Biocidal Compounds from Mentha sp. Essential Oils and Their Structure–Activity Relationships

Essential oils from Greek Mentha species showed different chemical compositions for two populations of M. pulegium, characterized by piperitone and pulegone. Mentha spicata essential oil was characterized by endocyclic piperitenone epoxide, piperitone epoxide, and carvone. The bioactivities of these essential oils and their components have been tested against insect pests (Leptinotarsa decemlineata, Spodoptera littoralis and Myzus persicae), root‐knot nematodes (Meloydogine javanica) and plants (Lactuca sativa, Lolium perenne, Solanum lycopersicum). The structure–activity relationships of these compounds have been studied including semi‐synthetic endocyclic trans‐carvone epoxide, exocyclic carvone epoxide, a new exocyclic piperitenone epoxide and trans‐pulegone epoxide. Leptinotarsa decemlineata feeding was affected by piperitenone and piperitone epoxide. Spodoptera littoralis was affected by piperitone epoxide and pulegone. The strongest nematicidal agent was piperitenone epoxide, followed by piperitone epoxide, piperitenone and carvone. Germination of S. lycopersicum and L. perenne was significantly affected by piperitenone epoxide. This compound and carvone epoxide inhibited L. perenne root and leaf growth. Piperitenone epoxide also inhibited the root growth of S. lycopersicum. The presence of a C(1) epoxide resulted in strong antifeedant, nematicidal and phytotoxic compounds regardless of the C(4) substituent. New natural crop protectants could be developed through appropriate structural modifications in the p‐menthane skeleton.     

Larvicidal and Structure–Activity Studies of Natural Phenylpropanoids and Their Semisynthetic Derivatives against the Tobacco Armyworm Spodoptera litura (Fab.) (Lepidoptera: Noctuidae)

The larvicidal activity of 18 phenylpropanoids, 1 – 18 , including phenylpropenoate, phenylpropenal, phenylpropene, and their semisynthetic analogues, were evaluated against the tobacco armyworm, Spodoptera litura (Fab .), to identify promising structures with insecticidal activity. Amongst various phenylpropanoids, isosafrole, a phenylpropene, showed the best activity, with an LC₅₀ value of 0.6 μg/leaf cm², followed by its hydrogenated derivative dihydrosafrole (LC₅₀=2.7 μg/leaf cm²). The overall larvicidal activity of various phenylpropene derivatives was observed in the following order: isosafrole ( 6 )>dihydrosafrole ( 16 )>safrole ( 12 )>anethole ( 4 )>methyl eugenol ( 11 )>eugenol ( 13 )>β‐asarone ( 8 )>dihydroasarone ( 18 )>dihydroanethole ( 15 ). Dihydrosafrole might be a promising compound, although presenting a lower larvicidal activity than isosafrole, because of its better stability and resistance to oxidative degradation (due to the removal of the extremely reactive olefinic bond) in comparison to isosafrole. Such structure–activity relationship studies promote the identification of lead structures from natural sources for the development of larvicidal products against S. litura and related insect pests.     

Development of a highly water-soluble peptide-based human neutrophil elastase inhibitor; AE-3763 for treatment of acute organ injury

A series of peptide-based transition-state human neutrophil elastase (HNE) inhibitors with N-terminal acidic moieties were synthesized and their inhibitory activity against HNE was evaluated both in vitro and in vivo. Our results show that compounds containing cyclic amide bridged acidic moieties at the N-terminal have not only improved water solubility but also high in vivo potency. Among these compounds, AE-3763 showed remarkable efficacy in hamster models of elastase-induced lung hemorrhage and lipopolysaccharide (LPS)-induced lung injury as well as in a mouse model of LPS/galactosamine-induced acute multiple organ dysfunctions. The water solubility of AE-3763 (>1000 mg/ml in H₂O) was also far superior to that of any of the other compounds synthesized. Thus, it is believed that AE-3763 would be useful for treatment of HNE-associated respiratory disorders, such as acute respiratory distress syndrome (ARDS), acute lung injury (ALI), and acute exacerbation of chronic obstructive pulmonary disease (COPD).     

Antitumor‐Promoting Effects and Cytotoxic Activities of Dammar Resin Triterpenoids and Their Derivatives

Nineteen known triterpenoids, 1 – 19 , and one known sesquiterpenoid, 20 , were isolated from dammar resin obtained from Shorea javanica K. & V. (Dipterocarpaceae). One of the acidic triterpenoids, dammarenolic acid ( 1 ), was converted to fourteen derivatives, namely, an alcohol, 21 , an aldehyde, 22 , and twelve L ‐amino acid conjugates, 23 – 34 . Compounds 1 – 34 were examined for their inhibitory effects on the induction of Epstein–Barr virus early antigen (EBV‐EA) by 12‐O‐tetradecanoylphorbol 13‐acetate (TPA) in Raji cells, a known primary screening test for antitumor promoters. All of the compounds tested, except for compounds 4, 5, 12 – 14, 16 , and 17 , showed inhibitory effects against EBV‐EA activation with potencies either comparable with or stronger than that of β‐carotene, a known natural antitumor promoter. In addition, (20S)‐20‐hydroxy‐3,4‐secodammara‐4(28),24‐dien‐3‐al ( 22 ) exhibited inhibitory effects on skin tumor promotion in an in vivo two‐stage mouse skin carcinogenesis test based on 7,12‐dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter. Furthermore, evaluation of the cytotoxic activities of compounds 1 – 34 against human cancer cell lines showed that reduction (i.e., 21 and 22 ) or conjugation with L ‐amino acids (i.e., 23 – 34 ) of compound 1 enhanced the cytotoxicity against human melanoma cell line CRL1579.     

Immunosuppressive Withanolides from Withania coagulans

Six new withanolides, withacoagulins A–F ( 1 – 6 , resp.), together with ten known withanolides, 7 – 16 , were isolated from the aerial parts of Withania coagulans. Their structures were determined by spectroscopic techniques including 1D‐ and 2D‐NMR (¹H, ¹³C, HMQC, and HMBC) and MS experiments. These compounds, including the crude extracts of this herb, exhibited strong inhibitory activities on the T‐ and B‐cell proliferation.     

Four Ardeemin Analogs from Endophytic Aspergillus fumigatus SPS‐02 and Their Reversal Effects on Multidrug‐Resistant Tumor Cells

Four ardeemin derivatives, 5‐N‐acetylardeemin ( 1 ), 5‐N‐acetyl‐15bβ‐hydroxyardeemin ( 2 ), 5‐N‐acetyl‐15b‐didehydroardeemin ( 3 ), and 5‐N‐acetyl‐16α‐hydroxyardeemin ( 4 ), were isolated from the fermentation broth of an endophytic Aspergillus fumigatus SPS‐02 associated with Artemisia annua L . The structures of these metabolites were elucidated by a combination of spectroscopic data, including 1D‐, 2D‐NMR and MS. In vitro chemosensitization assay indicated that these ardeemins had different activities of reversing the multidrug‐resistant (MDR) phenotype in three cancer cell lines, leukemia doxorubicin resistant cell K562/DOX, human lung adenocarcinoma cis‐platin‐resistant cell A549/DDP, and ovarian cancer cisplatin‐resistant cell SK‐OV‐S/DDP. Compound 4 exhibited the strongest MDR reversing effect at 5 μM concentration in K562/DOX and A549/DDP cell lines 5.2±0.18‐fold, 8.2±0.23‐fold, respectively, while compound 2 had the highest reversal capacity in SK‐OV‐S/DDP cell line with 10.8±0.28 fold. Preliminary investigation of their structure? activity relationship suggested that a OH group at C(15b) or C(16) in ardeemin plays a key role in reversing the MDR effect. It is the first report on ardeemin analogs from endophytic A. fumigatus with reversal effects on MDR cancer cell lines K562/DOX, A549/DDP and SK‐OV‐S/DDP.     

Synthesis,Characterization, and Anti‐Amoebic Activity of N‐(Pyrimidin‐2‐yl)benzenesulfonamide Derivatives

A new series of N‐(pyrimidin‐2‐yl)benzenesulfonamide derivatives, 3a – 3i and 4a – 4i , was synthesized from pyrimidin‐2‐amines, 2a – 2i , with the aim to explore their effects on in vitro growth of Entamoeba histolytica. The chemical structures of the compounds were elucidated by elemental analysis, FT‐IR, ¹H‐ and ¹³C‐NMR, and ESI mass‐spectral data. In vitro anti‐amoebic activity was evaluated against HM1 : IMSS strain of Entamoeba histolytica. The IC₅₀ values were calculated by using the double dilution method. The results were compared with the IC₅₀ value of the standard drug ‘metronidazole’. The selected compounds were tested for their cytotoxic activities by cell‐viability assay using H9C2 cardiac myoblasts cell line, and the results indicated that all the compounds displayed remarkable >80% viabilities to a concentration of 100 μg/ml.     

An Interactive SAR Approach to Discover Novel Hybrid Thieno Probes as Ligands for D2‐Like Receptors with Affinities in the Subnanomolar Range

A series of [(phenylpiperazinyl)alkyl]‐isoindole‐1,3‐dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound 6a showed the highest affinity towards D4 and D3 receptors with K_i values in the low nanomolar range, and D2/D4‐ and D2/D3‐selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4‐selective ligand thiophene‐2‐carboxamide 9a with a K_i(D4) value of 0.62 nM , and to its butyl analog, 10a , with K_i(D4) and K_i(D3) values of 0.03 and 0.26 nM , respectively. Docking experiments revealed the importance of the unique D4 residue Arg186 in manipulating the ligands' D4‐subtype‐receptor selectivity.     

Structure–Activity Relationship Studies on Derivatives of Eudesmanolides from Inula helenium as Toxicants against Aedes aegypti Larvae and Adults

An Aedes aegypti larval toxicity bioassay was performed on compounds representing many classes of natural compounds including polyacetylenes, phytosterols, flavonoids, sesquiterpenoids, and triterpenoids. Among these compounds, two eudesmanolides, alantolactone, and isoalantolactone showed larvicidal activities against Ae. aegypti and, therefore, were chosen for further structure–activity relationship study. In this study, structural modifications were performed on both alantolactone and isoalantolactone in an effort to understand the functional groups necessary for maintaining and/or increasing its activity, and to possibly lead to more effective insect‐control agents. All parent compounds and synthetic modification reaction products were evaluated for their toxic activities against Ae. aegypti larvae and adults. Structure modifications included epoxidations, reductions, catalytic hydrogenations, and Michael additions to the α,β‐unsaturated lactones. None of the synthetic isomers synthesized and screened against Ae. aegypti larvae were more active than isoalantolactone itself which had an LC₅₀ value of 10.0 μg/ml. This was not the case for analogs of alantolactone for which many of the analogs had larvicidal activities ranging from 12.4 to 69.9 μg/ml. In general, activity trends observed from Ae. aegypti larval screening were not consistent with observations from adulticidal screening. The propylamine Michael addition analog of alantolactone was the most active adulticide synthesized with an LC₅₀ value of 1.07 μg/mosquito. In addition, the crystal structures of both alantolactone and isoalantolactone were determined using CuK_α radiation, which allowed their absolute configurations to be determined based on resonant scattering of the light atoms.     

Semisynthesis and Antifungal Activity of Novel Oxime Ester Derivatives of Carabrone Modified at C(4) against Botrytis cinerea

To continuously improve the potential utility of the natural lead compound of carabrone in agrochemistry, carabrone oxime and 36 novel oxime ester derivatives of carabrone modified at C(4) were synthesized, and evaluated for their antifungal activities against Botrytis cinerea in vitro and in vivo. Of these 36 oxime ester derivatives, some compounds exhibited antifungal activities in vitro or in vivo. It was found that compounds with a pyridinyl residue can either efficiently inhibit spore germination or efficiently inhibit hyphal growth of B. cinerea, and compound 9 exhibited the highest activity in vitro and in vivo with IC₅₀ and EC₅₀ values of 1.17 and 12.9 μg/ml, respectively. Further, the structure? activity relationships are also discussed.     

Protocatechuate 4,5-dioxygenase from <Emphasis Type="Italic">Comamonas testosteroni</Emphasis> T-2: biochemical and molecular properties of a new subgroup within class III of extradiol dioxygenases

Comamonas testosteroni T-2 degraded at least eight aromatic compounds via protocatechuate (PCA), whose extradiol ring cleavage to 2-hydroxy-4-carboxymuconate semialdehyde (HCMS) was catalysed by PCA 4,5-dioxygenase (PmdAB). This inducible, heteromultimeric enzyme was purified. It contained two subunits, (PmdA) and (PmdB), and the molecular masses of the denatured proteins were 18 kDa and 31 kDa, respectively. PCA was converted stoichiometrically to HCMS with an apparent K_m of 55 M and at a maximum velocity of 1.5 kat. Structure–activity-relationship analysis by testing 16 related compounds as substrate for purified PmdAB revealed an absolute requirement for the vicinal diol and for the carboxylate group of PCA. Besides PCA, only 5-hydroxy-PCA (gallate) induced oxygen uptake. The N-terminal amino acid sequence of each subunit was identical to the corresponding sequences in C. testosteroni BR6020, which facilitated sequencing of the pmdAB genes in strain T-2. Small differences in the amino acid sequence had significant effects on enzyme stability. Several homologues of pmdAB were found in sequence databases. Residues involved in substrate binding are highly conserved among the homologues. Their sequences grouped within the class III extradiol dioxygenases. Based on our biochemical and genetic analyses, we propose a new branch of the heteromultimeric enzymes within that class.     

Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Histamine H₁ and serotonin 5-HT_2A receptors present in the CNS have been implicated in various neuropsychiatric disorders. 9-Aminomethyl-9,10-dihydroanthracene (AMDA), a conformationally constrained diarylalkyl amine derivative, has affinity for both of these receptors. A structure–affinity relationship (SAFIR) study was carried out studying the effects of N-methylation, varying the linker chain length and constraint of the aromatic rings on the binding affinities of the compounds with the 5-HT_2A and H₁ receptors. Homology modeling of the 5-HT_2A and H₁ receptors suggests that AMDA and its analogs, the parent of which is a 5-HT_2A antagonist, can bind in a fashion analogous to that of classical H₁ antagonists whose ring systems are oriented toward the fifth and sixth transmembrane helices. The modeled orientation of the ligands are consistent with the reported site-directed mutagenesis data for 5-HT_2A and H₁ receptors and provide a potential explanation for the selectivity of ligands acting at both receptors.     

Triterpene Glucosides from the Leaves of Aralia elata and Their Cytotoxic Activities

Three new triterpene glucosides, named congmuyenosides C–E ( 1 – 3 , resp.), along with four known ones, were isolated from an EtOH extract of Aralia elata (Miq .) Seem . leaves. The structures of the new compounds were identified as 3‐O‐{β‐D ‐glucopyranosyl‐(1→3)‐β‐D ‐glucopyranosyl‐(1→3)‐[β‐D ‐glucopyranosyl‐(1→2)]‐β‐D ‐glucopyranosyl}caulophyllogenin ( 1 ), 3‐O‐{β‐D ‐glucopyranosyl‐(1→3)‐β‐D ‐glucopyranosyl‐(1→3)‐[β‐D ‐glucopyranosyl‐(1→2)]‐β‐D ‐glucopyranosyl}hederagenin 28‐O‐β‐D ‐glucopyranosyl ester ( 2 ), 3‐O‐{β‐D ‐glucopyranosyl‐(1→3)‐β‐D ‐glucopyranosyl‐(1→3)‐[β‐D ‐glucopyranosyl‐(1→2)]‐β‐D ‐glucopyranosyl}echinocystic acid 28‐O‐β‐D ‐glucopyranosyl ester ( 3 ) on the basis of spectral analyses, including MS, ¹H‐NMR, ¹³C‐NMR, DEPT, HSQC, HMBC, NOESY, and HSQC‐TOCSY experiments. All isolates obtained were evaluated for their cytotoxic activities against three human tumor cell lines (HepG2, SKOV3, and A549). Compound 3 showed significant cytotoxicity against A549 cell line (IC₅₀ 9.9±1.5 μM ).     

From Cats and Blackcurrants: Structure and Dynamics of the Sulfur‐Containing Cassis Odorant Cat Ketone

Sulfur‐containing odorants and flavors play an important role in flavor and food industry, especially when meaty, garlic, onion, and vegetable scents are needed. Still, many S‐containing flavors also possess fruity scents and may be used in compositions of perfumes that require a fresh and fruity odor perception. They are naturally abundant in various fruits, essential oils, and food. Most of these compounds possess strong scents, and their scent composition is highly dependent on the concentration applied. At higher concentrations, they usually feature repellent off‐odors, while their sweet and fruity nature is only experienced at very low concentrations. This represents a challenge for their application in perfumery, as well as in food industry. From a molecular point of view, the endless structural and scent variety of these compounds makes them fascinating, especially as their O‐analogs are usually free of any malodors. Here, we report on the investigation of the gas‐phase structure and dynamics of the S‐containing blackcurrant odorant cat ketone (4‐methyl‐4‐sulfanylpentan‐2‐one). The work was performed by combining quantum‐chemical calculations and molecular‐beam Fourier‐transform microwave spectroscopy as complementary tools. Using this technique, we are able to determine the structures of sizeable molecules where energy differences are small and conformational distinction is not always possible by quantum‐chemical calculations alone. The presented results can be used for further structure? activity correlation studies, as well as for benchmarks to improve theoretical models, especially, as there is still significant interest in characterizing the various conformers of organic molecules in terms of relative energies, structures, and dipole moments.     

Inhibition of Lipopolysaccharide‐Induced Nitric Oxide Production by Antofine and Its Analogues in RAW 264.7 Macrophage Cells

Based on the anti‐inflammatory activity of phenanthroindolizidine alkaloids, the inhibitory effect of antofine and its analogues on lipopolysaccharide (LPS)‐induced nitric oxide (NO) production was examined, and structure–activity relationships are discussed. Antofine and several analogues suppressed NO production in LPS‐stimulated RAW 264.7 cells. The MeO group at C(2), and the bulkiness of the substituents at C(3) and C(6) in the phenanthrene ring might be critical for this effect. Besides, regulation of iNOS expression might be involved in the inhibitory effect of antofine on LPS‐induced NO production in macrophage cells.