Proposed mechanisms of action of herbal drugs and their biologically active constituents in the treatment of coughs: an overview.

Various medicinal plants find their use in cough treatment, based on traditions and long-term experience. Pharmacological principles of their action, however, are much less known. Herbal drugs usually contain a mixture of potentially active compounds, which can manifest diverse effects. Expectorant or antitussive effects, which can be accompanied by others, such as anti-inflammatory or antibacterial, are probably the most important in the treatment of coughs. The aim of this review is to summarize the current state of knowledge of the effects of medicinal plants or their constituents on cough, based on reliable pharmacological studies. First, a comprehensive description of each effect is provided in order to explain the possible mechanism of action in detail. Next, the results related to individual plants and substances are summarized and critically discussed based on pharmacological in vivo and in vitro investigation.

Sustainable ionic liquids-based molecular platforms for designing acetylcholinesterase reactivators.

We report a green chemistry approach for preparation of oxime-functionalized ILs as AChE reactivators: amide/ester linked IL, l-alanine, and l-phenylalanine derived salts bearing pyridinium aldoxime moiety. The reactivation capacities of the novel oximes were evaluated towards AChE inhibited by typical toxic organophosphates, sarin (GB), VX, and paraoxon (PON). The studied compounds are mostly non-toxic up to the highest concentrations screened (2 mM) towards Gram-negative and Gram-positive bacteria cell lines and both filamentous fungi and yeasts in the in vitro screening experiments as well as towards the eukaryotic cell (CHO-K1 cell line). Introduction of the oxime moiety in initially biodegradable structure decreases its ability to biodegradation. The compound 3d was shown to reveal remarkable activity against the AChE inhibited by VX, exceeding conventional reactivators 2-PAM and obidoxime. The regularities on antidotal activity, cell viability, plasma stability, biodegradability as well as molecular docking study of the newly synthesized oximes will be used for further improvement of their structures.

2-Substituted quinazolines: Partial agonistic and antagonistic ligands of the constitutive androstane receptor (CAR).

Following the discovery of 2-(3-methoxyphenyl)-3,4-dihydroquinazoline-4-one and 2-(3-methoxyphenyl)quinazoline-4-thione as potent, but non-specific activators of the human Constitutive Androstane Receptor (CAR, NR1I3), a series of quinazolinones substituted at the C2 phenyl ring was prepared to examine their ability to selectively modulate human CAR activity. Employing cellular and in vitro TR-FRET assays with wild-type CAR or its variant 3 (CAR3) ligand binding domains (LBD), several novel partial human CAR agonists and antagonists were identified. 2-(3-Methylphenyl) quinazolinone derivatives 7d and 8d acted as partial agonists with the recombinant CAR LBD, the former in nanomolar units (EC50 = 0.055 µM and 10.6 µM, respectively). Moreover, 7d did not activate PXR, and did not show any signs of cytotoxicity. On the other hand, 2-(4-bromophenyl)quinazoline-4-thione 7l possessed significant CAR antagonistic activity, although the compound displayed no agonistic or inverse agonistic activities. A compound possessing purely antagonistic effect was thus identified for the first time. These and related compounds may serve as a remedy in xenobiotic intoxication or, conversely, in suppression of undesirable hepatic CAR activation.

Reductive Amination Revisited: Reduction of Aldimines with Trichlorosilane Catalyzed by Dimethylformamide─Functional Group Tolerance, Scope, and Limitations.

Aldimines, generated in situ from aliphatic, aromatic, and heteroaromatic aldehydes and aliphatic, aromatic, and heteroaromatic primary or secondary amines, can be reduced with trichlorosilane in the presence of dimethylformamide (DMF) as an organocatalyst (≤10 mol %) in toluene or CH2Cl2 at room temperature. The reduction tolerates ketone carbonyls, esters, amides, nitriles, sulfones, sulfonamides, NO2, SF5, and CF3 groups, boronic esters, azides, phosphine oxides, C═C and C≡C bonds, and ferrocenyl nucleus, but sulfoxides and N-oxides are reduced. α,ß-Unsaturated aldimines undergo 1,2-reduction only, leaving the C═C bond intact. N-Monoalkylation of primary amines is attained with a 1:1 aldehyde to amine ratio, whereas excess of the aldehyde (≥2:1) allows second alkylation, giving rise to tertiary amines. Reductive N-alkylation of α-amino acids proceeds without racemization; the resulting products, containing a C≡C bond or N3 group, are suitable for click chemistry. This reaction thus offers advantages over the traditional methods (borohydride reduction or catalytic hydrogenation) in terms of efficiency and chemoselectivity. Solubility of some of the reacting partners appears to be the only limitation. The byproducts generated by the workup with aqueous NaHCO3 (i.e., NaCl and silica) are environmentally benign. As a greener alternative, DMA can be employed as a catalyst instead of DMF.

Enantioselective Construction of Spirooxindole-Fused Cyclopentanes.

The present study reports an asymmetric organocatalytic cascade reaction of oxindole derivates with α,ß-unsaturated aldehydes efficiently catalyzed by simple chiral secondary amine. Spirooxindole-fused cyclopentanes were produced in excellent isolated yields (up to 98%) with excellent enantiopurities (up to 99% ee) and moderate to high diastereoselectivities. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spiro compounds. In addition, a study showing the promising biological activity of selected enantioenriched products was accomplished.

Reaction Outcome Critically Dependent on the Method of Workup: An Example from the Synthesis of 1-Isoquinolones.

A striking dependence on the method of workup has been found for annulation of benzonitriles ArC≡N to N-methyl 2-toluamide (1), facilitated by n-BuLi (2 equiv): quenching the reaction by a slow addition of water produced the expected 1-isoquinolones 2; by contrast, slow pouring of the reaction mixture into water afforded the cyclic aminals 5 (retaining the NMe group of the original toluamide). The mechanism of the two processes is discussed in terms of the actual H+ concentration in the workup. Both 2 and 5 were then converted into the corresponding 1-chloroisoquinolines 3, coupling of which, mediated by (Ph3P)2NiCl2/Zn, afforded bis-isoquinolines 4.

Structure Elucidation and Cholinesterase Inhibition Activity of Two New Minor Amaryllidaceae Alkaloids.

Two new minor Amaryllidaceae alkaloids were isolated from Hippeastrum × hybridum cv. Ferrari and Narcissus pseudonarcissus cv. Carlton. The chemical structures were identified by various spectroscopic (one- and two-dimensional (1D and 2D) NMR, circular dichroism (CD), high-resolution mass spectrometry (HRMS) and by comparison with literature data of similar compounds. Both isolated alkaloids were screened for their human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE) inhibition activity. One of the new compounds, a heterodimer alkaloid of narcikachnine-type, named narciabduliine (2), showed balanced inhibition potency for both studied enzymes, with IC50 values of 3.29 ± 0.73 µM for hAChE and 3.44 ± 0.02 µM for hBuChE. The accommodation of 2 into the active sites of respective enzymes was predicted using molecular modeling simulation.

Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes.

Flavonoids are abundant polyphenols in nature. They are extensively biotransformed in enterocytes and hepatocytes, where conjugated (methyl, sulfate, and glucuronide) metabolites are formed. However, bacterial microflora in the human intestines also metabolize flavonoids, resulting in the production of smaller phenolic fragments (e.g., hydroxybenzoic, hydroxyacetic and hydroxycinnamic acids, and hydroxybenzenes). Despite the fact that several colonic metabolites appear in the circulation at high concentrations, we have only limited information regarding their pharmacodynamic effects and pharmacokinetic interactions. Therefore, in this in vitro study, we investigated the interactions of 24 microbial flavonoid metabolites with human serum albumin and cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes. Our results demonstrated that some metabolites (e.g., 2,4-dihydroxyacetophenone, pyrogallol, O-desmethylangolensin, and 2-hydroxy-4-methoxybenzoic acid) form stable complexes with albumin. However, the compounds tested did not considerably displace Site I and II marker drugs from albumin. All CYP isoforms examined were significantly inhibited by O-desmethylangolensin; nevertheless, only its effect on CYP2C9 seems to be relevant. Furthermore, resorcinol and phloroglucinol showed strong inhibitory effects on CYP3A4. Our results demonstrate that, besides flavonoid aglycones and their conjugated derivatives, some colonic metabolites are also able to interact with proteins involved in the pharmacokinetics of drugs.

Applicability of the OECD 455 in-vitro assay for determination of hERa agonistic activity of isoflavonoids.

The Organisation for Economic Co-operation and Development (OECD)-validated transactivation assay using the human estrogen receptor alpha (hERα) Hela9903 cell line is used for activity evaluation of hERα agonists and antagonists. Due to many advantages, this assay is broadly used as an initial screening process. However, response significantly higher from that of 17-ß estradiol (E2) was observed with phytoestrogens for concentrations commonly above 1 µM in previous studies. The main aim of this study was thus to ascertain the applicability of OECD protocol 455 for evaluation of estrogenic activity of natural flavonoids, including known phytoestrogens. The estrogenic activities of aglycones as well as of O-methylated and glycosylated flavonoids were evaluated. Supra-maximal luciferase activity was seen for most of the flavonoids tested at concentrations even below 1 µM. hERα-mediated luciferase expression was confirmed with the competition assay specified in OECD protocol 455. However, at concentrations above 1 µM, non-specific interactions were also observed. Instead of EC50 values, which could not be determined for most of the isoflavonoids tested, the concentrations corresponding to 10% (PC10) and 50% (PC50) of the maximum activity of the positive control, E2, were used for quantitative determination of estrogenic activities. Appropriate evaluation of the data obtained with the current OECD protocol 455 validated assay represents a valuable tool for initial screening of natural flavonoids for estrogenic activity.

The influence of microbial isoflavonoid specific metabolites on platelets and transition metals iron and copper.

BACKGROUND: Isoflavonoids seem to possess positive cardiovascular and other beneficial effects in humans. HYPOTHESIS: Their low bioavailability, however, indicates that small isoflavonoid metabolites formed by human microflora can significantly contribute to these activities. STUDY DESIGN: Testing antiplatelet activity ex vivo in human blood and interaction with transition metals in vitro. METHODS: The effect on platelet aggregation induced by different triggers (arachidonic acid, collagen, ADP, TRAP-6), and interactions with transition metals (iron and copper chelation/reduction) were evaluated against four isoflavonoid-specific metabolites: S-equol; O-desmethylangolensin; 2-(4-hydroxyphenyl) propionic acid (HPPA); and 4-ethylphenol. RESULTS: S-equol, 4-ethylphenol and O-desmethylangolensin blocked platelet aggregation induced by arachidonic acid and collagen. S-equol even matched the potency of acetylsalicylic acid in the case of collagen, which is the most physiological inducer of aggregation. Moreover, their effects in general seemed to be biologically relevant and attainable at achievable plasma concentrations, with the exception of HPPA which was ineffective. While only O-desmethylangolensin mildly chelated iron and copper, all four compounds markedly reduced cupric ions. Their direct free radical scavenging effects seem to have little clinical relevance. CONCLUSION: This study has shown that S-equol, O-desmethylangolensin and 4-ethylphenol, arising from isoflavonoid intake, can have biologically relevant effects on platelet aggregation.

A new class of prophylactic metallo-antibiotic possessing potent anti-cancer and anti-microbial properties.

Immunocompromised cancer patients are often at high risk of developing infections. Standard infection control measures are required to prevent the onset of infection but, under some circumstances, antimicrobial prophylaxis is necessary. We have developed a family of innovative metallo-antibiotics of general formula [Cu(N,N)(CipA)Cl] where N,N represents a phenanthrene ligand and CipA stands for a derivative of the clinically used fluoroquinolone antibiotic ciprofloxacin. The X-ray crystal structure of one member from this family, [Cu(phen)(CipA)Cl] (where phen is 1,10-phenanthroline), is also reported. These complexes combine into one drug entity a Cu-N,N-framework with DNA binding and DNA oxidant properties and an antibiotic derivative with known anti-proliferative and anti-microbial activities. The complexes were all found to exhibit excellent DNA recognition with binding affinity of lead agents in the order of ∼107 M(bp)-1. Biophysical studies involving calf thymus DNA indicate the complexes intercalate or semi-intercalate DNA via the minor groove. All complexes exhibited excellent nuclease activity with DNA strand scission being mediated predominantly via superoxide and hydroxyl radicals. The complexes were found to have promising anti-proliferative effects against a human breast adenocarcinoma cell line (MCF-7) and a human prostate carcinoma cell line (DU145) with low micromolar and, in some cases, nanomolar cytotoxicities observed. Selective targeting of Gram positive bacteria was also identified by this complex class with one lead compound having an order of magnitude greater potency against Methicillin-resistant S. aureus (MRSA) as compared to the CipA ligand. Importantly, from a clinical stand point, these complexes were also found to be well tolerated in an in vivo Galleria mellonella larvae model, which has both functional and structural similarities to that of the innate immune system of mammals.

A New Insight into the Stereoelectronic Control of the Pd0 -Catalyzed Allylic Substitution: Application for the Synthesis of Multisubstituted Pyran-2-ones via an Unusual 1,3-Transposition.

Pyran-2-ones 3 undergo a novel Pd0 -catalyzed 1,3-rearrangement to afford isomers 6. The reaction proceeds via an η2 -Pd complex, the pyramidalization of which (confirmed by quantum chemistry calculations) offers a favorable antiperiplanar alignment of the Pd-C and allylic C-O bonds (C), thus allowing the formation of an η3 -Pd intermediate. Subsequent rotation and rate-limiting recombination with the carboxylate arm then gives isomeric pyran-2-ones 6. The calculated free energies reproduce the observed kinetics semi-quantitatively.

Mono and dihydroxy coumarin derivatives: Copper chelation and reduction ability.

Due to the limited array of the currently available copper chelators, research of such compounds continues to be of clinical interest. Notably, o-dihydroxycoumarins have been previously shown to be potent iron chelators under neutral conditions. Within this study, the interaction of a series of natural coumarins and their synthetic analogs with copper has been evaluated in order to obtain structure-activity relationships under different pathophysiological pH conditions. Both competitive and non-competitive methods have been employed. Analysis of cupric ion reduction has also been performed. Under mildly competitive conditions, cupric chelation was observed for o-dihydroxycoumarins, and partially for o-diacetoxycoumarin. Non-competitive studies showed that cuprous ions are not chelated at all and that the stoichiometries of the most active 6,7- and 7,8-dihydroxycoumarins to cupric ions ranged from 1:1 to 2:1 depending on pH and concentration. Interestingly, under highly competitive conditions, coumarins were not capable of chelating cupric ions, either. Reduction experiments have shown that 13 out of the 15 coumarins included in this study reduced cupric ions. However, significant differences depending on their structures were apparent in their potencies. O-dihydroxycoumarins were the most potent ones again. CONCLUSION: O-dihydroxycoumarins are moderately active cupric ion chelators with potent copper reducing properties.

2-(3-Methoxyphenyl)quinazoline Derivatives: A New Class of Direct Constitutive Androstane Receptor (CAR) Agonists.

Constitutive androstane receptor (CAR) is a key regulator of xenobiotic and endobiotic metabolism. Together with pregnane X (PXR) and aryl hydrocarbon (AHR) receptors, it is referred to as "xenobiotic receptor". The unique properties of human CAR, such as its high constitutive activity, both direct (ligand-binding domain-dependent) and indirect activation have hindered the discovery of direct selective human CAR ligands. Herein, we report a novel class of direct human CAR agonists in a group of 2-(3-methoxyphenyl)quinazoline derivatives. The compounds are even more potent activators of human CAR than is prototype 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). The three most potent ligands are at the same time extremely potent activators of the other xenobiotic or hormonal receptors, namely PXR, AHR, and vitamin D receptor, which regulate major xenobiotic-metabolizing enzymes and efflux transporters. Thus, the novel CAR ligands can be also considered as constituting the first class of potent pan-xenobiotic receptor ligands that can serve as potential antidotes boosting overall metabolic elimination of xenobiotic or toxic compounds.

Synthesis of Amaryllidaceae Constituents and Unnatural Derivatives.

This update covers the syntheses of Amaryllidaceae alkaloids since the publication of the last major review in 2008. A short summary of past syntheses and their step count is provided for the major constituents; pancratistatin, 7-deoxypancratistatin, narciclasine, lycoricidine, lycorine, and for other natural constituents, as well as for unnatural derivatives. Discussion of biological activities is provided for unnatural derivatives. Future prospects and further developments in this area are covered at the end of the review. The literature is covered to the end of August 2015.

Fully substituted pyranones via quasi-heterogeneous genuinely ligand-free Migita-Stille coupling of iodoacrylates.

Migita-Stille coupling of (Z)-ß-iodoacrylates with (E)-α-stannyl allylic alcohols to furnish 5-alkylidene-4-substituted-5,6-dihydro-2H-pyran-2-ones is efficiently catalyzed by 2% Pd black in DMF, while Pd(PPh3)4 is inactive. Heterogeneous Pd released in solution is most likely responsible for the catalysis. The reaction is applicable to other substrates, without having to resort to ligands, additives, and/or solid support for Pd. The resulting pyranones can be rearranged to fully functionalized pyranones in another single step.

Chemical properties and biological activities of cyclopentenediones: a review.

Cyclopentenediones (CPDs) are secondary metabolites of higher plants, fungi, algae, cyanobacteria and bacteria. A common denominator of CPDs is the cyclopent-4-ene-1,3-dione skeleton (1), which is modified by several functional groups. The heterogeneity of these substitutions is reflected in around one hundred CPDs reported to date. Most of the derivatives were isolated primarily from plant sources. Synthetic analogues were then prepared with new biological activities and more interesting pharmacological potential. Antifungal substances called coruscanones (2, 3) are the most studied of the CPDs. Other intensely investigated CPDs include lucidone (4), linderone (5), asterredione (6), involutone (7), nostotrebin 6 (8), TX-1123 (9), G2201-C (10), madindolines (11, 12) and many others. In addition to antibacterial and antifungal effects, a broad spectrum of biological activities for CPDs has been reported in the past two decades, especially anti-inflammatory, cytostatic and specific enzyme inhibitory activities. The CPD skeleton has been identified in a number of substances isolated from the plant kingdom; hence, CPDs can be referred to as a new group of natural bioactive substances. The main goal of this review is to define CPDs with respect to basic chemistry, isolation, synthetic approaches and description of their biological effects. Special attention is given to a detailed view into biological activities of CPDs in vitro and their phamacological potential.

Novel bronchodilatory quinazolines and quinoxalines: synthesis and biological evaluation.

A series of heterocyclic derivatives analogous to (-)vasicinone, in which the vasicinone C-ring was replaced with alkyl chain terminated by tertiary amine was prepared. N3, C4-O, C4-S or C4-N were used as the sites of attachment. The 4-[3-(1-piperidyl)propylsulfanyl]derivatives displayed bronchodilatory effect at low micromolar concentrations on isolated rat trachea, and low toxicity both on Balb/c 3T3 mouse fibroblast cells and in mice.

Regulating bioactivity of Cu2+ bis-1,10-phenanthroline artificial metallonucleases with sterically functionalized pendant carboxylates.

The synthetic chemical nuclease, [Cu(1,10-phenanthroline)2](2+), has stimulated research within metallonuclease development and in the area of cytotoxic metallodrug design. Our analysis reveals, however, that this agent is "promiscuous" as it binds both dsDNA and protein biomolecules, without specificity, and induces general toxicity to a diversity of cell lineages. Here, we describe the synthesis and characterization of small-molecule metallonucleases containing the redox-active cation, [Cu(RCOO)(1,10-phen)2](+), where 1,10-phen = 1,10-phenanthroline and R = -H, -CH3, -C2H5, -CH(CH3)2, and -C(CH3)3. The presence of coordinated carboxylate groups in the complex cation functions to enhance dsDNA recognition, reduce serum albumin binding, and offer control of toxicity toward human cancer cells, Gram positive and negative bacteria, and fungal pathogens. The induction of genomic dsDNA breaks (DSBs) were identified in ovarian adenocarcinoma cells using immunodetection of γ-H2AX. Formate, acetate, and pivalate functionalized complexes induced DSBs in a higher percentage of cells compared with [Cu(1,10-phen)2](2+), which supports the importance of inner-sphere modification toward enhancing targeted biological application.