaBH4 ), nitration, 1,4-addition, bromination, and esterification reactions. Carbonic anhydrases (CA, E.C.4.2.1.1) are ubiquitous metalloenzymes present in almost all living organism that catalyze a simple reaction, the conversion of carbon dioxide (CO2 ) and water (H2 O) to bicarbonate ion (HCO3 (-) ) and a proton (H(+) ). CA isoenzymes I and II (hCA I and II) inhibition effects of synthesized eleven new and four known compounds (8-13 and 15-23) were investigated. Inhibition studies of the hCA I and II with 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene derivatives revealed that they possess effective inhibitory potency. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized 4-[2-(3,4-dimethoxybenzyl)cyclopentyl]-1,2-dimethoxybenzene derivatives with Ki s in the range of 313.16-1537.00 nm against hCA I and in the range of 228.31-1927.31 nm against hCA II, respectively.

Chemoenzymatic collective synthesis of optically active hydroxyl(methyl)tetrahydronaphthalene-based bioactive terpenoids.

Starting from succinic anhydride and 2-methylanisole, a chemoenzymatic collective formal/total synthesis of several optically active tetrahydronaphthalene based bioactive natural products has been presented via advanced level common precursors; the natural product and antipode (-)/(+)-aristelegone B. Regioselective benzylic oxidations, stereoselective introduction of hydroxyl groups at the α-position of ketone moiety in syn-orientation, efficient enzymatic resolutions with high enantiomeric purity, stereoselective reductions, samarium iodide induced deoxygenations and tandem acylation-Wittig reactions without racemization and/or eliminative aromatization were the key features. An attempted diastereoselective synthesis of (±)-vallapin has also been described.

N-(1'-naphthyl)-3,4,5-trimethoxybenzohydrazide as microtubule destabilizer: Synthesis, cytotoxicity, inhibition of cell migration and in vivo activity against acute lymphoblastic leukemia.

Tubulin-interacting agents, like vinca alkaloid and taxanes, play a fundamental role in cancer chemotherapy, making cellular microtubules (MT), one of the few validated anticancer targets. Cancer resistance to classical MT inhibitors has motivated the development of novel molecules with increased efficacy and lower toxicity. Aiming at designing structurally-simple inhibitors of MT assembly, we synthesized a series of thirty-one 3,4,5-trimethoxy-hydrazones and twenty-five derivatives or analogs. Docking simulations suggested that a representative N-acylhydrazone could adopt an appropriate stereochemistry inside the colchicine-binding domain of tubulin. Several of these compounds showed anti-leukemia effects in the nanomolar concentration range. Interference with MT polymerization was validated by the compounds' ability to inhibit MT assembly at the biochemical and cellular level. Selective toxicity investigations done with the most potent compound, a 3,4,5-trimethoxy-hydrazone with a 1-naphthyl group, showed remarkably selective toxicity against leukemia cells in comparison with stimulated normal lymphocytes, and no acute toxicity in vivo. Finally, this molecule was as active as vincristine in a murine model of human acute lymphoblastic leukemia at a weekly dose of 1 mg/kg.

A highly efficient asymmetric synthesis of vernakalant.

A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.

Synthesis of 13C and 15N labeled 2,4-dinitroanisole.

Syntheses of [(13)C6]-2,4-dinitroanisole (ring-(13)C6) from [(13)C6]-anisole (ring-(13)C6) and [(15)N2]-2,4-dinitroanisole from anisole using in situ generated acetyl nitrate and [(15)N]-acetyl nitrate, respectively, are described. Treatment of [(13)C6]-anisole (ring-(13)C6) with acetyl nitrate generated in 100% HNO3 gave [(13)C6]-2,4-dinitroanisole (ring-(13)C6) in 83% yield. Treatment of anisole with [(15)N]-acetyl nitrate generated in 10 N [(15)N]-HNO3 gave [(15)N2 ]-2,4-dinitroanisole in 44% yield after two cycles of nitration. Byproducts in the latter reaction included [(15)N]-2-nitroanisole and [(15)N]-4-nitroanisole.

1-(4-Methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamides: synthesis, molecular modeling, evaluation of their anti-inflammatory activity and ulcerogenicity.

A series of novel 1-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1H-1,2,4-triazole-3-carboxamides were synthesized and confirmed with different spectroscopic techniques. The prepared compounds exhibited remarkable anti-inflammatory activity that represents 38%-100% of indomethacin activity and 44%-115% of celecoxib activity after 3 h. The anilides 5a-l and hydrazide 6 exhibit low incidence of gastric ulceration compared to indomethacin which was confirmed with histopathological investigation. In vitro COX-1/COX-2 inhibition studies showed compounds 4b (COX-1 IC50 = 45.9 µM; COX-2 IC50 = 68.2 µM) and 6 (COX-1 IC50 = 39.8 µM; COX-2 IC50 = 46.3 µM) are the most potent COX inhibitors in the tested compounds. The binding mode for some of the tested compounds to the enzymes was predicted using docking studies.

Synthesis, antifeedant activity against Coleoptera and 3D QSAR study of alpha-asarone derivatives.

For the first time, a set of 56 compounds representing structural derivatives of naturally occurring alpha-asarone as an antifeedants against stored product pests Sitophilus granarius L., Trogoderma granarium Ev., and Tribolium confusum Duv., were subjected to the 3D QSAR studies. Three-dimensional quantitative structure-activity relationships (3D-QSAR) for 56 compounds, including 15 newly synthesized, were performed using comparative molecular field analysis s-CoMFA and SOM-CoMSA techniques. QSAR was conducted based on a combination of biological activity (against Coleoptera larvae and beetles) and various geometrical, topological, quantum-mechanical, electronic, and chromatographic descriptors. The CoMSA formalism coupled with IVE (CoMSA-IVE) allowed us to obtain highly predictive models for Trogoderma granarium Ev. larvae. We have found that this novel method indicates a clear molecular basis for activity and lipophilicity. This investigation will facilitate optimization of the design of new potential antifeedants.

Synthesis and antifeedant activity of novel alpha-asarone derivatives against stored-product pests.

BACKGROUND: Alpha-asarone (2,4,5-trimethoxypropenylbenzene) derivatives represent a new series of compounds that possess good antifeedant activity against different stored-product pests. RESULTS: A total of 23 novel alpha-asarone derivatives were synthesised and identified by (1) H NMR, (13) C NMR and IR, and their feeding deterrent activities were tested against Sitophilus granarius L., Trogoderma granarium Ev. and Tribolium confusum Duv. Ten compounds showed strong antifeedant activities. CONCLUSION: Some of the title compounds displayed very good and broad-spectrum activities against adult and larval Coleoptera. The results indicate that the presence of a double bond in the side chain and three methoxy groups is important for antifeedant activity.

Asymmetric synthesis and anti-protozoal activity of the 8,4'-oxyneolignans virolin, surinamensin and analogues.

The asymmetric synthesis of 8,4'-oxyneolignans (-)-virolin, (-)-surinamensin and a number of analogues has been achieved. A divergent synthesis was used, with all compounds being elaborated from a single chiral aldehyde derived from ethyl lactate. In the 15 compounds that were tested, the level of substitution on the A-ring was found to directly influence the activity against Leishmania donovani whilst the activity against Plasmodium falciparum was influenced by numerous substitution and stereochemical factors.