Molecular hybrids of substituted phenylcarbamoylpiperidine and 1,2,4-triazole methylacetamide as potent 15-LOX inhibitors: Design, synthesis, DFT calculations and molecular docking studies.

Inflammation is a multifaceted phenomenon triggered by potentially active mediators acutely released arachidonic acid metabolites partially in lipoxygenase (LOX) pathway which are primarily accountable for causing several diseases in humans. It is widely believed that an inhibitor of the LOX pathway represents a rational approach for designing more potent antiinflammatory leads with druggable super safety profiles. In our continual efforts in search for anti-LOX molecules, the present work was to design a new series of N-alkyl/aralkyl/aryl derivatives (7a-o) of 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol which was commenced in seriate formation of phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol (4). The aimed compounds were obtained by reacting 4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazole-3-thiol with assorted N-alkyl/aralkyl/aryl electrophiles. All compounds were characterized by FTIR, 1H-, 13C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry and screened against soybean 15-LOX for their inhibitory potential using chemiluminescence method. All the compounds except 7m and 7h inhibited the said enzyme remarkably. Compounds 7c,7l, 7j and 7a displayed potent inhibitions ranging from IC50 1.92 ± 0.13 µM to 7.65 ± 0.12 µM. Other analogues 7g, 7o, 7e, 7b, 7d, 7k and 7n revealed excellent inhibitory values ranging from IC50 12.45 ± 0.38 µM to 24.81 ± 0.47 µM. All these compounds did not reveal DPPH radical scavenging activity. Compounds 7i-o maintained > 90 % human blood mononuclear cells (MNCs) viability at 0.125 mM as assayed by MTT whilst others were found toxic. Pharmacokinetic profiles predicted good oral bioavailability and drug-likeness properties of the active scaffolds. SAR investigations showed that phenyl substituted analogue on amide side decreased inhibitory activity due to inductive and mesomeric effects while the mono-alkyl substituted analogues were more active than disubstituted ones and ortho substituted analogues were more potent than meta substituted ones. MD simulation predicted the stability of the 7c ligand and receptor complex as shown by their relative RMSD (root mean square deviation) values. Molecular docking studies displayed hydrogen bonding between the compounds and the enzyme with Arg378 which was common in 7n, 7g, 7h and baicalein. In 7a and quercetin, hydrogen bonding was established through Asn375. RMSD values exhibited good inhibitory profiles in the order quercetin (0.73 Å) < 7 g < baicalein < 7a < 7n < 7 h (1.81 Å) and the binding free energies followed similar pattern. Density functional theory (DFT) data established good correlation between the active compounds and significant activity was associated with more stabilized LUMO (lowest unoccupied molecular orbitals) orbitals. Nevertheless, the present studies declare active analogues like 7c, 7 l, 7a, 7j as leads. Work is ongoing in derivatizing active molecules to explore more effective leads as 15-LOX inhibitors as antiinflammatory agents.

Terpenoids as Human Neutrophil Elastase (HNE) Inhibitors: A Comprehensive Review of Natural Anti-inflammatory Isoprenoids.

Human neutrophil elastase (HNE) is an enzyme that plays a key role in the body's inflammatory response. It has been linked to several diseases such as chronic obstructive pulmonary disease (COPD), emphysema, and cystic fibrosis. As potential treatments for these diseases, HNE inhibitors are of great interest. Metabolites derived from plants, particularly terpenoids such as ß-caryophyllene found in black pepper and other plants, and geraniol present in several essential oils, are recognized as significant sources of inhibitors for HNE. Because of their ability to inhibit HNE, terpenoids are considered promising candidates for developing novel therapies to treat inflammatory conditions such as COPD and emphysema. Furthermore, nature can serve as an excellent designer, and it may offer a safer drug candidate for inhibiting HNE production and activity in the future. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were searched to get relevant and up-to-date literature on terpenoids as human neutrophil elastase inhibitors. This review focuses on the isolation, chemical diversity, and inhibition of human neutrophil elastase (HNE) of various terpenoids reported from natural sources up to 2022. A total of 251 compounds from various terpenoids classes have been reported. Further, it also provides a summary of HNE inhibitors and includes a thorough discussion on the structure-activity relationship.

Assessing p-tolyloxy-1,3,4-oxadiazole acetamides as lipoxygenase inhibitors assisted by in vitro and in silico studies.

The underlying correlation between the inflammation, innate immunity and cancer is extensively familiar and linked through a process mediated by three enzymes; cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). The ever increase in the reported side effects of the antiinflammatory drugs against the targeted enzymes and the resistance developed afterwards compels the researchers to synthesize new effective molecules with safer profile. On the basis of these facts, our ongoing research on 1,3,4-oxadiazole derivatives deals with the synthesis of a new series of N-alkyl/aralky/aryl derivatives of 5-((p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-ylthio)acetamide (6a-o) which were developed by the sequential conversion of p-tolyloxyacetic acid (a) into ester (1) hydrazide (2) and 5-(p-tolyloxymethyl)-4H-1,3,4-oxadiazole-2-thiol (3). The designed compounds (6a-o) were acquired by the reaction of 1,3,4-oxadiazole (3) with numerous electrophiles (5a-o) in KOH. The synthesized analogues (6a-o) were characterized by FTIR, 1H-, 13C NMR spectroscopy, EI-MS and HR-EI-MS spectrometry, and were further assessed for their inhibitory potential against the soybean 15-LOX enzyme. The results showed excellent inhibitory potential of the compounds against the said enzyme, specifically 6o, 6b, 6n and 6e with inhibitory values (IC50 ± SEM) of 21.5 ± 0.76, 24.3 ± 0.45, 29.1 ± 0.65 and 31.3 ± 0.78 µM, respectively. These compounds displayed < 55 % blood mononuclear cells (MNCs) cellular viability as measured by MTT assay at 0.25 mM concentration. Other compounds demonstrated moderate inhibitory activities with IC50 values in the range of 33.2 ± 0.78 to 96.3 ± 0.73 µM and exhibited little cellular viability against MNCs except 6i, 6j, 6 m and 6 k that showed 61-79 % cellular viability. It was observed that most of the compounds (6o, 6b, 6n, 6e) were found more toxic towards MNCs at studied concentration of 0.25 mM. SAR studies revealed that the positions and nature of substituents accompanying phenyl ring have great influence on 15-LOX inhibitory activity. In the most active compound 6o, the amino acids Asp768 and Val126 were involved in hydrogen bonding, Thr529 was linked with π-anion interaction and π-sulphur interaction was displayed with Tyr525 and two π-alkyl interactions were formed with the benzene ring and amino acid residues Pro530 and Arg533. The in silico pharmacokinetics profiles and density functional theory calculations of the compounds further supported the in vitro findings. Further work on the synthesis of more oxadiazole derivatives is in progress in search for potential 'leads' for the drug discovery as LOX inhibitors.

Discovery of Phenylcarbamoylazinane-1,2,4-Triazole Amides Derivatives as the Potential Inhibitors of Aldo-Keto Reductases (AKR1B1 & AKRB10): Potential Lead Molecules for Treatment of Colon Cancer.

Both members of the aldo-keto reductases (AKRs) family, AKR1B1 and AKR1B10, are over-expressed in various type of cancer, making them potential targets for inflammation-mediated cancers such as colon, lung, breast, and prostate cancers. This is the first comprehensive study which focused on the identification of phenylcarbamoylazinane-1, 2,4-triazole amides (7a−o) as the inhibitors of aldo-keto reductases (AKR1B1, AKR1B10) via detailed computational analysis. Firstly, the stability and reactivity of compounds were determined by using the Guassian09 programme in which the density functional theory (DFT) calculations were performed by using the B3LYP/SVP level. Among all the derivatives, the 7d, 7e, 7f, 7h, 7j, 7k, and 7m were found chemically reactive. Then the binding interactions of the optimized compounds within the active pocket of the selected targets were carried out by using molecular docking software: AutoDock tools and Molecular operation environment (MOE) software, and during analysis, the Autodock (academic software) results were found to be reproducible, suggesting this software is best over the MOE (commercial software). The results were found in correlation with the DFT results, suggesting 7d as the best inhibitor of AKR1B1 with the energy value of −49.40 kJ/mol and 7f as the best inhibitor of AKR1B10 with the energy value of −52.84 kJ/mol. The other potent compounds also showed comparable binding energies. The best inhibitors of both targets were validated by the molecular dynamics simulation studies where the root mean square value of <2 along with the other physicochemical properties, hydrogen bond interactions, and binding energies were observed. Furthermore, the anticancer potential of the potent compounds was confirmed by cell viability (MTT) assay. The studied compounds fall into the category of drug-like properties and also supported by physicochemical and pharmacological ADMET properties. It can be suggested that the further synthesis of derivatives of 7d and 7f may lead to the potential drug-like molecules for the treatment of colon cancer associated with the aberrant expression of either AKR1B1 or AKR1B10 and other associated malignancies.

Exploring phenylcarbamoylazinane-1,2,4-triazole thioethers as lipoxygenase inhibitors supported with in vitro, in silico and cytotoxic studies.

Searching small molecules as an auspicious approach to develop new anti-inflammatory drugs is a challenge for the researchers especially by modifying active pharmacophoric groups in the targeted molecules. In the current work, a series of new S-alkyl/aralky derivatives (8a-h; 9a-h) of 2-(4-ethyl/phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,2,4-triazol-3-ylthio)ether were synthesized and assessed for their inhibitory action against the 15-lipoxygenase from soybean (15-sLOX). The basic precursor ethyl piperidine-4-carboxylate (a) was consecutively changed into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazides (3/4) and N-ethyl/phenyl-5-(1-phenylcarbamoylpiperidine)-1,2,4-triazoles (5/6), which further in association with electrophiles (7a-h) promoted to the final products (8a-h; 9a-h). The synthesized derivatives were characterized by FT-IR, 1H-, 13C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. Amongst these, 8a, 8c, and 9c, expressed potent inhibitory profiles against the 15-sLOX enzyme with IC50 values of 12.52 ± 0.35 to 35.64 ± 0.29 µM, followed by the compounds 9b, 9g, 9d, 9a, 8b, 8e, 8d, 8g, 8h, 8f and 9h with IC50 values in the range of 43.78 ± 0.43 to 108.65 ± 0.38 µM. All compounds exhibited variable cellular viability levels by MTT assay. Flow cytometric data demonstrated that 8f, 8g, 8h have maximal lymphocyte cellular viability and all compounds affected cells in the late apoptosis phase. In silico ADMET studies supported the drug-likeness of most of the molecules. These studies were supported by molecular docking against 15-sLOX, human 5-LOX (5-hLOX) and human 15-LOX (5-hLOX); that inhibitors of 15-sLOX docked-in the active pocket of either 5-hLOX or 15-hLOX and docking score remained constant for all three enzymes within a narrow range (-6.8 to -9.7) as did it for standard quercetin (-8.4 to -9.0). The most dominant bonding interactions were π-π, π-anion, and π-alkyl type along with the hydrogen bonding. The data collected altogether demonstrates the better possibility of some of these compounds as good LOX inhibitors in search for 'lead' as anti-inflammatory agents in the process of drug discovery and development.

Identification of phenylcarbamoylazinane-1,3,4-oxadiazole amides as lipoxygenase inhibitors with expression analysis and in silico studies.

In search for new anti-inflammatory agents that inhibit the enzymes of arachidonic acid pathway as the drug targets, the present article describes the screening of 1,3,4-oxadiazole analogues against lipoxygenase (LOX) enzyme. The work is based on the synthesis of new N-alkyl/aralky/aryl derivatives (6a-o) of 2-(4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,3,4-oxadiazol-3-ylthio)acetamide which were obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a-o), in KOH. The synthesized analogues showed potent to moderate inhibitory activity against the soybean 15-LOX enzyme; especially 6g, 6b, 6a and 6l displayed the potent inhibitory potential with IC50 values 7.15 ± 0.26, 9.32 ± 0.42, 15.83 ± 0.45 & 18.37 ± 0.53 µM, respectively, while excellent to moderate inhibitory profiles with IC50 values in the range of 26.13-98.21 µM were observed from the compounds 6k, 6m, 6j, 6o, 6h, 6f, 6n and 6c. Most of the active compounds exhibited considerable cell viability against blood mononuclear cells (MNCs) at 0.25 mM by MTT assay except 6f, 6h, 6k and 6m which showed around 50% cell viability. Flow cytometry studies of the selected compounds 6a, 6j and 6n revealed that these caused 79.5-88.51% early apoptotic changes in MNCs compared with 4.26% for control quercetin at their respective IC50 values. The relative expression of 5-LOX gene was monitored in MNCs after treatment with these three molecules and all down-regulated the enzyme activity. In silico ADME and molecular docking studies further supported these studies of oxadiazole derivatives and considered it as potential 'lead' compounds in drug discovery and development.

Identification of NSAIDs as lipoxygenase inhibitors through highly sensitive chemiluminescence method, expression analysis in mononuclear cells and computational studies.

Here we report the inhibitory effects of nine non-steroidal anti-inflammatory drugs (NSAIDs) on soybean 15-lipoxygenase (15-LOX) enzyme (EC 1.13.11.12) by three different methods; UV-absorbance, colorimetric and chemiluminescence methods. Only two drugs, Ibuprofen and Ketoprofen, exhibited enzyme inhibition by UV-absorbance method but none of the drug showed inhibition through colorimetric method. Chemiluminescence method was found highly sensitive for the identification of 15-LOX inhibitors and it was more sensitive and several fold faster than the other methods. All tested drugs showed 15-LOX-inhibition with IC50 values ranging from 3.52 ± 0.08 to 62.6 ± 2.15 µM by chemiluminescence method. Naproxen was the most active inhibitor (IC50 3.52 ± 0.08 µM) followed by Aspirin (IC50 4.62 ± 0.11 µM) and Acetaminophen (IC50 6.52 ± 0.14 µM). Ketoprofen, Diclofenac and Mefenamic acid showed moderate inhibitory profiles (IC50 24.8 ± 0.24 to 39.62 ± 0.27 µM). Piroxicam and Tenoxicam were the least active inhibitors with IC50 values of 62.6 ± 2.15 µM and 49.5 ± 1.13 µM, respectively. These findings are supported by expression analysis, molecular docking studies and density functional theory calculations. The expression analysis and flow cytometry apoptosis analysis were carried out using mononuclear cells (MNCs) which express both human 15-LOX and 5-LOX. Selected NSAIDs did not affect the cytotoxic activity of MNCs at IC50 concentrations and the cell death showed dose dependent effect. However, MNCs apoptosis increased only at the higher concentrations, demonstrating that these drugs may not induce loss of immunity in septic and other inflammatory conditions at the acceptable inhibitory concentrations. The data collectively suggests that NSAIDs not only inhibit COX enzymes as reported in the literature but soybean 15-LOX and MNCs LOXs are also inhibited at differential values. A comparison of the metabolomics studies of arachidonic acid pathway after inhibition of either COX or LOX enzymes may reconfirm these findings.

Probing phenylcarbamoylazinane-1,2,4-triazole amides derivatives as lipoxygenase inhibitors along with cytotoxic, ADME and molecular docking studies.

Hunting small molecules as anti-inflammatory agents/drugs is an expanding and successful approach to treat several inflammatory diseases such as cancer, asthma, arthritis, and psoriasis. Besides other methods, inflammatory diseases can be treated by lipoxygenase inhibitors, which have a profound influence on the development and progression of inflammation. In the present study, a series of new N-alkyl/aralky/aryl derivatives (7a-o) of 2-(4-phenyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide was synthesized and screened for their inhibitory potential against the enzyme 15-lipoxygenase. The simple precursor ethyl piperidine-4-carboxylate (a) was successively converted into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and N-phenylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4), then in combination with electrophiles (6a-o) through further multistep synthesis, final products (7a-o) were generated. All the synthesized compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. Almost all the synthesized compounds showed excellent inhibitory potential against the tested enzyme. Compounds 7c, 7f, 7d, and 7g displayed potent inhibitory potential (IC50 9.25 ± 0.26 to 21.82 ± 0.35 µM), followed by the compounds 7n, 7h, 7e, 7a, 7b, 7l, and 7o with IC50 values in the range of 24.56 ± 0.45 to 46.91 ± 0.57 µM. Compounds 7c, 7f, 7d exhibited 71.5 to 83.5% cellular viability by MTT assay compared with standard curcumin (76.9%) when assayed at 0.125 mM concentration. In silico ADME studies supported the drug-likeness of most of the molecules. In vitro inhibition studies were substantiated by molecular docking wherein the phenyl group attached to the triazole ring was making a π-δ interaction with Leu607. This work reveals the possibility of a synthetic approach of compounds in relation to lipoxygenase inhibition as potential lead compounds in drug discovery.

Investigation on the Phytochemical Composition, Antioxidant and Enzyme Inhibition Potential of Polygonum Plebeium R.Br: A Comprehensive Approach to Disclose New Nutraceutical and Functional Food Ingredients.

The present work describes medicinal potential and secondary metabolic picture of the methanol extract (PP-M) of Polygonum plebeium R.Br. and its fractions; hexane (PP-H), ethyl acetate (PP-E) and water (PP-W). In total bioactive component estimation, highest contents of phenolic (89.38±0.27 mgGAE/g extract) and flavonoid (51.21±0.43 mgQE/g extract) were observed in PP-E, and the same fraction exhibited the highest antioxidant potential in DPPH (324.80±4.09 mgTE/g extract), ABTS (563.18±11.39 mgTE/g extract), CUPRAC (411.33±15.49 mgTE/g extract) and FRAC (369.54±1.70 mgTE/g extract) assays. In Phosphomolybdenum activity assay, PP-H and PP-E showed nearly similar potential, however, PP-H was the most active (13.54±0.24 mgEDTAE/g extract) in metal chelating activity assay. PP-W was the stronger inhibitor (4.03±0.05 mgGALAE/g extract) of the enzyme AChE, while PP-H was potent inhibitor of BChE (5.62±0.27 mg GALAE/g extract). Interestingly, PP-E was inactive against BChE. Against tyrosinase activity, PP-E was again the most active fraction with inhibitory value of 71.89±1.44 mg KAE/g extract, followed by the activity of PP-M and PP-W. Antidiabetic potential was almost equally distributed among PP-M, PP-H and PP-E. For mapping the chemodiversity of P. plebeium, PP-M was analyzed through UHPLC/MS, which led to the identification of more than 50 compounds. Flavonoids were the main components derived from isovitexin, kaempferol and luteolin however, gallic acid, protocatechuic acid, gingerols and lyoniresinol 9'-sulfate were among important bioactive phenols. These findings prompted to conclude that Polygonum plebeium can be a significant source to offer new ingredient for nutraceuticals and functional foods.

Molecular and functional analysis of naphthalene-degrading bacteria isolated from the effluents of indigenous tanneries.

During present study, four naphthalene- metabolizing bacteria were isolated from tanneries effluents through enrichment on naphthalene as sole carbon source in minimal salt medium. The bacteria were analyzed to document growth pattern, naphthalene removal efficiency, biochemical and molecular characteristics, antibiotic sensitivity, and metabolic profile. The 16S ribosomal RNA gene sequences were compared through BLAST (basic local alignment search tool) similarity search tool and three isolates were found homologous to Brevibacillus agri strain NBRC 15538 and one similar to Burkholderia lata strain 383. The naphthalene removal efficiencies ranged from 1.16 ± 0.056 mg/h (IUBN1) to 1.379 ± 0.021 mg/h (IUBN26). All isolates were positive for p-nitrophenyl phosphate (PO4 ), esculin, and inulin fermentation tests. Majority were positive for glucosaminidase (IUBN3, 17, and 26) and a few for mannitol and sorbitol fermentation (IUBN1). Identification of metabolites through gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry analysis allowed tracing pathways associated with naphthalene degradation. Intermediates such as cis-dihydrodiolnaphthalene, 2-hydroxychromene-2-carboxylate, 6-hydroxyhexanoic acid, acetyl-CoA confirmed that the present study bacteria can metabolize naphthalene through a pathway which differs from the pathways reported in earlier known bacteria. Due to fast growth rates, high naphthalene removal potentials, and multiple degradation pathways, these bacteria can be exploited for bioremediation of naphthalene.

Toluene degradation via a unique metabolic route in indigenous bacterial species.

Tanneries are the primary source of toluene pollution in the environment and toluene due to its hazardous effects has been categorized as persistent organic pollutant. Present study was initiated to trace out metabolic fingerprints of three toluene-degrading bacteria isolated from tannery effluents of Southern Punjab. Using selective enrichment and serial dilution methods followed by biochemical, molecular and antibiotic resistance analysis, isolated bacteria were subjected to metabolomics analysis. GC-MS/LC-MS analysis of bacterial metabolites helped to identify toluene transformation products and underlying pathways. Three toluene-metabolizing bacteria identified as Bacillus paralicheniformis strain KJ-16 (IUBT4 and IUBT24) and Brevibacillus agri strain NBRC 15538 (IUBT19) were found tolerant to toluene and capable of degrading toluene. Toluene-degrading potential of these isolates was detected to be IUBT4 (10.35 ± 0.084 mg/h), IUBT19 (14.07 ± 3.14 mg/h) and IUBT24 (11.1 ± 0.282 mg/h). Results of GC-MS analysis revealed that biotransformation of toluene is accomplished not only through known metabolic routes such as toluene 3-monooxygenase (T3MO), toluene 2-monooxygenase (T2MO), toluene 4-monooxygenase (T4MO), toluene methyl monooxygenase (TOL), toluene dioxygenase (Tod), meta- and ortho-ring fission pathways. But additionally, confirmed existence of a unique metabolic pathway that involved conversion of toluene into intermediates such as cyclohexene, cyclohexane, cyclohexanone and cyclohexanol. LC-MS analysis indicated the presence of fatty acid amides, stigmine, emmotin A and 2, 2-dinitropropanol in supernatants of bacterial cultures. As the isolated bacteria transformed toluene into relatively less toxic molecules and thus can be preferably exploited for the eco-friendly remediation of toluene.

A novel five-step synthetic route to 1,3,4-oxadiazole derivatives with potent α-glucosidase inhibitory potential and their in silico studies.

A series of new N-aryl/aralkyl derivatives of 2-methyl-2-{5-(4-chlorophenyl)-1,3,4-oxadiazole-2ylthiol}acetamide were synthesized by successive conversions of 4-chlorobenzoic acid (a) into ethyl 4-chlorobenzoate (1), 4-chlorobenzoylhydrazide (2) and 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol (3), respectively. The required array of compounds (6a-n) was obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a-n) in the presence of DMF (N,N-dimethylformamide) and sodium hydroxide at room temperature. The structural determination of these compounds was done by infrared, 1 H-NMR (nuclear magnetic resonance), 13 C-NMR, electron ionization mass spectrometry, and high-resolution electron ionization mass spectrometry analyses. All compounds were evaluated for their α-glucosidase inhibitory potential. Compounds 6a, 6c-e, 6g, and 6i were found to be promising inhibitors of α-glucosidase with IC50 values of 81.72 ± 1.18, 52.73 ± 1.16, 62.62 ± 1.15, 56.34 ± 1.17, 86.35 ± 1.17, 52.63 ± 1.16 µM, respectively. Molecular modeling and ADME (absorption, distribution, metabolism, excretion) predictions supported the findings. The current synthesized library of compounds was achieved by utilizing very common raw materials in such a way that the synthesized compounds may prove to be promising drug leads.

New norterpenoids and a sphingolipid from Carissa opaca.

Chemical investigations on the aerial parts of Carissa opaca resulted in the isolation and characterization of two new nor-triterpenoids (compounds 1 and 2) and a new sphingolipid (compound 3) together with six known compounds. The structures of all the isolates were established using spectral data. All the isolated compounds showed DPPH radical scavenging and enzyme inhibitory activities against enzymes acetylcholinesterase, butyrylcholinesterase, and lipoxygenase.

Bioactive triterpenoids from Atriplex lasiantha.

Chromatographic purification of the ethyl acetate soluble fraction from the methanolic extract of Atriplex lasiantha yielded a new triterpenoid, 7ß,15α,16ß-trihydroxyolean-12-ene-28,30-dioic acid-3-O-ß-D-xylopyranoside (1), along with two known triterpenoids, rotundifolioside I (2) and corchorusin B (3). Structures of the compounds 1-3 were elucidated through sophisticated NMR studies and high resolution mass spectrometry. The three isolates (1-3) were evaluated for antibacterial, antioxidant, and antiurease activities. Compound 2 exhibited the best antibacterial activity against Escherichiacoli with IC50 value of 66.25 µg/ml, whereas, all the tested compounds exhibited antioxidant (IC50 values of 68.7-75.4 µg/ml) and antiurease (IC50 values of 25.5-49.3 µg/ml) activities, respectively.

Absolute configuration of oplopanone derivatives from Serphidium stenocephalum: ECD spectra of acyclic ketones with front-octant contributions.

The electronic circular dichroism (ECD) spectra of two sesquiterpenoids (1 and 2) related to oplopanone, obtained from a methanolic extract of the plant Serphidium stenocephalum (Artemisia stenocephala), were measured and reproduced by means of time-dependent density functional theory (TDDFT) calculations, establishing their absolute configuration. The application of ketone octant rule for carbonyl n-π* ECD band to compounds 1 and 2, which include an acyclic carbonyl group, was critically assessed. The peculiar oplopanone skeleton makes a straightforward application of the octant rule impossible, because of the uncertainty related to the shape of the so-called third nodal surface separating front and back octants. The various group contributions to the carbonyl n-π* ECD band were estimated with TDDFT calculations on selected molecular models obtained by consecutive dissections from 1.

α-Glucosidase and lipoxygenase inhibitory derivatives of cryptosporioptide from the endophytic fungus Cryptosporiopsis sp.

Two new cryptosporioptide-derived polyketides cryptosporioptides A (2) and B (3) were isolated from the extract of endophytic fungus Cryptosporiopsis sp. associated with the shrub, Viburnum tinus. The structures of the isolates were determined through spectral analysis including 1D NMR ((1)H, (13)C) and 2D NMR (HSQC, HMBC, COSY) techniques, HR-FAB-MS and by comparison with the reported data of cryptosporioptide (1). The relative stereochemistry was assigned with the help of NOESY analysis, the molecular model, and comparison of the optical rotation values with the reference compound 1.

New acylated flavonoid glycosides from flowers of Aerva javanica.

Chromatographic purification of ethyl acetate soluble fraction of the methanolic extract of the flowers of Aerva javanica yielded three new acylated flavone glycosides: kaempferol-3-O-ß-d-[4‴-E-p-coumaroyl-α-l-rhamnosyl(1 â†’ 6)]-galactoside (1), kaempferol-3-O-ß-d-[4‴-E-p-coumaroyl-α-l-rhamnosyl(1 â†’ 6)]-(3″-E-p-coumaroyl)galactoside (2), and kaempferol-3-O-ß-d-[4‴-E-p-coumaroyl-α-l-rhamnosyl(1 â†’ 6)]-(4″-E-p-coumaroyl)galactoside (3), along with p-coumaric acid (4), caffeic acid (5), gallic acid (6), eicosanyl-trans-p-coumarate (7), hexadecyl ferulate (8), and hexacosyl ferulate (9). The compounds 1-9 were characterized using 1D ((1)H, (13)C) and 2D NMR (HMQC, HMBC, and COSY) spectroscopy and mass spectrometry (EI-MS, HR-EI-MS, FAB-MS, and HR-FAB-MS) and in comparison with the reported data in the literature. Compound 1 showed weak inhibitory activity against enzymes, such as acetylcholinesterase, butyrylcholinesterase, and lipoxygenase with IC50 values 205.1, 304.1, and 212.3 µM, respectively, whereas compounds 2 and 3 were only weakly active against the enzyme acetylcholinesterase.

New lipoxygenase inhibitory sphingolipids from Chrozophora plicata.

Two new sphingolipids plicatin A [(2S,3S,4R)-2-{[(2R)-2-hydroxyoctdecanoyl]amino}hexaeicosane-1,3,4-triol (1)] and plicatin B [(2S,3S,4R,10E)-2-{[(2R)-2-hydroxyoctdecanoyl]amino}tricont-10-ene-1,3,4-triol (2)], together with 4-hydroxybenzaldehyde, scopoletin, uracil, and dl-threonolactone were isolated from the methanolic extract of the whole plant of Chrozophora plicata. The structures of these compounds were established using 1D ((1)H, (13)C) and 2D NMR (HMQC, HMBC, and COSY) spectroscopy and mass spectrometry (EI-MS and HR-EI-MS) and in comparison with the reported data in the literature. Compounds 1 and 2 showed inhibitory potential against enzyme lipoxygenase with IC50 values 195.1 and 102.3 µM, respectively.

Bioactive phenolics from Seriphidium stenocephalum.

Chromatographic separation of the ethyl acetate soluble part of the methanolic extract from Seriphidium stenocephalum yielded three new compounds: stenocepflavone (1), stenocepflavan (2), and stenocephol (3), together with cirsimaritin (4), 5,7,5'-trihydroxy-3',4',6-trimethoxyflavone (5), 5,6,7,5'-tetrahydroxy-4'-methoxyflavone (6), and axillaroside (7). All isolates were characterized with the help of spectroscopic data including 1D, 2D NMR, and high resolution mass spectrometry and/or in comparison with the related compounds in literature. All compounds were tested for in vitro enzyme inhibitory activities against acetylcholinesterase, butyrylcholinesterase, and lipoxygenase. Compounds 1 and 4-7 exhibited significant activity against all the tested enzymes, whereas compounds 2 and 3 were found inactive.

Targeting new N-furfurylated 4-chlorophenyl-1,2,4-triazolepropionamide hybrids as potential 15-lipoxygenase inhibitors supported with in vitro and in silico studies.

Lipoxygenases (LOXs) are a group of enzymes that catalyze the oxidation of polyunsaturated fatty acids and initiate the biosynthesis of secondary metabolites that are involved to control inflammation. In search of new and more potent LOX inhibitors, a series of new 3-(5-(4-chlorophenyl)-4-(2-furylmethyl)-1,2,4-triazole hybrids was prepared and screened for its LOX inhibitory potential. 4-Chlorobenzoic acid (a) was metamorphosed into N-furfuryl-5-(4-chlorophenyl)-4-(2-furylmethyl)-1,2,4-triazole (4) via intermediates like benzoate (1), hydrazide (2) and semicarbazide (3). Finally, triazole (4) was fused with propionamides (6a-o) and transformed it into the aimed derivatives (7a-o). The structural interpretations of the prepared derivatives (7a-o) were accomplished via FTIR, 1H-, 13C-NMR spectroscopy, EI-MS and HR-EI-MS spectrometry. The inhibitory potency of the compounds against soybean 15-LOX was determined by in vitro assay using chemiluminescence method. Compounds 7a and 7f exhibited potent LOX inhibitory profiles with IC50 21.83 ± 0.56 and 25.72 ± 0.51 µM, whereas 7d and 7e showed comparable inhibitory potential with IC50 values of 34.52 ± 0.39 and 39.12 ± 0.46 µM, respectively. Compounds 7a, 7f, 7d and 7e exhibited 65.58 ± 1.4%, 54.72 ± 1.3%, 58.52 ± 1.2% and 63.56 ± 1.4% blood mononuclear cells viability, respectively. Density functional theory and molecular docking studies further strengthened the studies of the synthesized compounds and these derivatives perceived to be potential 'lead' compounds in drug discovery as anti-LOX.Communicated by Ramaswamy H. Sarma.