Bioassay-guided fractionation of the leaves of Perovskia atriplicifolia (Russian sage) resulted in the isolation of four previously known flavonoid derivatives, 5-hydroxy-6,7,3′,4′-tetramethoxyflavone (1), 5,7-dihydroxy-6,3′,4′-trimethoxyflavone (2), 5-hydroxy-6,7,4′-trimethoxyflavone (3), and 5,7-dihydroxy-6,4′-dimethoxyflavone (4). Compounds 1, 3, and 4 showed displacement of the radioligand for the cloned human δ opioid receptor with Ki values ranging from 3.1 to 26.0 μM. In addition, the binding mode of the compounds in the active site of the δ opioid receptor was investigated through molecular modeling algorithms. This study may have implications in better understanding non-nitrogenous δ opioid receptor ligands.

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity.

•Phytochemical study of Miconia prasina.•One new flavanone glycoside and five known flavanones were isolated.•In vitro binding assays using cannabinoid receptors (CB1 and CB2) were evaluated.A glycosidic flavanone miconioside C (1) has been isolated from the methanolic extract of the stems of Miconia prasina, together with 7-O-β-d-apiofuranosyl-(1 → 6)-β-d-glucopyranosylmatteucinol (2), miconioside B (3), matteucinol (4), farrerol (5) and desmethoxymatteucinol (6). Their structures were mainly established by extensive NMR studies (1H NMR, 13C NMR, DEPT, 1H–1H COSY, HSQC, HMBC) and mass spectrometry. The compounds 1–3 were evaluated for in vitro binding assays using cannabinoid receptors (CB1 and CB2).

The first reported synthesis of potential kinase inhibitors, 4-oxo-4,5-dihydrothieno[3,2-\(c\)]quinoline-2-carboxylic acid derivatives starting from aniline is described. This efficient high yielding sequence was carried out in six steps without any chromatographic purification. A tandem nucleophilic aromatic substitution/cyclization reaction was used as a key step in the sequence. The versatile intermediate 2-carboxylic acid was used as a suitable precursor to access the functionalization of the C-ring, by convergent analog synthesis of several novel derivatives.

Bioassay-guided fractionation of a fungus Neocosmospora sp. (UM-031509) resulted in the isolation of three new resorcylic acid lactones, neocosmosin A (2), neocosmosin B (3), and neocosmosin C (4). Three known resorcylic acid lactones, monocillin IV (1), monocillin II (5), and radicicol (6), were also isolated and identified. The structures of these compounds were established on the basis of extensive 1D and 2D NMR spectroscopic analysis, mass spectrometric (ESIMS) data, and X-ray crystallography. Compounds 4–6 show good binding affinity for the human opioid receptors. These findings have important implications for evaluating the potential psychoactive effects with this class of compounds.

Bioassay-guided fractionation of Cladosporium cladosporioides (Fresen.) de Vries extracts led to the isolation of four compounds, including cladosporin, 1; isocladosporin, 2; 5′-hydroxyasperentin, 3; and cladosporin-8-methyl ether, 4. An additional compound, 5′,6-diacetylcladosporin, 5, was synthesized by acetylation of compound 3. Compounds 1–5 were evaluated for antifungal activity against plant pathogens. Phomopsis viticola was the most sensitive fungus to the tested compounds. At 30 μM, compound 1 exhibited 92.7, 90.1, 95.4, and 79.9% growth inhibition against Colletotrichum acutatum, Colletotrichum fragariae, Colletotrichum gloeosporioides, and P. viticola, respectively. Compound 2 showed 50.4, 60.2, and 83.0% growth inhibition at 30 μM against Co. fragariae, Co. gloeosporioides, and P. viticola, respectively. Compounds 3 and 4 were isolated for the first time from Cl. cladosporioides. Moreover, the identification of essential structural features of the cladosporin nuclei has also been evaluated. These structures provide new templates for the potential treatment and management of plant diseases.

Bioassay-guided fractionation of the EtOAc extracts of the epiphytic fungus Emericella nidulans resulted in the isolation of a mixture of two fatty acids. This mixture showed 98% binding affinity to human δ opioid receptor. These two fatty acids were identified as palmitic (PAM), 1, and linoleic acids (LNA), 2, by 1D NMR as well as by GC/MS analysis, after their methylation. We found that different ratio mixtures of 1 and 2 showed variations in selective binding activities to human δ opioid receptors. Five more fatty acids, arachidonic acid (ARA), 3, cis-4,7,10,13,16,19-docosahexanoic acid (DHA), 4, cis-5,8,11,14,17-eicosapentaenoic acid (EPA), 5, linolenic acid (ALA), 6, and γ-linolenic acid (GLA), 7, were evaluated for their binding affinity for opioid receptors. ARA, 3, displayed affinity to δ and μ human opioid receptors with 68% and 80%, respectively. GLA, 7, showed selective binding affinity to μ receptor with a value of 55%. These findings provide fascinating insight into the use of foods with high concentrations of fatty acids.

Bioassay-guided fractionation of the fungus Eurotium repens resulted in the isolation of two new benzyl derivatives, (E)-2-(hept-1-enyl)-3-(hydroxymethyl)-5-(3-methylbut-2-enyl)benzene-1,4-diol (1) and (E)-4-(hept-1-enyl)-7-(3-methylbut-2-enyl)-2,3-dihydrobenzofuran-2,5-diol (2), along with seven known compounds (3–9) including five benzaldehyde compounds, flavoglaucin (3), tetrahydroauroglaucin (4), dihydroauroglaucin (5), auroglaucin (6), and 2-(2′,3-epoxy-1′,3′- heptadienyl)-6-hydroxy-5-(3-methyl-2-butenyl)benzaldehyde (7), one diketopiperazine alkaloid, echinulin (8), and 5,7-dihydroxy-4-methylphthalide (9). The chemical structures of these compounds were established on the basis of extensive 1D and 2D NMR and HRMS data. Compounds 1–4 and 6 showed good binding affinity for human opioid or cannabinoid receptors. These findings have important implications for psychoactive studies with this class of compounds.

A new compound, euparvic acid (1, C14H16O6), and the known compounds 5,7-dihydroxy-4-methylphthalide (2), 6-(3-carboxybutyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (3), 6-(5-carboxy-3-methylpent-2-enyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (4), and 6-(5-carboxy-4-hydroxy-3-methylpent-2-enyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one (5) were isolated from the EtOAc extract of Eupenicillium parvum. The structure of 1 was determined by interpretation of MS and homo- and heteronuclear 2D NMR spectroscopic data and confirmed by X-ray crystallography. The absolute configuration of 5 was determined via MPA ester derivatization.

A series of m-terphenyl amines was synthesized and evaluated as a novel class of cyclooxygenase (COX) inhibitors. Structure–activity relationships (SAR) were investigated by functional group modification at the para-position of the C-1′ and C-2′ phenyl substituents on the central aromatic ring. Anilines 6a, b, d, and h demonstrated nonselective inhibition of COX-1 and -2 in human whole blood. Compounds 6c and e demonstrated preferential inhibition of the COX-2 isozyme at 10 μM. Molecules 6f, i, and j inhibited only COX-1, and the disubstituted ethoxy derivative (6g) was inactive as a COX inhibitor (≤ 100 μM). Molecular docking studies of these compounds indicate that the COX-1 binding site amino acid Ile523 anchors the m-terphenyl system statically within the enzyme’s active site, while the slightly smaller amino acid Val523 in COX-2 allows the ligand to “roll,” fashioning several acceptable conformers.