Design,synthesis, antimicrobial evaluations and in silico studies of novel pyrazol-5(4H)-one and 1H-pyrazol-5-ol derivatives

A new series of 1,4-disubstituted 3-methylpyrazol-5(4H)-one derivatives were synthesized by reacting various substituted aromatic aldehydes with 3-methylpyrazol-5(4H)-one derivatives through Knoevenagel condensation by conventional as well as by exposure to microwave irradiations. After that newly synthesized compounds of 1,4-disubstituted 3-methyl-1H-pyrazol-5-ol were prepared from these derivatives by reduction reaction of sodium borohydride at 0–5 °C. Sixty-four heterocyclic compounds containing a pyrazole moiety were synthesized with good to excellent yields (51 to 91%). Compounds (3d, 3m, 4a, 4b, 4d, and 4g) showed potent antibacterial activity against MSSA (Methicillin-susceptible strains of Staphylococcus aureus) and MRSA (Methicillin-resistant strains of Staphylococcus aureus) with MIC (the minimum inhibitory concentration) ranging between 4 and 16 µg/mL as compared to ciprofloxacin (MIC = 8–16 µg/mL). Compounds (4a, 4h, 4i, and 4l) showed potent antifungal activity against Aspergillus niger with MIC ranging between 16 and 32 µg/mL as compared to fluconazole (MIC = 128 µg/mL). In particular, compound 4a exhibited the strongest activity among the synthesized compounds in both bacterial and fungal strains with MIC ranging between 4 and 16 µg/mL. Furthermore, the nine most active compounds showed a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile in comparison to ciprofloxacin and fluconazole as reference drugs. Molecular docking predicted that DHFR (dihydrofolate reductase) protein from Staphylococcus aureus and NMT (N-myristoyl transferase) protein from Candida albicans are the most suitable targets for the antimicrobial activities of these potent compounds.     

Nematicidal quinone derivatives from three Rubia plants

Five new quinone derivatives, rubiasins D-F (1–3), rubialatones A and B (4 and 5), have been isolated from the roots and rhizomes of three Rubia species, Rubia alata, R. wallichiana and R. schumanniana, together with 26 known quinones (6–31). Their structures have been elucidated on the basis of NMR, MS spectra and computational methods. The compounds have been evaluated for their toxicity to the saprophytic nematode Caenorhabditis elegans and the root-knot nematode Meloidogyne incognita. Compounds 1, 6 and 7 showed toxicity to C. elegans with the LC₅₀ values at 8.50, 9.44 and 44.82?μg/mL, respectively; and 6 showed toxicity to M. incognita with the LC₅₀ value at 35.22?μg/mL. Meanwhile, compounds 1 and 6 showed inhibitory effect on egg hatch of C. elegans with the LC₅₀ values at 5.60 and 48.95?μg/mL.     

Rakicidins G - I,cyclic depsipeptides from marine Micromonospora chalcea FIM 02-523

Rakicidins G-I (1–3), three new cyclic depsipeptides including a long aliphatic chain without terminal methyl branching were isolated from culture broth of Micromonospora chalcea FIM 02–523, along with rakicidin E (4). Their structures were elucidated by extensive NMR and HR-ESI-MS analyses. Compounds 1–4 were evaluated for their cytotoxic activities against HCT-8 and PANC-1 human tumor cell lines under the hypoxic and normoxic conditions. They were approximately 18.2–20.3-fold more cytotoxic under hypoxic than under normoxic conditions on PANC-1, and compared with 7.4–8.7-fold more cytotoxic under hypoxic than under normoxic conditions on HCT-8. Meanwhile, compounds 1–3 were also tested inhibitory activities against gram positive anaerobic bacteria and the results exhibited MIC values in the range of 0.125–8?μg/mL.     

Grayanane diterpenoids with diverse bioactivities from the roots of Pieris formosa

During our continuing study on the roots of Pieris formosa, twelve new grayanane diterpenoids (1–12), together with eight known compounds (13–20), were obtained. Their structures with absolute configurations were characterized by a series of spectroscopic methods and X-ray diffraction. Compounds 1, 2, 4–5, 7–8, 14, and 19 exhibited significant analgesic activity in an acetic acid-induced writhing test. In particular, 7 and 14 were found to be 5 times more potent than morphine in the acetic acid-induced writhing test model. Compounds 1, 4, 9, 13, and 18 showed antifeedant activity against Plutella xylostella at 0.5 mg/mL. Compound 4 exhibited a 38.3% inhibitory effect against the KCNQ2 potassium channel at a concentration of 10 μM.     

Antifouling and cytotoxic constituents from the South China Sea sponge Acanthella cavernosa

A bioassay-guided chemical investigation of the South China Sea sponge Acanthella cavernosa resulted in the isolation of eight new diterpenoids, kalihinols M–T (1–8), together with seven known analogues (9–15). These compounds featured a trans-decalin ring bearing a tetrahydrofuran or a tetrahydropyran ring at C-7. Compounds 1 and 2, with a formamide functionality beared at C-4, extended the structure breadth of this diterpenoid family. The absolute stereostructures of 1–14 were determined by a combination of 2D NMR and CD spectroscopic analysis and single crystal X-ray diffraction. Compounds 1 and 2 were confirmed to have the configurations of 4S, 5S, whereas 3–14 were determined as 4R, 5R. Compounds 3–14 displayed significant antifouling activity against the barnacle Balanus amphitrite larvae, and the cytotoxic activities of 3–14 were evaluated against the H1299, A549, PC3, CT-26, and HCT-116 cancer cell lines.     

Cytotoxic Podophyllotoxin Type-Lignans from the Steam Bark of <em>Bursera fagaroides </em>var. <em>fagaroides</em>

The hydroalcoholic extract of the steam bark of B. fagaroides var. fagaroides displayed potent cytotoxic activity against four cancer cell lines, namely KB (ED₅₀ = 9.6 × 10^-2 μg/mL), PC-3 (ED₅₀ = 2.5 × 10^-1 μg/mL), MCF-7 (ED₅₀ = 6.6 μg/mL), and HF-6 (ED₅₀ = 7.1 × 10^-3 μg/mL). This extract also showed anti-tumour activity when assayed on mice inoculated with L5178Y lymphoma cells. Bioactivity-directed isolation of this extract, afforded seven podophyllotoxin-type lignans identified as podophyllotoxin (1), β-peltatin-A-methylether (2), 5'-desmethoxy-β-peltatin-A-methylether (3), desmethoxy-yatein (4), desoxypodophyllotoxin (5), burseranin (6), and acetyl podophyllotoxin (7) by 1D and 2DNMR and FAB-MS analyses, and comparison with reported values. All the isolated compounds showed potent cytotoxic activity in the cell lines tested, especially compound 3, which exhibited greater activity than camptothecin and podophyllotoxin against PC-3 (ED₅₀ = 1.0 × 10^-5 μg/mL), and KB (ED₅₀ = 1.0 × 10^-5 μg/mL). This is the first report of the isolation of podophyllotoxin and its acetate in a Bursera species.     

Briaviodiols B–E,new anti-inflammatory hydroperoxyfurancembranoids from Briareum violaceum

Four new hydroperoxyfurancembranoids, briaviodiols B–E (1–4), were obtained from an octocoral identified as Briareum violaceum. The structures of cembranoids 1–4 were established by using spectroscopic methods and comparing the spectroscopic data with those of known related analogues. Compounds 1, 3, and 4 were found to exhibit significant in vitro anti-inflammatory activity in LPS-induced RAW 264.7 macrophage cells by inhibiting the expression of iNOS protein.     

Synthesis,antimicrobial activity and docking study of some novel 4-(4,4-dimethyl-2,6-dioxocyclohexylidene)methylamino derivatives carrying biologically active sulfonamide moiety

A new series of 4-((4,4-dimethyl-2,6-dioxocyclohexylidene)methylamino)-N-(substituted)benzenesulfonamide 3–17, monosubstituted 2-((4-((4-aminophenyl)sulfonyl)phenyl)amino)methylene 18, and its disubstituted derivative 19 were synthesized from the starting material 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione 2. The crystal structures of compounds 2, 7 and 13 were reported by us through X-ray crystallography. All the prepared compounds were evaluated for their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis, Clostridium sporogenes), Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli), and antifungal activity against Aspergillus fumigatus, Penicillium chrysogenum, Fusarium oxysporum, Candida albicans. The synthesized compounds displayed interesting antimicrobial activity. Compounds 4 and 12 were the most potent in this study and displayed higher activity compared to the reference drugs, with MIC value of 3.9–31.3 μg/mL against a panel of Gram-positive, Gram-negative bacteria and fungi. Molecular modeling was performed inside the active site of dihydropteroate synthase. The synthesized compounds showed similar orientation and binding interactions to that of the co-crystallized ligand inside the binding pocket.     

Ultrasound assisted,VOSO4 catalyzed synthesis of 4-thiazolidinones: Antimicrobial evaluation of indazole-4-thiazolidinone derivatives

A simple and expedient multicomponent protocol was developed to synthesize 4-thiazolidinones by employing VOSO₄ as a catalyst under ultrasonic irradiation. The significant features of this protocol includes shorter reaction time, high yields, low catalyst loading, and also the catalyst can be recovered and reused up to next four cycles without significant loss in catalytic activity. All the synthesized novel indazole compounds were evaluated for their antibacterial and anti-biofilm activities. Compounds 9n, 9o and 9q showed promising activity (MIC value of 3.9?µg/mL) against K. planticola (MTCC 530). They also exhibited significant bactericidal activity against K. planticola (MTCC 530) (MBC value of 15.6?µg/mL). Additionally, 9n, 9o and 9q inhibited biofilm formation (IC₅₀ values ranging between 20.28–20.79?μg/mL) in this organism.     

Confluenines A–F, N-oxidized l-isoleucine derivatives from the edible mushroom Albatrellus confluens

The phytochemical study of the fruiting bodies of Albatrellus confluens afforded three pairs of new N-Oxidized l-Isoleucine derivatives epimers, confluenines A–F (1–6). The structures of these compounds were deduced using spectroscopic techniques, and the absolute configurations of the compounds were assigned by comparison between experimental and theoretical NMR and ECD data, respectively. Putative biosynthetic pathways toward the oxime, hydroxamate moieties and epimers were discussed. Compounds 5 and 6 exhibited weak antimicrobial activities against Staphylococcus aureus with MIC₉₀ values at 29.3?μg/mL and 56.7?μg/mL, respectively.     

Cage-like monoterpenoid indole alkaloids with antimicrobial activity from Alstonia scholaris

Three new cage-like monoterpenoid indole alkaloids, scholarisines T–V (1–3), together with three known analogues 4–6 were isolated from the leaves of Alstonia scholaris. Among them, 2 represents a unique degraded derivative, whereas 3 shares a rare 5,16-seco lactone scaffold. The structures were mainly established by extensive spectroscopic data analyses, and their plausible biosynthesis pathway from picrinine were proposed. Compared with positive control cefotaxime, alkaloid 2 showed remarkable antibacterial activity against Bacillus subtilis with an MIC value of 3.12?μg/mL, whereas 1–3 exhibited significant antibacterial effects on Escherichia coli with an MIC value of 0.78?μg/mL.     

Two new aromatic compounds and a new d-arabinitol ester from the mushroom Hericium erinaceum

Two new aromatic compounds (1, 2), new d-arabinitol ester (3), and two known compounds (4, 5) were isolated from mushroom Hericium erinaceum. The structures of 1–5 were elucidated on the basis of spectral data. Compounds 1, 2, 4, and 5 exhibited α-glucosidasae inhibitory activity.     

Cytotoxic sesquiterpenes from luminescent mushroom Neonothopanus nambi

Four new aristolane sesquiterpenes named nambinones A–C (1–3) and 1-epi-nambinone B (4), a new sesquiterpene, nambinone D (5), a known compound, aurisin A (6) as well as a new dimeric sesquiterpene, aurisin K (7), were isolated from two isolates of luminescent mushroom, Neonothopanus nambi, PW1 and PW2. These structures were established on the basis of spectroscopic evidence. The relative configuration of 6 was determined by X-ray crystallographic analysis. Compounds 6 and 7 exhibited antimalarial activity against Plasmodium falciparum and antimycobacterial activity against Mycobacterium tuberculosis. Compounds 3, 6, and 7 showed cytotoxicity against NCI-H187 cancer cell lines. In addition, 6 and 7 showed cytotoxicity against the cholangiocarcinoma cell lines.     

Njaoamines G and H, two new cytotoxic polycyclic alkaloids and a tetrahydroquinolone from the marine sponge Neopetrosia sp.

Two new polycyclic alkaloids, njaoamines G (1) and H (2) and 1,2,3,4-tetrahydroquinolin-4-one (3) have been isolated from the sponge Neopetrosia sp. collected at Pemba Island, Tanzania. Compounds 1 and 2 are close in structure to njaoamines A-F. Compound 3, known synthetically, is a new natural compound. The structures and relative stereochemistries of compounds 1 and 2 were elucidated on the basis of spectroscopic data. Njaoamines G and H are potent brine shrimp toxins with LD₅₀ values of 0.17 μg/mL and 0.08 μg/mL for 1 and 2, respectively.     

Pimprinols A–C,from the terrestrial actinomycete,Streptomyces sp.

A Streptomyces sp. Lv3-13, isolated from the rhizosphere soil of the plant Mespilus germanica, has yielded three new pimprinine derivatives, named pimprinols A–C (1–3) and the unknown (2-aminophenyl)(2-ethyloxazol-5-yl) methanone (4) along with the known compounds 2-ethyl oxazole pimprinine and 2-propyl oxazole pimprinine. The structures of the compounds were elucidated based on spectroscopic methods including UV, HR-ESIMS and 1D, 2D NMR data. Compounds 1–4 were screened for antimicrobial and cytotoxic activities.     

Synthesis and biological evaluation of novel 1,2,4-triazole containing 1,2,3-thiadiazole derivatives

A series of novel 1,2,4-triazoles containing 1,2,3-thiadiazole derivatives were designed and synthesized. Their structures were confirmed by melting points, IR, 1H NMR, and elemental analysis and ESI-MS or HRMS. Preliminary bioassays indicated that these compounds exhibited very good insecticidal activity against Aphis laburni at 100 μg/mL, with mortality no less than 95%. Compounds 6a, 6c, 6f, 61 showed higher curative activity against TMV and compound 6h showed a higher induction effects against TMV in vivo at 100 μg/mL. Collectively, our data demonstrate a new strategy for control of insects and viruses.     

Novel quinazolin-4(3H)-one derivatives containing a 1,3,4-oxadiazole thioether moiety as potential bactericides and fungicides: Design,synthesis, characterization and 3D-QSAR analysis

A series of quinazolin-4(3H)-one derivatives containing a 1,3,4-oxadiazole thioether moiety were designed, synthesized and evaluated for their biological activities against phytopathogenic microorganisms. Antimicrobial bioassays in vitro indicated that most of the target compounds exhibited more significant antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) than the agricultural bactericide thiadiazole-copper. A comparative molecular similarity index analysis (CoMSIA) model with cross-validated q² and non-cross-validated r² values of 0.561 and 0.882 was generated to investigate the structure-activity relationships of title compounds against Xoo. Title compound 6w, which was rationally designed under the guidance of obtained CoMSIA model, exhibited the excellent anti-Xoo effect in vitro with an EC₅₀ value of 29.10 μg/mL, which is approximately 3-folds more effective than thiadiazole-copper (113.93 μg/mL). In addition, compound 6i demonstrated the impressive antifungal effects against Rhizoctonia solani (Rs) and Fusarium graminearum (Fg) in vitro, with the corresponding EC₅₀ values of 11.01 μg/mL and 36.00 μg/mL, which is obviously better than the agricultural fungicide hymexazol (76.74 μg/mL and 56.19 μg/mL, respectively). The above researches indicate that quinazolin-4(3H)-one derivatives containing a 1,3,4-oxadiazole thioether moiety could be further studied as template molecules of novel agricultural microbicides.     

Nitricquinomycins A-C,uncommon naphthopyrrolediones from the Streptomyces sp. ZS-A45

Nitricquinomycins A-C (1～3), three uncommon naphthopyrrolediones, together with one new compound (4), were isolated from the modified rice solid fermentation of the marine-derived Streptomyces sp. ZS-A45, an actinobacterium isolated from the marine sediments collected from Zhoushan island. Their structures were elucidated on the basis of MS, NMR spectroscopic and quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Compounds 3 and 4 exhibited significant cytotoxicity against A2780 cell lines with IC₅₀ values of 4.77 and 2.92 μM, respectively; on the other hand, compound 3 exhibited moderate antibacterial activities against Escherichia coli, Staphylococcus aureus and Candida albicans with MIC values of 20.0 40.0 and 40.0 μM, respectively.     

Dihydroanthracenone metabolites from the endophytic fungus Diaporthe melonis isolated from Annona squamosa

Chemical investigation of the endophytic fungus Diaporthe melonis, isolated from Annona squamosa, yielded two new dihydroanthracenone atropodiastereomers, diaporthemins A (1) and B (2), together with the known flavomannin-6,6′-di-O-methyl ether (3). The structures of the new compounds were established on the basis of extensive 1D and 2D NMR spectroscopy, as well as by high resolution mass spectrometry and by CD spectroscopy. Compounds 1–3 were tested for their antimicrobial activity against a multi-resistant clinical isolate of Staphylococcus aureus 25697, a susceptible reference strain of S. aureus ATCC 29213 and against Streptococcus pneumoniae ATCC 49619. Compound 3 strongly inhibited S. pneumonia growth with a MIC value of 2 μg/mL, and showed moderate activity against the S. aureus multi-resistant clinical isolate and susceptible reference strain (MIC 32 μg/mL), whereas 1 and 2 were not active against the tested strains.     

Synthesis and biological evaluation of 1,4-pentadien-3-one derivatives containing 1,2,4-triazole

A series of new 1,4-pentadien-3-one derivatives containing 1,2,4-triazole moiety were synthesized. The structures of the synthesized compounds were charactered via ¹H NMR, ¹³C NMR and HRMS. Antibacterial bioassays indicated that some of compounds showed potential antibacterial activities against Ralstonia solanacearum (Rs), Xanthomonas oryzae pv. Oryzae (Xoo) and Xanthomonas axonopodis pv. Citri (Xac). Compounds F₈ and F₁₇ showed good in vitro antibacterial activities against Rs, with the EC₅₀ values of 18.6 and 18.6 μg/mL, respectively, which were better than commercial agent bismerthiazol (55.2 μg/mL). Furthermore, compounds F₁₂ and F₁₅ showed good in vitro antibacterial activities against Xoo, with the EC₅₀ values of 10.9 and 17.5 μg/mL, which were better than commercial agent bismerthiazol (69.3 μg/mL). Moreover, compounds F₂, F₉, F₁₆ and F₁₇ showed good in vitro antibacterial activities against Xac, with the EC₅₀ values of 6.6, 5.4, 7.5 and 7.8 μg/mL, respectively, which were better than commercial agent bismerthiazol (54.9 μg/mL). The effect of compound F₉ on Xac bacterial cell membrane rupture was observed by scanning electron microscopy (SEM). In addition, antiviral bioassays indicated that some of compounds showed excellent protection activities against tobacco mosaic virus (TMV). Compounds F₅ and F₁₅ showed good protecting activity against TMV, with the EC₅₀ values of 108.3 and 105.4 μg/mL, respectively, which were better than commercial agent ningnanmycin (214.7 μg/mL). Microscale thermophoresis (MST) also showed that the binding of compound F₂ to TMV coat protein (TMV-CP) yielded a Kd value of 1.260 ± 0.654 μmol/L, which was very close to ningnanmycin (1.058 ± 0.286 μmol/L). Similarly, the molecular docking studies for F₂ and F₅ with TMV-CP (PDB code: 1EI7, ID: 4QGH) indicated that compounds F₂ and F₅ had partially interacted with TMV-CP.