Benzothieno[3,2-b]quinolinium and 3-(phenylthio)quinolinium compounds: Synthesis and evaluation against opportunistic fungal pathogens

Substitution around 5-methyl benzothieno[3,2-b]quinolinium (2) ring system was explored in order to identify positions of substitution that could improve its antifungal profile. The 3-methoxy (10b) was active against C. albicans, C. neoformans, and A. fumigatus and the 4-chloro (10f) analog showed moderate increases in anti-cryptococcal and anti-aspergillus activities. The effectiveness of 10b and 10f were validated in murine models of candidiasis and cryptococcosis, respectively. The efficacy of 10f in reducing brain cryptococcal infection and its observation in the brain of mice injected with this quaternary compound confirm the capacity of these compounds to cross the blood-brain barrier of mice. Overall, several of the chloro and methoxy substituted compounds showed significant improvements in activity against A. fumigatus, the fungal pathogen prevalent in patients receiving organ transplant. Opening the benzothiophene ring of 2 to form 1-(5-cyclohexylpentyl)-3-(phenylthio)quinolinium compound (3) resulted in the identification of several novel compounds with over 50-fold increases in potency (cf. 2) while retaining low cytotoxicities. Thus, compound 3 constitutes a new scaffold for development of drugs against opportunistic infections.     

Syntheses, structures, thermal behavior and solution studies of two types of Hg(II) complexes with [1,3-di(2-methoxy)benzene]triazene

The reaction of [1,3-di(2-methoxy)benzene]triazene, [HL], with Hg(CH₃COO)₂ and Hg(SCN)₂ in methanol as solvent, resulted in the formation of [HgL₂] (1) and [HgL(SCN)] (2), respectively. These compounds were characterized by means of X-ray diffraction, FT-IR spectroscopy, CHN and TGA-DTA analysis. In the lattice of the compound 1, the mono-nuclear complexes were connected to dimer structure by intermolecular non-classical C-H···O hydrogen bonds. Also, weak Hg-η²-arene π-interactions link the dimers into 1D supramolecular chains. The compound 2 is a 2D coordination polymer induced by C-H···π stacking interactions between 1D chains produced by weak Hg-η³-η³-arene π-interactions. The results of studies of the stoichiometry and formation of complexes of 1 and 2 in methanol solution were found to be in support of their solid state stoichiometry.     

Osteogenic constituents from Pterospermum acerifolium Willd. flowers

Phytochemical investigation of ethanol extracts of the Pterospermumacerifolium flowers led to the isolation and identification of two new flavones, 4′-(2-methoxy-4-(1,2,3-trihydroxypropyl) phenoxy luteolin (1) and 5,7,3′-trihydroxy-6-O-β-d-glucopyranosyl flavone (2), and one new lactone, 3,5-dihydroxyfuran-2(5H)-one (3) along with 14 known compounds (4-17). The structure of compounds 1-17 was established based on MS, 1D and 2D NMR, spectroscopic analysis. Eight of these compounds (1-6, 8 and 9) were assessed for osteogenic activity by using primary cultures of rat osteoblast. The compounds 1, 3 and 4 significantly stimulated osteoblast differentiation and mineralization as evident from a marked increase in expression of alkaline phosphatase and alizarin red-S staining of osteoblasts.     

Phytotoxicity of constituents of glandular trichomes and the leaf surface of camphorweed, Heterotheca subaxillaris

Camphorweed, Heterotheca subaxillaris (Lam.) Britt. & Rusby, has a camphor-like odor, and its leaf surfaces contain glandular trichomes of the type shown to contain high levels of isoprenoids in other species. Borneol (1), the phytotoxic calamenene-type sesquiterpenes (2-5, 9-11), and methylated flavones (12-15) were isolated from the dichloromethane rinsate of camphorweed aerial tissues. The strongest plant growth inhibitor against Agrostis stolonifera and Lactuca sativa seedlings, as well as duckweed (Lemna pausicostata), was 2-methoxy-calamenene-14-carboxylic acid (2). Esterification of calamenene carboxylic acids decreased their biological activity.     

A new ursane-type triterpenoid glycoside from Centella asiatica leaves modulates the production of nitric oxide and secretion of TNF-α in activated RAW 264.7 cells

One new ursane-type triterpenoid glycoside, asiaticoside G (1), five triterpenoids, asiaticoside (2), asiaticoside F (3), asiatic acid (4), quadranoside IV (5), and 2α,3β,6β-trihydroxyolean-12-en-28-oic acid 28-O-[α-l-rhamnopyranosyl-(1→4)-β-d-glucopyranosyl-(1→6)-β-d-glucopyranosyl] ester (6), and four flavonoids, kaempferol (7), quercetin (8), astragalin (9), and isoquercetin (10) were isolated from the leaves of Centella asiatica. Their chemical structures were elucidated by mass, 1D- and 2D-nuclear magnetic resonance (NMR) spectroscopy. The structure of new compound 1 was determined to be 2α,3β,23,30-tetrahydroxyurs-12-en-28-oic acid 28-O-[α-l-rhamnopyranosyl-(1→4)-β-d-glucopyranosyl-(1→6)-β-d-glucopyranosyl] ester. The anti-inflammatory activities of the isolated compounds were investigated on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Asiaticoside G (1) potently inhibited the production of nitric oxide and tumor necrosis factor-α with inhibition rates of 77.3% and 69.0%, respectively, at the concentration of 100 μM.     

β-Diketiminato 3d-metal compounds: Synthesis, characterization and catalytic behavior towards ethylene

The lithium β-diketiminate (1c, [Li{N(2,6-ⁱPr₂C₆H₃)C(Ph)CHC(^tBu)NH}]₂ represented as (LiL)₂) reacted with 3d-metal (II) chlorides to afford the corresponding compounds (2-7). All metal compounds were fully characterized by elemental, spectroscopic analyses and the single-crystal X-ray diffraction. The coordination geometries around the metals are shown to be tetrahedral within the trinuclear Co₂Li compound (2), planar in ML₂ (M = Co, 3), pseudo-tetrahedral conformation in the ML₂ with M as Mn (4), Fe (5) or Zn (6), and square planar in the dinickel compound (7). Indicated by the trimetallic Co₂Li compound 2, a six-membered ring is constructed of three metal atoms and three bridged chlorides as a twisted conformation. An inversion center is present in the centroid of the Ni₂Cl₂ four-membered ring within compound 7. The plausible mechanism of forming ML₂ was proposed through the chloro-bridged multinuclear compounds on the basis of isolated intermediates of trinuclear (2) and dinuclearic (7) compounds. Upon treatment with methylaluminoxane (MAO), the nickel compound 7 possessed good activity towards ethylene oligomerization, whereas the other metal compounds showed moderate activities towards ethylene polymerization.     

Sargachromanols as inhibitors of Na+/K+ ATPase and isocitrate lyase

Sargachromanols A-P (1-16), 16 meroterpenoids of the chromene class isolated from the brown alga Sargassum siliquastrum, were evaluated for their inhibitory activities toward Na⁺/K⁺ ATPase from porcine cerebral cortex and isocitrate lyase (ICL) from Candida albicans. These studies led to the identification of compounds 4, 6, 8, and 12 as potent Na⁺/K⁺ ATPase inhibitors. Compounds 12, 13, and 16 exhibited moderate ICL inhibitory activity. Compound 12 also showed weak antibacterial activity. The preliminary structure-activity relationship of these compounds is described to elucidate the essential structural requirements.     

Spirodiketopiperazine-based CCR5 antagonist: discovery of an antiretroviral drug candidate

Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.     

Synthesis of some novel androstanes as potential aromatase inhibitors

Novel pyrazole and isoxazole derivatives (6-9) were synthesized as a aromatase inhibitors. Pyrazole was synthesized from hydrazine hydrate and isoxazoles from hydroxylamine hydrochloride under different conditions. Molecular docking studies were carried out for the synthesized compounds. The best score was obtained for the compound (9) followed by compound (6) while compound (8) afforded poorest of the score. Aromatase inhibitory activity for compound (6) having pyrazole ring at 2,3 position showed highest activity followed by nitrile derivative (9). Isomeric forms of isoxazole (7 and 8) showed very poor activity compared to fadrozole and aminoglutethimide. Preliminary kinetic studies have shown that both of the active compounds (6 and 9) are reversible inhibitors of the enzyme.     

Synthesis, characterization and bioactivity of two novel trinuclear Cu(II)/Ni(II) complexes with pentadentate ligand N-2-methyl-acryloyl-salicylhydrazide

Two new trinuclear complexes, Cu₃L₂(py)₂ (1) and Ni₃L₂(py)₄ (2), have been synthesized and characterized, where L³⁻ is N-2-methyl-acryloyl-salicylhydrazidate. Central metal ion and two terminal metal ions in the two complexes are combined by two bridging deprotonated L³⁻ ligands, forming a bent trinuclear structure unit with an M-N-N-M-N-N-M core. The bent angles in complexes 1 and 2 are 167.6(1)° and 75.4(1)°, respectively. Three nickel ions in compound 2 exhibit alternating square-planar and octahedral geometries, while three copper ions in compound 1 follow square-planar mode. The studies in solution integrity and stability of compounds 1 and 2 show they are soluble and stable in DMF. UV-Vis titrations demonstrate compound 1 is stable in DMF even in the presence of excess metal ions. Antibacterial screening data indicate the two compounds all have stronger antimicrobial activities against the tested microorganisms than ligand. The trinuclear copper compound 1 is more active than monocopper compounds in the previous study, and the trinuclear nickel compound 2 is less active than tetranuclear nickel compound in the previous study.     

Phytotoxic constituents from Nimbya alternantherae

A phytotoxic compound identified as 6-(3,3-dimethylallyloxy)-4-methoxy-5-methylphthalide (1), was isolated from the phytopathogenic fungus Nimbya alternantherae, cultivated on solid media. Catalytic hydrogenation of 1 resulted in the quantitative formation of second compound (2). Both compounds (1, 2) act by inhibiting the ATP synthesis in spinach thylakoids. A detailed investigation on the mechanism of action indicates that compound 1 acts as a Hill reaction inhibitor and uncoupler of photosynthesis.     

Unusual stilbenoids and a stilbenolignan from seeds of Syagrus romanzoffiana

Stilbenoids, syagrusins A-B (1-2), and a stilbenolignan, 5-hydroxyaiphanol (3), along with three known phenylpropanoids (4-6), were isolated from seeds of Syagrus romanzoffiana. Compounds 1 and 2 possess unusual 1,4,4a,9a-tetrahydrofluoren-9-one and bicyclo[3.3.0]octanedione skeletons, respectively, whereas compound 3 is a stilbenolignan belonging to a very rare structural class of plant secondary metabolites. Their structures were elucidated by spectroscopic analyses. Compounds 1-3 exhibited moderate inhibitory activity against α-glucosidase with IC₅₀ values of 16.9 μM (1), 23.7 μM (2) and 12.8 μM (3), respectively.     

Four new copper(II) complexes with di-substituted s-triazine-based ligands

In this paper, two di-substituted triazine-based ligands, 6-chloro-N,N,N′N′-tetrakis-pyridin-2-ylmethyl-[1,3,5]triazine-2,4-diamine (L1), and 6-chloro-N,N′-bis-pyridin-2-ylmethyl-N,N′-bis-thiophen-2-ylmethyl-[1,3,5]triazine-2,4-diamine (L2), have been prepared. Reaction of CuCl₂·2H₂O and Cu(NO₃)₂·3H₂O with L1 and L2 results in the formation of [Cu₂Cl₄(L1)]·3MeOH (compound 1), [Cu₄(NO₃)₈(L1)₂]·2.07CH₂Cl₂·0.93MeOH (compound 2), [Cu₂Cl₄(L2)₂] (compound 3) and [Cu(NO₃)₂(L2)]·CH₂Cl₂ (compound 4), respectively, which have been fully characterized and determined by single-crystal X-ray crystallography, FT-IR, elemental analysis, thermogravimetric measurement and magnetic susceptibility. The dinuclear compound 1 shows strong π-π interactions between the neighboring pyridine rings. The nitrate-π (1,3,5-triazine ring) interaction with the distance of 2.755 Å in compound 2, is the closest contact reported so far. Compounds 3 and 4 are mononuclear copper(II) compounds, in which none of thiophene rings coordinates with copper(II) ion. In addition, the different orientations of two thiophene rings in compounds 3 and 4 lead to the π-π and CH₂Cl₂-π (thiophene ring) interactions in compound 4, but not in compound 3.     

Cellular reactive oxygen species inhibitory constituents of Hypericum thasium Griseb

The phytochemical investigation of the ethyl acetate extract of Hypericum thasium has led to the characterization of four benzophenone derivatives 1-4, a known benzophenone 5 and four known flavonoids, quercetin (6), quercitrin (7), isoquercetin (8), and 3, 8′′-biapigenin (9). Lucigenin- and luminal-based chemiluminescence assays were employed to monitor the inhibitory activity of these compounds towards the production of reactive oxygen species (ROS) by human polymorphoneutrophils (PMNs). The assay results showed that benzophenones 1 and 3 are extracellular inhibitors of ROS production, while flavonoids 6, 8, and 9 can modulate intracellular ROS production.     

Chemical constituents from fruits of Harrisonia perforata

Eight limonoids (1-8) including three A, B and D-seco-16-nor-type ones, 5,6-dehydrodesepoxyharperforin C2 (1), harrpernoid B (2), and its C-9S epimer, harrpernoid C (3), along with six known compounds (9-14), were isolated from fruits of Harrisonia perforata. Extensive spectroscopic analysis was used to elucidate their structures and stereochemistries. Further confirmation of structures of 1 and 2 were obtained by single-crystal X-ray diffraction. Limonoids (1-8) were evaluated for their anti-tobacco mosaic virus activity and in vitro cytotoxicity against A549 and HL60 cell lines; only compound 2 showed weak activity.     

Ecdysteroids and a sucrose phenylpropanoid ester from Froelichia floridana

Phytoecdysteroid glycosides (1-5) and a phenylpropanoid ester of sucrose (6) were isolated from the whole plant of Froelichia floridana, along with eight known compounds including three ecdysteroids (7-9), four flavonoids (10-13), and one phenolic compound (14). Structures were determined using a combination of spectroscopic techniques. Compounds 1, 2 and 6-14 were tested in vitro for their activity against human DNA topoisomerase I. Compound 13 (diosmetin) showed marginal inhibition against topoisomerase I with IC₅₀ of 130 μM in conjunction with low intercalation ability.     

The investigation of structural and thermosensitive properties of new phosphazene derivative bearing glycol and aminoalcohol

Three isomers (nongeminal cis-2,4,6 (2); nongeminal trans-2,4,6 (3); geminal 2,2,4 (4)) were isolated from the reaction of hexachlorocyclotriphosphazatriene (trimer) (1) with diethylene glycol monobutyl ether (DEGBE). The substitution reactions of cis-tris isomer (2) with 3-amino-1-propanol were investigated under different solutions conditions to provide amphiphilic phosphazene (5). All of compounds were characterized by using elemental analysis, ³¹P NMR and mass spectroscopies. Thermosensitive properties of compound 5 were studied. The compound 5 is soluble in both water and organic media. This indicates that compound 5 is an amphiphilic molecule. Concentration-dependent LCST (Lower Critical Solution Temperature) behavior of 5 was measured in water. Compound 5 exhibited a reversible and thermosensitive phase transition in aqueous medium, from soluble to insoluble states. Compound 5 showed LCST at 37 °C (for 7 wt.% concentration) which is near to body temperature.     

Synthesis, characterization and crystal structures of the organotin(IV) compounds with the Schiff base ligands of pyruvic acid thiophene-2-carboxylic hydrazone and salicylaldehyde thiophene-2-carboxylic hydrazone

A series of organotin (IV) compounds of the type [R₃SnL]₂, R is Me (1), Bu (2), [R₂SnL]₂, R is Ph (3), Me (4), Bu (5), L is pyruvic acid thiophene-2-carboxylic hydrazone, and R₂SnL, R is Me (6), Bu (7), Ph (8), L is salicylaldehyde thiophene-2-carboxylic hydrazone have been synthesized in 1:1 molar ratio. All compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR and ¹¹⁹Sn NMR spectra. The crystal structure of compounds 1, 3, 4, 8 have been determined by X-ray single crystal diffraction analyses, study found that the compounds 1 and 3 are rendered one-dimensional chain structure and the tin atoms are five-coordinated in a distorted trigonal-bipyramidal geometry. The compound 4 has a dimeric structure and the central tin atom is rendered seven-coordinate in a distorted pentagonal-bipyramid configuration. While the compound 8 is a monomer in which the tin atom adopts five-coordinated in distorted trigonal-bipyramidal geometry.     

The identification, and optimisation of hERG selectivity, of a mixed NET/SERT re-uptake inhibitor for the treatment of pain

Hit compound 1, a selective noradrenaline re-uptake transporter (NET) inhibitor was optimised to build in potency at the serotonin re-uptake transporter (SERT) whilst maintaining selectivity against the dopamine re-uptake transporter (DAT). During the optimisation of 1 it became clear that selectivity against the Kv11.1 potassium ion channel (hERG) was also a parameter for optimisation within the series. Discrete structural changes to the molecule as well as a lowering of global cLogP successfully increased the hERG selectivity to afford compound 11m, which was efficacious in a mouse model of inflammatory pain, complete Freund’s adjuvant (CFA) induced thermal hyperalgesia and a rat model of neuropathic pain, spinal nerve ligation (SNL) induced mechanical allodynia.