Synthesis,anti-diabetic evaluation and molecular docking studies of 4-(1-aryl-1H-1, 2, 3-triazol-4-yl)-1,4-dihydropyridine derivatives as novel 11-β hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitors

11-Beta-Hydroxysteroid dehydrogenase-1(11β-HSD1) inhibitors are one of the emerging classes of molecules to fight against diabetic complications. A novel series of 4-(1-substituted-1H-1,2,3-triazol-4-yl)-1,4-dihydropyridine derivatives were synthesized and evaluated for their anti-diabetic activity. Two compounds showed anti-diabetic activity very effectively. To clarify the mechanism of action of these compounds, the most potent compounds (5g and 5h) of the synthesized analogs were further studied by testing its 11-Beta Hydroxysteroid dehydrogenase-1 inhibitory activity through in vitro enzymatic experiments. The results showed that the 11β-HSD1 inhibitory activity of compounds 5g and 5h was stable and efficient. Molecular docking studies revealed compounds 5g (−9.758) and 5h (−8.495) to have a stable binding patterns to the human 11-Beta-Hydroxysteroid dehydrogenase-1.     

Synthesis and cytotoxic evaluation of a series of resveratrol derivatives

A total of 17 resveratrol (=(E)-5-[2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol) derivatives were synthesized from resveratrol (RES) through a facile approach. Among them, 13 compounds, 2 and 6-17, were reported for the first time, while 1 and 3-5 had already been reported several years ago. The cytotoxic activities of these compounds were evaluated against human nasopharyngeal epidermoid tumor cell line KB, and compounds 1 and 8-11 showed strong anticancer activities in vitro, comparable with that of 5-fluorouracil, an anticancer drug. On the basis of the experimental data obtained, structure-activity relationships are discussed.     

Design, synthesis and vasodilative activity of tanshinone IIA derivatives

A new series of tanshinone IIA (DIIA) derivatives were synthesized through the reaction of brominated tanshinone IIA (1-Br DIIA) and aromatic acids in the presence of K(2)CO(3). Twenty compounds were synthesized, and all of them were novel. Vasodilative activities for synthesized compounds were valuated in vitro on the contractile response of vascular thoracic aorta smooth muscle from Wistar rats. The results showed that most compounds exhibited a concentration-dependent inhibition on the contractile response of norepinephrine. Four prepared compounds, 4, 5, 8 and 13 revealed relatively remarkable vasodilative activity.     

In vitro effects of androgens upon the spontaneous rat uterine contractility

The effectiveness of ring A reduced (5 alpha and 5 beta) testosterone (T) derivatives upon the rat uterus spontaneous contractility was tested in vitro. Compounds with the 3 alpha-hydroxy-5 alpha reduced configuration, such as androsterone and androstanediol, and one 5 beta reduced (5 beta-dihydrotestosterone) elicited a remarkable inhibitory effect upon the myometrial activity. Although steroids with 5 beta reduction were less potent than 3 alpha-hydroxy-5 alpha reduced compounds for depressing the myometrial activity, they were somewhat more potent than T, DHEA, androstenedione and the remaining 5 alpha reduced compounds tested. Therefore, T could act as a "prehormone", accounting for the maintenance of the physiological myometrial activity through its 5-reduced derivatives.     

Amelioration of PXR-mediated CYP3A4 induction by mGluR2 modulators

This work describes the rational amelioration of Cytochrome P450 4/5 (CYP3A4/5) induction through the Pregnane-X Receptor (PXR) pathway in a series of compounds that modulate the metabotropic glutamate Receptor 2 (mGluR2) via an allosteric mechanism. The compounds were initially shown to induce CYP3A4/5 via the gold-standard induction assay measured in primary human hepatocytes. This was followed up by testing the compounds in a PXR assay which correlated well with the assay in primary cells. Further, one of the compounds was crystallized with PXR (pdb code 6DUP). Analysis of this co-crystal structure, together with previously published PXR co-crystal structures, lead to modification ideas. The compounds synthesized based on these ideas were shown not to be CYP3A4/5 inducers. The mGluR2 activity of the resulting compounds was maintained.     

Synthesis, anticancer activity and apoptosis inducing ability of bisindole linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates

A series of bisindole-pyrrolobenzodiazepine conjugates (5a-f) linked through different alkane spacers was prepared and evaluated for their anticancer activity. All compounds exhibited significant anticancer potency and the most potent compounds 5b and 5e were taken up for detailed studies on MCF-7 cell line. Cell cycle effects were examined apart from investigating the inhibition of tubulin polymerization for compounds 2a, 2b, 5b and 5e at 2μM. FACS analysis showed that at higher concentrations (4 and 8μM) there was an increase of sub-G1 phase cells and decrease of G2/M phase cells, thus indicating that compounds 5b and 5e are effective in causing apoptosis in MCF-7 cells. It was also observed that compounds 5b and 5e showed the down regulation of histone deacetylase protein levels such as HDAC1, 2, 3, 8 and increase in the levels of p21, followed by apoptotic cell death. The apoptotic nature of these compounds was further evidenced by increased expression of cleaved-PARP and active caspase-7 in MCF-7 cells.     

Synthesis and bioactivity evaluation of brassinosteroid analogs

Four new analogs of 28-homocastasterone have been synthesized and completely characterized for the first time from stigmasterol. (22R, 23R,24S)-3beta-acetoxy-22,23-dihydroxy-5alpha-stigmastan+ ++-6-one (17), (22R,23R,24S)-3beta-bromo-22,23-dihydroxy-5alpha-stigmast an-6-one (18), (22R,23R,24S)-3beta-acetoxy-5,22, 23-trihydroxy-5alpha-stigmastan-6-one (20), and (22R,23R, 24S)-3beta-bromo-5,22,23-trihydroxy-5alpha-stigmastan-6-one (21), were obtained through a synthetic route based on regioselective Delta(5) epoxidation. Compounds 17 and 18, bearing a 5alphaH moiety, were prepared through a reductive opening of the 5beta,6beta epoxy precursor, and compounds 20 and 21, analogs with a 5alphaOH moiety were obtained by hydrolytic opening of a mixture of 5alpha,6alpha and 5beta,6beta epoxy precursors. Known compounds 19 and 22 were also obtained following the described synthetic routes, respectively. The new compounds were tested with the traditional auxin-like bioassay for brassinosteroids with 19 and 22 as standards. All compounds were comparatively evaluated for their inhibitory effect on the replication of DNA (HSV-1) virus.     

Synthesis and in vitro antifungal activities of new 3-substituted benzopyrone derivatives

A series of new benzopyrone compounds were designed and synthesized and their antifungal activities in vitro were evaluated. The results showed that the benzopyrone derivatives with short terminal alkyl chain exhibited potent antifungal activity, which represent a novel class of promising leads for the development of novel non-azole antifungal agents. Compound 5j is the most potent one with MIC(80) value 1.5 μg/mL against Trichophyton rubrum. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CA-CYP51 through hydrophobic and van der Waals interactions.     

Probing the structural requirements for vitamin D3 inhibition of the hedgehog signaling pathway

A structure-activity relationship study to elucidate the structural basis for hedgehog (Hh) signaling inhibition by vitamin D3 (VD3) was performed. Functional and non-functional regions of VD3 and VD2 were obtained through straightforward synthetic means and their biological activity was determined in a variety of cell-based assays. Several of these compounds inhibited Hh signaling at levels comparable to the parent VD3 with no effects on canonical vitamin D signaling. Most notably, compounds 5 and 9, demonstrated potent inhibition of the Hh pathway, exhibited no binding affinity for the vitamin D receptor (VDR), and did not activate VDR in cell culture. In addition, several compounds exhibited anti-proliferative activity against two human cancer cell lines through a mechanism distinct from the Hh or VDR pathways, suggesting a new cellular mechanism of action for this class of compounds.     

New 4-(4-methyl-phenyl)phthalazin-1(2H)-one derivatives and their effects on alpha1-receptors

Continuing our research aimed at obtaining new compounds with high affinity and selectivity toward alpha(1)-AR, a new series of arylpiperazine derivatives was designed, synthesized, and biologically tested. The new compounds 1-17 are characterized by a phenylphthalazin-1(2H)-one fragment connected through an alkyl chain to an arylpiperazine residue. The pharmacological profile of these compounds was evaluated for their affinity and selectivity toward alpha(1)-AR, alpha(2)-AR and toward 5HT(1A) serotoninergic receptor. A discussion on the structure-activity relationship (SAR) of these compounds is also reported.     

Inhibition of Histo-blood Group Antigen Binding as a Novel Strategy to Block Norovirus Infections

Noroviruses (NoVs) are the most important viral pathogens that cause epidemic acute gastroenteritis. NoVs recognize human histo-blood group antigens (HBGAs) as receptors or attachment factors. The elucidation of crystal structures of the HBGA-binding interfaces of a number of human NoVs representing different HBGA binding patterns opens a new strategy for the development of antiviral compounds against NoVs through rational drug design and computer-aided virtual screening methods. In this study, docking simulations and virtual screening were used to identify hit compounds targeting the A and B antigens binding sites on the surface of the capsid P protein of a GII.4 NoV (VA387). Following validation by re-docking of the A and B ligands, these structural models and AutoDock suite of programs were used to screen a large drug-like compound library (derived from ZINC library) for inhibitors blocking GII.4 binding to HBGAs. After screening >2 million compounds using multistage protocol, 160 hit compounds with best predicted binding affinities and representing a number of distinct chemical classes have been selected for subsequent experimental validation. Twenty of the 160 compounds were found to be able to block the VA387 P dimers binding to the A and/or B HBGAs at an IC₅₀<40.0 µM, with top 5 compounds blocking the HBGA binding at an IC₅₀<10.0 µM in both oligosaccharide- and saliva-based blocking assays. Interestingly, 4 of the top-5 compounds shared the basic structure of cyclopenta [a] dimethyl phenanthren, indicating a promising structural template for further improvement by rational design.     

Novel N-benzylpyridinium moiety linked to arylisoxazole derivatives as selective butyrylcholinesterase inhibitors: Synthesis,biological evaluation,and docking study

A novel series of N-benzylpyridinium moiety linked to arylisoxazole ring were designed, synthesized, and evaluated for their in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Synthesized compounds were classified into two series of 5a-i and 5j-q considering the position of positively charged nitrogen of pyridinium moiety (3- or 4- position, respectively) connected to isoxazole carboxamide group. Among the synthesized compounds, compound 5n from the second series of compounds possessing 2,4-dichloroaryl group connected to isoxazole ring was found to be the most potent AChE inhibitor (IC₅₀ = 5.96 µM) and compound 5j also from the same series of compounds containing phenyl group connected to isoxazole ring demonstrated the most promising inhibitory activity against BChE (IC₅₀ = 0.32 µM). Also, kinetic study demonstrated competitive inhibition mode for both AChE and BChE inhibitory activity. Docking study was also performed for those compounds and desired interactions with those active site amino acid residues were confirmed through hydrogen bonding as well as π-π and π-anion interactions. In addition, the most potent compounds were tested against BACE1 and their neuroprotectivity on Aβ-treated neurotoxicity in PC12 cells which depicted negligible activity. It should be noted that most of the synthesized compounds from both categories 5a-i and 5j-q showed a significant selectivity toward BChE. However, series 5j-q were more active toward AChE than series 5a-i.     

Chemical Constituents from the Stems of Excoecaria acertiflia

Six new compounds, including two diterpenoids excocarinols F and G ( 1 and 2 , resp.), two carotane (daucane) sesquiterpenoids excoecafolinols A and B ( 3 and 4 , resp.), one lignanoid compound, excoecanol A ( 5 ), and one simple phenol, excoecanol B ( 6 ), together with 17 known compounds, were isolated from the BuOH extract of Excoecaria acerifolia Didr . stems. Their structures were elucidated through the analysis of the spectroscopic data. The AChE‐inhibitory activities of 17 compounds were evaluated and revealed that four of them possessed moderate inhibitory activities against AChE.     

The Chemical Constituents from Podocarpus imbricatus

Ten compounds were isolated from the leaves and barks of Podocarpus imbricatus BI (Podocarpaceae) for the first time. They are identified as β-sitosterol(1), daucosterol(2), sequoyitol (3) sandaracopimaric acid (4), trans-communic acid(5), cis-communic acid (6), heveaflavone (7), amentoflavone-7,7″-dimethyl ether(8), imbricataflavone A(9), and imbri-cataflavone B(10), by means of spectral analysis, comparison of physico-chemical data and through chemical methods. 9 and 10 are new compounds.     

Chemical and anti-platelet constituents from Formosan Zanthoxylum simulans

A pyrrole alkaloid, pyrrolezanthine [5-hydroxymethyl-1-[2-(4-hydroxyphenyl)-ethyl]-1H-pyrrole-2-carbaldehyde]; a lignan, (-)-simulanol [4- [3-hydroxymethyl-5-((E)-3-hydroxypropenyl)-7-methoxy-2,3-dihydrobenzofuran-2-yl]-2,6-dimethoxy-phenol] and a monocyclic gamma-pyrone, zanthopyranone [3,5-dimethoxy-2-methyl-pyran-4-one], together with 28 known compounds were isolated from the stem wood of Formosan Zanthoxylum simulans. Their structures were determined through spectral analyses. Among the isolates, 11 compounds showed anti-platelet aggregation activity in vitro.     

Three components coupling catalysed by NaHSO(4).Sio(2) - a convenient synthesis, antibacterial and antifungal activities of novel 6-Aryl-1,2,4,5-tetrazinan-3-ones

A novel method has been developed for the synthesis of 6-aryl-1,2,4,5-tetrazinan-3-ones through a one-pot reaction of urea, various substituted aromatic benzaldehyde having electron donating and electron withdrawing groups and ammonium acetate in the presence of reusable NaHSO(4).SiO(2) heterogeneous catalyst in dry media under microwave irradiation. FT-IR, (1)H NMR, D(2)O Exchange, (13)C NMR, Heteronuclear Single Quantum Correlation (HSQC) spectra, MS and elemental analysis characterized all the synthesized compounds. In vitro antibacterial/fungal activities were evaluated for six new compounds. The antibacterial studies revealed that compounds 1-6 had better activity against tested Gram-positive and Gram-negative organisms. Compounds 1 and 5 were more active against beta-Heamolytic streptococcus, a Gram-positive bacteria and Pseudomonas, a Gram-negative bacteria, respectively, than the standard drug ciprofloxacin. Besides, of all the compounds tested, compound 5 was more effective against Aspergillus flavus, a fungal strain than the standard drug fluconazole.     

6-(2-Furanyl)-9H-purin-2-amine derivatives as A2A adenosine antagonists

Structure-activity relationships have been investigated through substitutions at the 9-position of the 2-amino-6-(2-furanyl) purine (5) to identify novel and selective A(2A) adenosine receptor antagonists. Several potent and selective antagonists were identified. In particular, compounds 20, 25, and 26 show very high affinity with excellent selectivity.     

New pterocarpanquinones: Synthesis,antineoplasic activity on cultured human malignant cell lines and TNF-α modulation in human PBMC cells

A new pterocarpanquinone (5a) was synthesized through a palladium catalyzed oxyarylation reaction and was transformed, through electrophilic substitution reaction, into derivatives 5b–d. These compounds showed to be active against human leukemic cell lines and human lung cancer cell lines. Even multidrug resistant cells were sensitive to 5a, which presented low toxicity toward peripheral blood mononuclear cells (PBMC) cells and decreased the production of TNF-α by these cells. In the laboratory these pterocarpanquinones were reduced by sodium dithionite in the presence of thiophenol at physiological pH, as NAD(P)H quinone oxidoredutase-1 (NQO1) catalyzed two-electron reduction, and the resulting hydroquinone undergo structural rearrangements, leading to the formation of Michael acceptors, which were intercepted as adducts of thiophenol. These results suggest that these compounds could be activated by bioreduction.