Pinostrobin and Cajanus lactone isolated from Cajanus cajan (L.) leaves inhibits TNF-α and IL-1β production: In vitro and in vivo experimentation

The tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) inhibitory activities of Cajanus cajan (leaves) crude methanolic extract, its fractions and its phytochemical constituents were evaluated in lipopolysaccharide (LPS) stimulated RAW 264.7 and J774A.1 cells. Phytochemical investigation of the active ethyl acetate (CCE) and n-butanol (CCB) fractions of C. cajan L. leaves yielded 14 compounds. It was observed that both pinostrobin (9) and cajanus lactone (4) were found to be most active in inhibiting TNF-α (IC₅₀ < 22 μM) and IL-1β (IC₅₀ < 40 μM) whereas compounds 2, 3, 5–8, 10 and 14 showed moderate and mild effects (IC₅₀ = 35.50–81.22 μM for TNF-α and 38.23–89.10 μM for IL-1β) in both the cell lines. Furthermore, at dose of 20 mg/kg, both pinostrobin (9) and cajanus lactone (4) were found to reduce LPS-induced TNF-α levels by 48.6% and 55.0% respectively and IL-1β levels by 53.1% and 41.8% respectively in Sprague Dawley (SD) rats. These findings suggest that C. cajan L. leaves can be developed as an effective herbal remedy for the treatment and prevention of inflammation or associated ailments.     

New nemadectin congeners with acaricidal and nematocidal activity from Streptomyces microflavus neau3 Y-3

Two nemadectin congeners 1 and 2 were isolated from the fermentation broth of a mutant strain (Y-3) of Streptomyces microflavus neau3. Their structures were determined on the basis of extensive spectroscopic analysis and comparison with data from the literature. Compound 2 possessed a 5-membered ring lactone that is unprecedented among known milbemycins and avermectins. Both compounds 1 and 2 exhibited potent acaricidal activity and nematocidal activity. Especially, compound 2 demonstrated impressive acaricidal activity against adult mites with an IC₅₀ of 2.3 ± 0.9 μg/mL and mite eggs with an IC₅₀ of 17.5 ± 2.1 μg/mL and nematocidal activity against Caenorhabditis elegans with an IC₅₀ of 0.7 ± 0.2 μg/mL, which are higher than those of nemadectin and the known commercial acaricide and nematocide milbemycin A3/A4.     

Synthesis of benzimidazole derivatives as potent β-glucuronidase inhibitors

Twenty five 4, 6-dichlorobenzimidazole derivatives (1–25) have been synthesized and evaluated against β-glucuronidase inhibitory activity. The compounds which actively inhibit β-glucuronidase activity have IC₅₀ values ranging between 4.48 and 46.12 μM and showing better than standard d-saccharic acid 1,4 lactone (IC₅₀ = 48.4 ± 1.25 μM). Molecular docking provided potential clues to identify interactions between the active molecules and the enzyme which further led us to identify plausible binding mode of all the benzimidazole derivatives. This study confirmed that presence of hydrophilic moieties is crucial to inhibit the human β-glucuronidase.     

Lactones 34 [1]. Application of alcohol dehydrogenase from horse liver (HLADH) in enantioselective synthesis of δ- and ɛ-lactones

The ability of horse liver alcohol dehydrogenase (HLADH) to the enantioselective oxidation of primary–primary, primary–secondary and primary-tertiary aliphatic 1,5- and 1,6-diols 1a–i was studied. No enantioselectivity of the transformations of primary–primary 1,6-diols 1a–d to ɛ-lactones 4a–d was observed. Regioselective oxidation of primary–secondary 1,6-diols 1e,f and 1,5-diols 1h,i afforded enantiomerically enriched ɛ-lactones 4e,f and δ-lactones 4h,i. ɛ-Lactones 4e,f were formed with higher enantiomeric excesses (e.e. = 85–99%). Enzymatic oxidation of primary–tertiary 1,6-diol 1g did not give lactone product.     

Microbial alcohol dehydrogenase screening for enantiopure lactone synthesis: Down-stream process from microtiter plate to bench bioreactor

One-pot conversion with whole cells of bacteria was performed for biooxidation of meso monocyclic (3a–b) and bicyclic diols (3c–e) into corresponding chiral lactones of bicyclo[4.3.0]nonane structure (2a–b) as well as exo- and endo-bridged lactones with the structure of [2.2.1] (3c–d) and [2.2.2] (3e). Micrococcus sp. DSM 30771 was selected as biocatalyst with significant alcohol dehydrogenase activity. Among tested strains, microbial oxidation of meso diols 3a–e catalyzed by Micrococcus sp. afforded enantiomerically pure ((+)-(2S,3R)-2c (ee = 99%), (+)-(2S,3R)-2e (ee = 99%)) or enriched ((+)-(1S,5R)-2a (ee = 90%), (−)-(1S,5R)-2b (ee = 86%), (+)-(2S,3R)-2d (ee = 80%)) lactone moieties. Comparative study with respect to microbial cultivation as well as biooxidation was undertaken to verify agreement of secondary metabolite biosynthesis in different scales: from MTP (4 mL), across shake flask (100 mL) till bioreactor (4 L). The results from biotransformations showed quite similar dependence in oxidation of all substrates 3a–e in MTP and flasks as well, thereby confirmed the validity and reasonable approach of using MTP for preliminary studies.     

Synthesis,in vitro β-glucuronidase inhibitory activity and in silico studies of novel (E)-4-Aryl-2-(2-(pyren-1-ylmethylene)hydrazinyl)thiazoles

Current research is based on the synthesis of novel (E)-4-aryl-2-(2-(pyren-1-ylmethylene)hydrazinyl)thiazole derivatives (3–15) by adopting two steps route. First step was the condensation between the pyrene-1-carbaldehyde (1) with the thiosemicarbazide to afford pyrene-1-thiosemicarbazone intermediate (2). While in second step, cyclization between the intermediate (2) and phenacyl bromide derivatives or 2-bromo ethyl acetate was carried out. Synthetic derivatives were structurally characterized by spectroscopic techniques such as EI-MS, ¹H NMR and ¹³C NMR. Stereochemistry of the iminic double bond was confirmed by NOESY analysis. All pure compounds 2–15 were subjected for in vitro β-glucuronidase inhibitory activity. All molecules were exhibited excellent inhibition in the range of IC₅₀ = 3.10 ± 0.10–40.10 ± 0.90 μM and found to be even more potent than the standard d-saccharic acid 1,4-lactone (IC₅₀ = 48.38 ± 1.05 μM). Molecular docking studies were carried out to verify the structure-activity relationship. A good correlation was perceived between the docking study and biological evaluation of active compounds.     

Synthesis and pharmacological evaluation of optically pure,novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists

A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT_2B and 5-HT₇ receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT_2B (K_i = 5.1 nM) and 5-HT₇ (K_i = 1.7 nM) receptors with high selectivity over 5-HT_2A, 5-HT_2C, α₁, D₂ and M₁ receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.     

Synthesis and biological evaluation of novel N-arylidenequinoline-3-carbohydrazides as potent β-glucuronidase inhibitors

Thirty N-arylidenequinoline-3-carbohydrazides (1–30) have been synthesized and evaluated against β-glucuronidase inhibitory potential. Twenty four analogs showed outstanding β-glucuronidase activity having IC₅₀ values ranging between 2.11 ± 0.05 and 46.14 ± 0.95 than standard d-saccharic acid 1,4 lactone (IC₅₀ = 48.4 ± 1.25 μM). Six analogs showed good β-glucuronidase activity having IC₅₀ values ranging between 49.38 ± 0.90 and 80.10 ± 1.80. Structure activity relationship and the interaction of the active compounds and enzyme active site with the help of docking studies were established. Our study identifies novel series of potent β-glucuronidase inhibitors for further investigation.     

Triterpenes from the roots of Lantana montevidensis with antiprotozoal activity

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13β-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12β,13β-dihydroxyolean-3-oxo-28-oic acid (2) and 12β,13β,22β-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3β,25β-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19α-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with β-sitosterol (11) and β-sitosterol-3-O-β-d-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC₅₀ values against both organisms of 2.1 μM and compound 10 showed activity against same organisms with IC₅₀ values 8.74 and 8.09 μM, respectively, compared to the positive control ciprofloxacin (IC₅₀ = 0.3 μM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC₅₀ values ranging between (2.54–14.95 μM) and IC₉₀ values ranging between (11.90–19.47 μM), using pentamidine as a control (IC₅₀ values 2.09 ≥ 16.8 μM) and IC₉₀ values ranging between (4.72 ≥ 16.8 μM). These compounds also showed highly potent antitrypanosomal activity with IC₅₀ values ranging between (0.39–7.12 μM) and IC₉₀ values ranging between (1.91–10.51 μM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC₅₀ and IC₉₀values 11.82 and 30.82 μM).     

Langaside,a novel secoiridolactone glycoside derivative from Tachiadenus longiflorus Griseb. (Gentianaceae) formed by a [2+2] cycloaddition reaction

Langaside (1), a secoiridoid lactone glucoside possessing a novel skeleton formed by a [2 + 2] cycloaddition reaction between the secoiridolactone glucoside, 1,9-trans-9,5-cis-sweroside, and p-coumaric acid was isolated from the fruits and flowers of the Malagasy Tachiadenus longiflorus Griseb. (Gentianaceae), alongside another seven known compounds. The structure of langaside was established using HRESIMS, IR and NMR spectroscopy and comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Langaside was screened for its neuritogenic activity against SHSY-5Y cells and anticancer activity against the NCI59 human tumour cell panel but not found to be active.     

Flavonol triglycosides of leaves from Maytenus robusta with acetylcholinesterase inhibition

Although Maytenus robusta aqueous infusions of leaves are used in Brazilian traditional medicine for stomach disease treatment, only a few chemical studies of this species are found in literature. The phytochemical investigation of methanol extract from M. robusta leaves yielded the known compound kaempferol (3) and two new flavonol glycosides: kaempferol-3-O-β-d-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-β-d-glucopyranoside (1) and quercetin-3-O-β-d-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-β-d-glucopyranoside (2). The chemical structures of 1 and 2 were elucidated by 1D/2D NMR, ESI–MS and ESI–MS² spectral data. It is the first time flavonoids have been reported from M. robusta. Flavonols 1 and 2 showed 66% and 80% acetylcholinesterase (AChE) inhibition, compared to 93% of the standard eserine, by the Ellman’s method. These substances are one of the few active flavonols linked to a trisaccharide chain in the literature presenting this activity, and contribute to the screening for new types of natural AChE inhibitors.     

A novel enantioselective epoxide hydrolase from Agromyces mediolanus ZJB120203: Cloning,characterization and application

A new strain Agromyces mediolanus ZJB120203, capable of enantioselective epoxide hydrolase (EH) activity was isolated employing a newly established colorimetric screening and chiral GC analysis method. The partial nucleotide sequence of an epoxide hydrolase (AmEH) gene from A. mediolanus ZJB120203 was obtained by PCR using degenerate primers designed based on the conserved domains of EHs. Subsequently, an open reading frame containing 1167 bp and encoding 388 amino acids polypeptide were identified. Expression of AmEH was carried out in Escherichia coli and purification was performed by Nickel-affinity chromatography. The purified AmEH had a molecular weight of 43 kDa and showed its optimum pH and temperature at 8.0 and 35 °C, respectively. Moreover, this AmEH showed broad substrates specificity toward epoxides. In this study, it is demonstrated that the AmEH could unusually catalyze the hydrolysis of (R)-ECH to produce enantiopure (S)-ECH. Enantiopure (S)-ECH could be obtained with enantiomeric excess (ee) of >99% and yield of 21.5% from 64 mM (R,S)-ECH. It is indicated that AmEH from A. mediolanus is an attractive biocatalyst for the efficient preparation of optically active ECH.     

Phytotoxic activity in Flourensia campestris and isolation of (−)-hamanasic acid A as its active principle compound

An aqueous extract from Flourensia campestris (Asteraceae) dry aerial parts showed strong inhibition on the germination and growth of Lactuca sativa. Based on bio-guided chromatographic fractionation of aq. extracts from dry and fresh leaves and spectroscopic means, (-)-hamanasic acid A (7-carboxy-8-hydroxy-1(2), 12(13)-dien-bisabolene (1)) was isolated as the most inhibitory active principle on germination (ECg₅₀ = 2.9 mM) and on root (ECr₅₀ = 1.5 mM)/shoot (ECs₅₀ = 2.0 mM) growth. As measured by GC, and correlated with a simple designed 2D-TLC, compound 1 was distributed throughout the plant, with a remarkably high concentration (1.6%) in the leaves and the inflorescences. At least a quarter of the amount of 1 was found in aqueous extracts suggesting that leaching would be a key route for its release into the environment. By contrast, leaf essential oils (HD) between 0.5 and 1.5 μl ml⁻¹ did not show herbicidal effects and 1 was not found in them (TLC) nor among volatiles (HS-SPME). Volatile compositions were assessed by GC-FID and GC–MS and led to the identification of 23 compounds (4 monoterpenes and 19 sesquiterpenes) with a wide seasonal (spring–summer%) variation, represented principally by bicyclo-germacrene (37–6%), spathulenol (4–32%), globulol (20–0%), beta-caryophyllene (15–6%), caryophyllene oxide (1–13%) and bicycloelemene (10–1%), respectively. The high amount of 1 in F. campestris together with its feasibility of being extracted with water suggest that (−)-hamanasic acid A is an allelochemical in this species. Species-specific studies must be carried out to evaluate the potential of 1 as a natural herbicidal compound.     

Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via one-pot multi-component reaction as potent cytotoxic agents against cancer cell lines

In this study, twenty-five (25) substituted aryl thiazoles (SAT) 1–25 were synthesized, and their in vitro cytotoxicity was evaluated against four cancer cell lines, MCF-7 (ER^+ve breast), MDA-MB-231 (ER^−ve breast), HCT116 (colorectal) and HeLa (cervical). The activity was compared with the standard anticancer drug doxorubicin (IC₅₀ = 1.56 ± 0.05 μM). Among them, compounds 1, 4–8, and 19 were found to be toxic to all four cancer cell lines (IC₅₀ values 5.37 ± 0.56–46.72 ± 1.80 μM). Compound 20 was selectively active against MCF7 breast cancer cells with IC₅₀ of 40.21 ± 4.15 μM, whereas compound 19 was active against MCF7 and HeLa cells with IC₅₀ of 46.72 ± 1.8, and 19.86 ± 0.11 μM, respectively. These results suggest that substituted aryl thiazoles 1 and 4 deserve to be further investigated in vivo as anticancer leads.     

Structure–activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids,and their tricyclic and bicyclic analogues

Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2-methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-β-carboline, showed the best in vitro activity, with an IC₅₀ value of 0.45 μM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI > 1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure–activity relationships are discussed and compared with related naturally occurring compounds.     

Substituted hydrazinecarbothioamide as potent antitubercular agents: Synthesis and quantitative structure–activity relationship (QSAR)

A series of novel substituted hydrazinecarbothioamides was synthesized and evaluated for anti-TB activity. Three most active compounds viz. 1, 6 and 12 were found to exhibit minimum inhibitory concentration (MIC) of 0.4 μg/mL, whereas four compounds viz. 3, 5, 10 and 11 showed comparatively lesser activity with MIC value of 0.8 μg/mL against Mycobacterium tuberculosis strain. A highly significant QSAR equation explaining 81.8% variance is described.     

Acylated iridoid glycosides and acylated rhamnopyranoses from Gmelina arborea flowers

Nine acylated iridoid glycosides (1–9), five acylated rhamnopyranoses (10–14) and verbascoside (15) were isolated from Gmelina arborea flowers, including 5 new compounds (1, 2, and 10–12). The cytoprotective activity of 11 selected compounds (1–8, 10, 11, and 15) against CCl₄-induced cytotoxicity on liver was determined. Compounds 1, 2, 4, 7, 8 and 15 displayed hepatoprotective activity. 6-O-α-l-(2″, 3″-di-O-trans-p-hydroxycinnamoyl)rhamnopyranosylcatalpol (2) exhibited the most potent cytoprotective effect with an EC₅₀ value of 42.5 μM (SI = 19.3) compared with biphenyldimethylesterate (DDB, EC₅₀ = 277.3 μM, SI = 9.8) and bicylo-ethanol (EC₅₀ = 279.2 μM, SI = 12.2). Among the acylated iridoid glycosides, the compounds (2 and 8) containing phenolic hydroxy groups were more active than were those lacking them.     

Design,synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.     

Rheediinosides A and B,two antiproliferative and antioxidant triterpene saponins from Entada rheedii

Two triterpenoid saponins have been isolated from the seed kernels of Entada rheedii. Their structures have been established using 1D- and 2D-NMR and mass spectrometry as 3-O-β-d-xylopyranosyl-(1 → 3)-O-α-l-arabinopyranosyl-(1 → 6)-2-acetylamino-2-deoxy-β-d-glucopyranosylentagenic acid 28-O-β-apiofuranosyl-(1 → 3)-β-d-xylopyranosyl-(1 → 2)-β-d-glucopyranoside (Rheediinoside A, 1) and 3-O-β-d-glucopyranosyl-(1 → 3)-O-[β-d-xylopyranosyl-(1 → 3)-α-l-arabinopyranosyl-(1 → 6)]-2-acetylamino-2-deoxy-β-d-glucopyranosylentagenic acid 28-O-β-apiofuranosyl-(1 → 3)-β-d-xylopyranosyl-(1 → 2)-β-d-glucopyranoside (Rheediinoside B, 2). Compounds 1 and 2 were tested for their antiproliferative activity against T98G, A431, PC3 and B16-F1 cell lines, and further for their antioxidant properties. Moderate cytotoxic potency and antioxidant properties were found for these compounds whereas Rheediinoside B was in all assays more active than Rheediinoside A.     

Dihydropyrano [2,3-c] pyrazole: Novel in vitro inhibitors of yeast α-glucosidase

Inhibition of α-glucosidase enzyme activity is a reliable approach towards controlling post-prandial hyperglycemia associated risk factors. During the current study, a series of dihydropyrano[2,3-c] pyrazoles (1–35) were synthesized and evaluated for their α-glucosidase inhibitory activity. Compounds 1, 4, 22, 30, and 33 were found to be the potent inhibitors of the yeast α-glucosidase enzyme. Mechanistic studies on most potent compounds reveled that 1, 4, and 30 were non-competitive inhibitors (K_i = 9.75 ± 0.07, 46 ± 0.0001, and 69.16 ± 0.01 μM, respectively), compound 22 is a competitive inhibitor (K_i = 190 ± 0.016 μM), while 33 was an uncompetitive inhibitor (K_i = 45 ± 0.0014 μM) of the enzyme. Finally, the cytotoxicity of potent compounds (i.e. compounds 1, 4, 22, 30, and 33) was also evaluated against mouse fibroblast 3T3 cell line assay, and no toxicity was observed. This study identifies non-cytotoxic novel inhibitors of α-glucosidase enzyme for further investigation as anti-diabetic agents.