Studies on fungal metabolites—XXXIII: Synthesis of model compounds of rugulosin

A biomimetic synthesis of rugulosin-type compounds (8b,c) from flavoskyrin-type compounds (5b,c) is described. The intermediate quinonic compounds (7b and 7c) were obtained by the oxidation of flavoskyrin-type compounds (5b and 5c). The compounds 7b and 7c were readily converted into rugulosin-type compounds (8b and 8c), respectively by the intramolecular Michael-type condensation.     

Synthesis,anticancer activity,toxicity evaluation and molecular docking studies of novel phenylaminopyrimidine—(thio)urea hybrids as potential kinase inhibitors

Thirty-two novel urea/thiourea compounds as potential kinase inhibitor were designed, synthesized and evaluated for their cytotoxic activity on breast (MCF7), colon (HCT116) and liver (Huh7) cancer cell lines. Compounds 10, 19 and 30 possessing anticancer activity with IC₅₀ values of 0.9, 0.8 and 1.6 μM respectively on Huh7 cells were selected for further studies. These hit compounds were tested against liver carcinoma panel. Real time cell electronic sensing assay was used to evaluate the effects of the compounds 10, 19 and 30 on the growth pattern of liver cancer cells. Apoptotic cell death and cell cycle analysis upon treatment of liver carcinoma cells with hit compounds were determined. A significant apoptotic cell death was detected upon treatment of Huh7 and Mahlavu cells with compound 30 after 48 h of treatment. Additionally, compound 10 caused cell cycle arrest at G0/G1 phase. Mutagenicity of hit compounds was evaluated. Assertively, these compounds were not found to be mutagenic on Salmonella typhimurium strains TA98 and TA100. To understand the binding modes of the synthesized compounds, molecular docking studies were performed using the crystal data of VEGFR and Src-kinase enzymes in correlation with anticancer activities.     

Synthesis and conformational analysis of exo-and endo-7-substituted-3-azabicyclo[3.3.1]nonanes

The synthesis of some 7-substituted-3-azabicyclo[3.3.1]nonanes is described. Routes followed were the debenzoylation of the 7-benzoyl derivative 7 and the decarboxylation of the 7-carboxy compounds 21 and 27. The so-obtained 7-oxo-N-tosyl-3-azabicyclo[3.3.1]nonanes 8and 11 show an extremely low reactivity towards a series of nucleophilic reagents. From analysis of the ¹H NMR spectral data of a series of derivatives, the twin-chain conformation for the 7-exo compounds and the chair-boat conformation for the 7-endo compounds is indicated.     

Reduction of cephalosporanic acids with chromium(II) salts : Synthesis of 3-methylenecepham derivatives

7-Acylaminocephalosporanic acid derivatives (1) were converted into 7-acylamino-3-methylenecepham-4-carboxylic acids (2) by treatment with chromium(II) salts in aqueous media. The esters (4a or 4b) of 7-acylamino-3-methylenecepham compounds were readily isomerized to the 3-methyl-3-cephem compounds (5a or 5b) under basic conditions. The reaction mechanism is discussed.     

Synthesis of chiral non-racemic azetidines by lipase-catalysed acetylations and their transformation into amino alcohols: precursors of chiral catalysts

Azetidinic mono-acetate 7, diol 6b and di-acetate 10a were prepared with high e.e. using PPL-catalysed acetylations. The absolute configurations of all new enantioenriched compounds were assigned by chemical correlation with known compounds. Mono-acetate 7 was then transformed into 30, an amino alcohol of noteworthy potential interest since it represents an interesting precursor for chiral catalysts, such as 32.     

Antioxidant and anticancer activities of α-aminophosphonates containing thiadiazole moiety

In the current study, α-aminophosphonates containing thiadiazole moiety (1–4) was synthesized, characterized and their antioxidant and anticancer activities were carried out. The compounds (1–4) were synthesized from the reaction of 2-amino-5-methyl-1,3,4-thiadiazole with various aldehydes, triphenylphosphite and mixed valence Cu(I)/Cu(II) inorganic coordination polymer as a catalyst. The elucidation of compounds structures were carried out using different spectroscopic techniques. The antioxidant properties were carried out using radical scavenging methods (DPPH) which exhibited excellent scavenging activity particularly with compound 3. The cytotoxic effects of the five compounds on the human hepato cellular carcinoma (HepG2) and breast adeno carcinoma (MCF7) cell lines were evaluated using MTT assay which revealed the presence of cytotoxic effect with highest activity for compound 3 on HepG2 and compound 1 on MCF7. This suggests that these five compounds, particularly compounds 1 and 3, have antioxidant and anticancer effect and could be used as novel chemotherapeutic compounds but this needs further in vivo investigation to confirm our in vitro results.     

Novel thiosemicarbazone derivatives containing benzimidazole moiety: Green synthesis and anti-malarial activity

A series of (E)-2-[5-chloro-1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (7a–7t) and (E)-2-[1-(1H-benzo[d]imidazol-2-yl)ethylidene] N-(substituted) hydrazine carbothioamide (8a–8t) were prepared via the synthesis of 1-(substituted-1H-benzimidazol-2-yl) ethanol (3a–3b) which was synthesized by the condensation of substituted o-phenylenediamine (2a–2b) with dl-lactic acid (1) followed by oxidation with sodium hypochlorite in mild acidic condition to form the corresponding ketones 4a–4b. Final compounds were formed by condensation of 4a–4b with different thiosemicarbazides 6a–6t. A total of 40 compounds were synthesized and characterized by FT-IR, ¹H NMR, ¹³C NMR, Mass spectral technique and elemental analysis, in addition they were evaluated for anti-malarial properties. Among the compounds tested 7o, 7p, 7q, 7r, 7s, 8e and 8h exhibited good antimalarial activity in vitro.     

Aromatic polyketides from a caterpillar associated Alternaria sp.

Five new aromatic polyketides, alternaphenols A–E (1–5), and two known compounds (6–7) were isolated from a liquid culture of Alternaria sp. (strain no. NF2198), a caterpillar associated fungus. Their structures were determined by extensive spectroscopic analysis and single crystal X-ray crystallography. Compounds 1–7 were evaluated for their cytotoxic activities against a human skin melanoma A-375 cell line. Only compounds 4 and 5 showed weak cytotoxic activities.     

Alkaloids Isolated from the Lateral Root of <em>Aconitum carmichaelii</em>

Two new alkaloids, aconicarmine (1) and aconicaramide (5), were isolated from the EtOH extract of the lateral roots of Aconitum carmichaelii, together with five known compounds: fuziline (2), neoline (3), N-ethylhokbusine B (4), 5-hydroxymethylpyrrole-2-carbaldehyde (6), and oleracein E (7). Their structures were elucidated by physical and NMR analysis. Pyrrole alkaloids were isolated from A. carmichaelii for the first time. In the in vitro assays, compounds 2 and 3 showed activity against pentobarbital sodium-induced cardiomyocytes damage by obviously recovering beating rhythm and increasing the cell viability, while compounds 5 and 7 showed moderate antibacterial activity.     

Design and synthesis of some novel pyridothienopyrimidine derivatives and their biological evaluation as antimicrobial and anticancer agents targeting EGFR enzyme

A new series of pyridothienopyrimidine derivatives was designed and evaluated as antimicrobial and anticancer agents. The target compounds were synthesized starting with 3-aminothieno[2,3-b]pyridine-2-carboxamide derivative 1 which underwent cyclocondensation reaction with aromatic aldehydes to give the key intermediates 2a,b. By further treatment of 2a,b with various reagents, the target 2,4-disubstituted-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidines 3a,b–11a,b were obtained. To evaluate the antimicrobial activity of the new compounds, they were tested against five bacterial and five fungal strains. Compounds 6c, 8b, 9a and 9b revealed the most significant antimicrobial activity against the tested microorganisms with MIC values range (4–16 μg/mL). Also, compounds 2a,b–11a,b were screened for their in vitro cytotoxic activity against HepG-2 and MCF-7 cancer cell lines compared with doxorubicin and cisplatin as references drugs. Moreover, compounds (2b, 4a, 6a, 7b, 7c and 9a) which exhibited the most potent anticancer activity, were further subjected to EGFR^WT enzyme inhibition assay utilizing erlotinib as a standard drug. The compounds 6a, 7b, 7c and 9a which showed the most promising suppression effects were also evaluated as inhibitors against the mutant forms EGFR^L858R and EGFR^T790M. The 4-aminopyrazolone analogue 9a showed superior anticancer activity against both HepG-2 and MCF-7 cell lines (IC50 = 1.27, 10.80 μM, respectively) and more potent enzymatic inhibition activity against EGFR^WT and its mutant forms EGFR^L858R and EGFR^T790M than that obtained by erlotinib (IC₅₀ = 0.021, 0.053, 0.081 µM, respectively, IC_50erlotinib; 0.027, 0.069, 0.550 µM, respectively). Finally, the molecular docking study showed good binding patterns of the most active compounds with the prospective target EGFR^WT.     

A novel plant growth regulator from Pholiota lubrica

Nine compounds including a new cinnamamide (1), N-(1-cinnamoylpyrrolidin-2-yl)cinnamamide, and two compounds (8 and 9) first isolated from natural sources, were obtained from the edible mushroom Pholiota lubrica. Their structures were determined by the interpretation of spectroscopic data. Compounds 1, 3 and 9 exhibited the inhibitory activity against lettuce, while compounds 2 and 7 promoted the growth of lettuce.     

New dimeric and monomeric chromanones,gonytolides D–G,isolated from the fungus Gonytrichum sp.

In the course of the screening of innate immune regulators from natural resources, we isolated new dimeric and monomeric chromanones, gonytolides D–G (4–7), from Gonytrichum sp. along with a known innate immune promoter, gonytolide A (1). The structures of these compounds were determined by spectral analysis, chemical conversion, and biogenetic consideration. The compounds 4–7 were evaluated on the innate immune response, indicating that the 8,8′-linked bischromanone rings were crucial for innate immune-promoting activity.     

Cytotoxic principles and α-pyrone ring-opening derivatives of bufadienolides from Kalanchoe hybrida

Purification of the cytotoxic fractions of the methanol extracts of Kalanchoe hybrida leads to three new compounds with the basic skeleton of α-pyrone ring-opening products of bufadienolides, namely, kalanhybrin A-C (1-3). Moreover, four bufadienolides (4-7) and eight other compounds were also characterized from the title plant. The isolated compounds (1-7) were evaluated for their cytotoxicity toward MCF-7, NCI-H460, and SF-268 tumor cell lines. Among them, compounds 4 and 6 displayed significant cytotoxicity toward MCF-7 and NCI-H460 tumor cell lines at the tested concentration. In addition, the biosynthetic pathway of these α-pyrone ring-opening derivatives was also proposed.     

Synthesis and cytotoxic evaluation of new colchicine derivatives bearing 1, 3, 4-thiadiazole moieties

In search of novel anticancer agents, a series of N-methyl colchiceinamide derivatives (7a-7i) containing 1,3,4-thiadiazole moieties were synthesized, and their structures were confirmed by spectral analysis. Cytotoxicity of these compounds was evaluated by MTT assay in vitro against four human tumor cell lines, i.e. A2780, A549, BEL7402, and MCF-7. The results indicated that most of the derivatives showed significant anticancer activities, particularly, compounds 7h and 7i showed more potent cytotoxic activities of all screened cancer cells than colchicine.     

Design,synthesis, computational and biological evaluation of new benzodiazepines as CNS agents

Two series of new benzodiazepines were synthesized and the target compounds (E1-10 and G1-10) were evaluated for antianxiety and skeletal muscle relaxant activity as CNS agents in albino mice. The chemical structures of the compounds were confirmed on the basis of their TLC, IR, ¹H NMR and ¹³C NMR analysis. In computational studies, the physicochemical similarity of the target compounds was assessed by calculating from a set of physicochemical properties using software programs and test compounds demonstrated moderate physiochemical similarity with respect to diazepam. Log P values of the target compounds indicates good penetration to CNS. Molecular docking studies revealed that the target compounds correctly dock into the binding pocket of the GABA_A receptor, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. The test compounds (E1-10 and G1-10) were screened for antianxiety and skeletal muscle relaxant activity using Elevated plus maze and Rotarod method respectively. Among them, the compounds E10 and G7 showed maximum potency as CNS agents.     

Ceratoluteolin: A new flavonoid from Salvia ceratophylla from Jordan

Ceratoluteolin 1, a new luteolin derivative was isolated from Salvia Ceratophylla growing wild in Jordan along with other 14 known compounds including two sterols, two triterpenes, four flavonoids and six phenolic compounds, one of which is reported for the first time from Lamiaceae family. The isolated compounds were genkwanin-4′-methyl ether 2, β-sitosterol 3, oleanolic acid 4, ursolic acid 5, apigenin 6, β-sitosteryl glucoside 7, p-hydroxyphenyl caffeate 8, caffeic acid 9, shimobashiric acid B 10, methyl rosmarinate 11, butyl rosmarinate 12, luteolin 13, luteolin-7-O-glucoside 14 and rosmarinic acid 15. Complete structural verification of the isolated compounds was achieved by careful inspection of their spectral data including NMR (1D & 2D) and HREIMS.     

Three new inositol derivatives from Chisocheton paniculatus

Three new inositol derivatives (1–3) were isolated from the leaves of Chisocheton paniculatus collected in Vietnam, along with four known compounds, including a limonoid (4), two triterpenoids (5–6), and a tocopherol (7). The structures of the new compounds were elucidated by 1D- and 2D-NMR and HRESIMS analyses. Compound 4 showed the highest cytotoxicities against the human lung cancer A549 and cervical cancer HeLa cell lines, with IC₅₀ values of 7.3 and 8.8 µM, respectively, among the isolated compounds. Compounds 5 and 7 displayed moderate to weak cytotoxicities against the A549, HeLa, and human stomach cancer GSU cell lines, with IC₅₀ values ranging from 17.7 to 68.0 µM.     

Bioactive compounds from the scale insect fungus Conoideocrella tenuis BCC 44534

Eleven new compounds, including two quinone derivatives of bioxanthracene, conoideocrellones A (1) and B (2), two bioxanthracenes 3 and 4, four isocoumarins and isocoumarin glycosides 7–10, two phenolic compounds 16 and 17, and a diterpenoid compound, conoideocin A (18), were isolated from culture of the scale-insect pathogenic fungus Conoideocrella tenuis BCC 44534. Seventeen known compounds, compounds 5 and 6, ES-242-2 and its atropisomer, isocoumarins and isocoumarin glycosides 11–15, 3,4,6-trihydroxymellein, cis-4,6-dihydroxymellein, metarhizins A (19) and B (20), BR-050 (21), 5α,8α-epidioxy-24(R)-methylcholesta-6,22-dien-3β-ol, zeorin, and conoideocrellide A, were also isolated from this fungus. Structures of these compounds were elucidated by NMR and MS data analyses. Compound 4 was active against Plasmodium falciparum K1 (IC₅₀ 6.6?μg/mL), while it did not show cytotoxicity. Conoideocrellone A (1) and compounds 3 and 7 exhibited cytotoxic activity, while conoideocin A (18) showed broad range of biological activities including antimalarial, antibacterial, and cytotoxic activities.     

Terpenoids with potent antimycobacterial activity against Mycobacterium tuberculosis from Trigonostemon reidioides roots

Phytochemical investigation of Trigonostemon reidioides roots led to the isolation of fourteen compounds. These included six new diterpenoids, trigonoreidons A?F (1?6), together with eight known diterpenoids 7?14. The structures of the new compounds were elucidated by spectroscopic techniques and the absolute configuration at the asymmetric carbon was determined by the modified Mosher's method. The structure of trigonoreidon B (2) was confirmed by X-ray crystallographic analysis. The known compounds were identified by comparison of the spectroscopic and physical data with those of reported values. The isolated compounds were evaluated for antimycobacterial activity against Mycobacterium tuberculosis. Among the compounds that exhibited antimycobacterial activity, the diterpenoids rediocide C (12) and rediocide G (14) were the most active compounds, with the MIC value of 3.84 μM.     

Spiroketals,isocoumarin, and indoleformic acid derivatives from saline soil derived fungus Penicillium raistrickii

Six new compounds, named peneciraistins A–F (1–6), were isolated from saline soil derived fungus Penicillium raistrickii. Among them, compounds 1 and 2 are rare benzannulate 6,6-spitoketals, and compounds 5 and 6 are the first naturally occurring 3-indoleformic acid derivatives. Their structures were elucidated by means of their detailed NMR and MS spectroscopic data. Their absolute configurations were assigned by the modified Mosher method, CD excitation chirality method or optical rotation by comparison with those of known compounds. Their cytotoxicities were also reported against A549 and MCF-7 cell lines along with radical scavenging activities against DPPH (1,1-diphenyl-2-picrylhydrazyl).