Design,synthesis and evaluation of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA,adefovir) as potent HBV inhibitors

A series of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir) were synthesized and their anti-hepatitis B virus (HBV) activity was evaluated in HepG2 2.2.15 cells, with adefovir dipivoxil as a reference drug. In the cell assays, compounds 7b and 7d exhibited anti-HBV activity comparable to that of adefovir dipivoxil, while compound 7c, with an IC₅₀ value of 0.12 μM, was found to be three times more potent than the reference compound. In vitro stability studies showed that (S_P,S)-7c, the diastereomer of compound 7c, was stable in human blood plasma but underwent rapid metabolism to release the parent drug PMEA in liver microsomes. The possible metabolic pathway of (S_P,S)-7c in human liver microsomes was described. These findings suggest that compound (S_P,S)-7c is a promising anti-HBV drug candidate for further development.     

Design,synthesis, and biological evaluation of deuterated phenylpropionic acid derivatives as potent and long-acting free fatty acid receptor 1 agonists

The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda’s compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series. Further optimizations of deuterated series led to the discovery of compound 18, which exhibited a superior balance in terms of in vitro activity, lipophilicity, and solubility. Better still, compound 18 revealed a lower clearance (CL = 0.44 L/h/kg), higher maximum concentration (C_max = 7584.27 μg/L), and longer half-life (T_1/2 = 4.16 h), resulting in a >23-fold exposure than compound 1. In subsequent in vivo pharmacodynamic studies, compound 18 showed a robustly glucose-lowering effect in rodent without the risk of hypoglycemia.     

Identification of a Novel Selenium-containing Compound,Selenoneine, as the Predominant Chemical Form of Organic Selenium in the Blood of Bluefin Tuna

A novel selenium-containing compound having a selenium atom in the imidazole ring, 2-selenyl-N_α,N_α,N_α-trimethyl-l-histidine, 3-(2-hydroseleno-1H-imidazol-5-yl)-2-(trimethylammonio)propanoate, was identified from the blood and other tissues of the bluefin tuna, Thunnus orientalis. The selenium-containing compound was purified from the tuna blood in several chromatographic steps. High resolution mass spectrometry and nuclear magnetic resonance spectroscopy showed that the exact mass of the [M+H]⁺ ion of the compound was 533.0562 and the molecular formula was C₁₈H₂₉N₆O₄Se₂. Its gross structure was assigned as the oxidized dimeric form of an ergothioneine selenium analog in which the sulfur of ergothioneine is replaced by selenium. Therefore, we named this novel selenium-containing compound “selenoneine.” By speciation analysis of organic selenium compounds using liquid chromatography inductively coupled plasma mass spectrometry, selenoneine was found widely distributed in various tissues of the tuna, with the highest concentration in blood; mackerel blood contained similar levels. Selenoneine was measurable at 2–4 orders of magnitude lower concentration in a limited set of tissues from squid, tilapia, pig, and chicken. Quantitatively, selenoneine is the predominant form of organic selenium in tuna tissues.     

Synthesis,Crystal Structure and Thermal Decomposition of the New Cadmium Selenite Chloride,Cd4(SeO3)2OCl2

A synthetic study in the Cd-Se-O-Cl system led to formation of the new oxochloride compound Cd₄(SeO₃)₂OCl₂ via solid state reactions. The compound crystallizes in the orthorhombic space group Fmmm with cell parameters a = 7.3610(3) Å, b = 15.4936(2) Å, c = 17.5603(3) Å, Z = 8, S = 0.969, F(000) = 2800, R = 0.0185, R_w = 0.0384. Single crystal X-ray data were collected at 293 K. The crystal structure can be considered as layered and the building units are distorted [Cd(1)O₆] octahedra, distorted [Cd(2)O₈] cubes, irregular [Cd(3)O₄Cl₂] polyhedra and SeO₃E trigonal pyramids. There are two crystallographically unique Cl atoms that both are half occupied. Thermogravimetric studies show that the compound starts to decompose at 500°C. The crystal structure of the new compound is closely related to the previously described compound Cd₄(SeO₃)₂Cl₄(H₂O).     

Design,synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles

A series of deuterated apalutamide were designed and prepared. Compared to its prototype compound 18, deuterated analogues 19 and 21 showed obviously higher plasma concentrations and better PK parameters after oral administration in mice. In rats, N-trideuteromethyl compound 19 displayed 1.8-fold peak concentration (C_max), and nearly doubled its drug exposure in plasma (AUC_0–∞) compared to compound 18. Unsurprisingly, compounds 18 and 19 had similar affinity for AR in vitro. In summary, the deuteration strategy could obviously improve PK parameters of apalutamide.     

Synthesis,anticancer assessment on human breast,liver and colon carcinoma cell lines and molecular modeling study using novel pyrazolo[4,3-c]pyridine derivatives

The key intermediate 3-aminopyrazolo[4,3-c]pyridine-4,6-dione (2) is considered as a precursor for some novel pyrazolo[4,3-c]pyridines 4a-c, arylhydrazopyrazolo[4,3-c]pyridines 8a-e, pyrazolo[4,5,1-ij][1,6]naphthyridines 11a-e and pyrido[4′,3′:3,4]pyrazolo[1,5-a]-pyrimidines 15a-d through Knovenegal condensation, coupling reaction and Michael addition. Some of the newly synthesized pyrazolo[4,3-c]pyridine derivatives were investigated for anticancer activity. The results of the cytotoxic activity revealed that compound 6b was the most active compound against the breast and liver carcinoma cell lines which gives IC₅₀ values of 1.937 and 3.695 µg/mL, respectively compared to reference drug (doxorubicin) with IC₅₀ values of 2.527 and 4.749 µg/ml, respectively. Moreover, compound 6c was potent compound against the colon carcinoma cell line which gives the value of IC₅₀ = 2.914 µg/ml compared to doxorubicin with IC₅₀ value of 3.641 µg/ml. Some selected of the novel synthesized compounds were docked inside the active site of ERK2 enzyme and were found display a suitable binding with the active site amino acids according to their bond lengths, angles and conformational energy.     

One-dimensional ladder like and two-dimensional polymorphs of heterometallic thiocyanate bridged copper(II) and mercury(II) coordination polymer: Syntheses, structural, vibration, luminescence and EPR studies

The 1D triclinic {CuHg(en)(μ-NCS-N,S)₄}_n (1) and 2D monoclinic {CuHg(en)(μ-NCS-N,S)₃(SCN)}_n (2) (en = ethylenediamine) heterometallic coordination polymers, as the two polymorphs of the {CuHg(en)(NCS)₄}_n, were synthesized at room temperature by the reaction of mercuric thiocyanate, potassium thiocyanate, copper(II) malonate and ethylenediamine using different reagent ratios. XRD on single crystals shows that the compound 1 consists of 1D ladder like zigzag ribbons extended along the b axis, whereas compound 2 shows a 2D wavy polymeric structure running parallel to the ab plane. In the crystal packing of the both polymorphs, the polymeric structures are further interlinked to each other via weak interactions and hydrogen bonding to afford a 3D network. Diagnostic ligand and metal-ligand bands in the IR, far-IR and Raman spectra are assigned for the studied compounds. While compound 1 shows no significant emission upon excitation at any wavelength in the UV-Vis region, compound 2 exhibits intense emission at around 410 nm. Moreover, the room temperature X-band EPR spectrum of a powdered sample of 1, shows a signal of rhombic symmetry with g₁ = 2.2637, g₂ = 2.0765 and g₃ = 2.0483. In contrast to this, 2 reveals an axial signal with g_⊥ = 2.0742; however, the g_|| is unresolved.     

Design,synthesis and biological evaluation of novel serotonin and dopamine receptor ligands being 6-bromohexyl saccharine derivatives

Due to numerous side effects of current antidepressants, the search for new, safer bioactive compounds is still a valid research topic in medical chemistry. In our research we decided to synthesize and determine SAR for new hexyl arylpiperazines (LACPs) derivated with saccharin moiety. High biological activity has been explained using molecular modelling methods. The compounds obtained show high affinity for the 5-HT_1A (compound 18, K_i = 4 nM – antagonist mode) and D₂ (compound 15, K_i = 7 nM – antagonist mode) receptor, and in some cases also 5-HT₇ receptor (compound 17, K_i = 20 nM). A preliminary ADME analysis showed that the compounds exhibit CNS drugability properties. We have proved that carbon-chain lengthening may have a beneficial effect on increasing the activity towards serotonin and dopamine receptors.     

Semisynthesis,cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives

In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC₅₀?=?3.4?µM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC₅₀?>?400?µM), showing selectivity towards parasites (selectivity index?>?117.47). In combination with artemisinin, compound 7b showed an additive effect (CI?=?1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of ?7.02?kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC₅₀?=?93?µM) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3β-butanoyl betulinic acid on Plasmodium may be related to other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources.     

Design,synthesis, bioactivity and mechanism of dithioacetal derivatives containing dioxyether moiety

The present work designed and synthesized a series of dithioacetal derivatives containing dioxyether, as well as evaluated their antiviral activities against tobacco mosaic virus (TMV). Bioassays demonstrated that the target compounds showed excellent anti-TMV activities in vivo and in vitro. Compound 24c has excellent anti-TMV activities, and its curative, protective and inactivating activities for TMV were 50.9%, 58.9% and 81.8%, respectively, which are obviously superior to those of ribavirin (50.2%, 41.3% and 69.5%, respectively). Moreover, the EC₅₀ of the inactivating activities of the anti-TMV of compound 24c is 67.9 mg/L, which is superior to that of ribavirin (149.5 mg/L). Transmission electron microscopy showed that compound 24c caused great damage to the morphology of TMV particles, causing fracture and bending. Molecule docking model revealed that this compound formed five conventional hydrogen bonds with the active sites of amino acids GLN57, ASN73, TYR139, and SER138. Furthermore, the test results of Fluorescence titration and microscale thermophoresis showed that compound 24c has a strong binding force with TMV coat protein (TMV CP), with an association constant (K_a) of 1.04 × 10⁵ L/mol and dissociation constant (K_d) of 1.6 ± 0.6 μM. These results indicate that the dithioacetal derivatives containing dioxyether are worthy of further research and development as novel antiviral agents.     

pH kinetic studies of the N-demethylation of N,N-dimethylaniline catalyzed by chloroperoxidase

The effect of pH on the kinetic parameters for the chloroperoxidase-catalyzed N-demethylation of N,N-dimethylaniline supported by ethyl hydroperoxide was investigated from pH 3.0 to 7.0. Chloroperoxidase was found to be stable throughout the pH range studied. Initial rate conditions were determined throughout the pH range. The V_max for the demethylation reaction exhibited a pH optimum at approximately 4.5. The K_m for N,N-dimethylaniline increased with decreasing pH, while the K_m for ethyl hydroperoxide varied in a manner paralleling V_max. Comparison of the $\text{V}{}_{\mathrm{<mtext>max</mtext>}}\text{K}{}_{\mathrm{m}}$ values for N,N-dimethylaniline and ethyl hydroperoxide indicated that the interaction of N,N-dimethylaniline with chloroperoxidase compound I was rate-limiting below pH 4.5, while compound I formation was rate-limiting above pH 4.5. The log of the $\text{V}{}_{\mathrm{<mtext>max</mtext>}}\text{K}{}_{\mathrm{m}}$ for ethyl hydroperoxide was independent of pH, indicating that chloroperoxidase compound I formation is not affected by ionizations in this pH range. The plot of the log of the $\text{V}{}_{\mathrm{<mtext>max</mtext>}}\text{K}{}_{\mathrm{m}}$ for N,N-dimethylaniline versus pH indicated an ionization on compound I with a pK of approximately 6.8. The plot of the log of the V_max versus pH indicated an ionization on the compound I-N,N-dimethylaniline complex, with a pK of approximately 3.1. The results show that chloroperoxidase can demethylate both the protonated and neutral forms of N,N-dimethylaniline (pK approximately 5.0), suggesting that hydrophobic binding of the arylamine substrate is more important in catalysis than ionic bonding of the amine moiety. For optimal catalysis, a residue in the chloroperoxidase compound I-N,N-dimethylaniline complex with a pK of approximately 3.1 must be deprotonated, while a residue in compound I with a pK of approximately 6.8 must be protonated.     

Synthesis,characterization and bioactivity of four novel trinuclear copper(II) and nickel(II) complexes with pentadentate ligands derived from N-acylsalicylhydrazide

Four novel trinuclear copper(II)/nickel(II) complexes with four trianionic pentadentate ligands, N-(3-t-butylbenzoyl)-5-nitrosalicylhydrazide (H₃3-t-bbznshz), N-(3,5-dimethylbenzoyl)salicylhydrazide (H₃3,5-dmbzshz), N-(phenylacetyl)-5-bromosalicylhydrazide (H₃pabshz) and N-(3-t-butylbenzoyl)salicylhydrazide (H₃3-t-bbzshz) have been synthesized and characterized by X-ray crystallography. These trinuclear compounds all have an M–N–N–M–N–N–M core formed by three metal ions and two ligands. The geometries of three Cu(II) ions in compound Cu₃(3-t-bbznshz)₂(H₂O)(DMF)(py)₂ · DMF (1) alternate between distorted square pyramidal and square planar, while in compound Cu₃(3,5-dmbzshz)₂(py)₂ (2), they are all square planar. Three Ni(II) ions in compound Ni₃(pabshz)₂(DMF)₂(py)₂ (3) and Ni₃(3-t-bbzshz)₂(py)₄ · 2H₂O (4) follow square-planar/octahedral/square-planar coordination geometry. Compounds 1, 2 and 4 are bent trinuclear, with the bend angles of 156.4°, 141.49° and 127.1°, respectively, while the three nickel ions in compound 3 are strictly linear, with an angle of 180°. Studies on the trinuclear Ni(II) complexes show that the β-branched N-acylsalicylhydrazide ligands with sterically flexible Cα methylene groups are easier to yield linear trinuclear Ni(II) complexes, while α-branched N-acylsalicylhydrazides ligands tend to form bent trinuclear Ni(II) complexes. Antibacterial screening data indicate that the trinuclear Cu(II) compound 2 is more active than 1 and mononuclear Cu(II) compound, bent trinuclear Ni(II) compound 4 is more active than linear compound 3 and less active than tetranuclear nickel compound in the previous study.     

Design,synthesis and fungicidal evaluation of novel pyraclostrobin analogues

A series of novel pyraclostrobin derivatives were designed and prepared as antifungal agents. Their antifungal activities were tested in vitro with five important phytopathogenic fungi, namely, Batrylis cinerea, Phytophthora capsici, Fusarium sulphureum, Gloeosporium pestis and Sclerotinia sclerotiorum using the mycelium growth inhibition method. Among these compounds, 5s displayed IC₅₀ value of 0.57?μg/mL against Batrylis cinerea and 5k-II displayed IC₅₀ value of 0.43?μg/mL against Sclerotinia sclerotiorum, which were close to that of the positive control pyraclostrobin (0.18?μg/mL and 0.15?μg/mL). Other compounds 5f, 5k-II, 5j, 5m and 5s also exhibited strong antifungal activity. Further enzymatic assay demonstrated compound 5s inhibited porcine bc₁ complex with IC₅₀ value of 0.95?μM. The statistical results from an integrated computational pipeline demonstrated the predicted total binding free energy for compound 5s is the highest. Consequently, compound 5s with the biphenyl-4-methoxyl side chain could serve as a new motif as inhibitors of bc₁ complex and deserve to be further investigated.     

Synthesis,biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novel β2-adrenoceptor agonists

A novel series of 2-amino-2-phenylethanol derivatives were developed as β₂-adrenoceptor agonists. Among them, 2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile (compound 2f) exhibited the highest activity (EC₅₀ = 0.25 nM) in stimulating β₂-adrenoceptor-mediated cellular cAMP production with a 763.6-fold selectivity over the β₁-adrenoceptor. The (S)-isomer of 2f was subsequently found to be 8.5-fold more active than the (R)-isomer. Molecular docking was performed to determine the putative binding modes of this new class of β₂-adrenoceptor agonists. Taken together, these data show that compound 2f is a promising lead compound worthy of further study for the development of β₂-adrenoceptor agonists.     

Isolation and Characterization of a New Antibiotic, ABBOTT 29119, from Streptomyces erythreus

A new antibiotic was isolated from fermentations of Streptomyces erythreus designed for erythromycin A production. Isolation of this compound was accomplished by use of ion-exchange chromatography and countercurrent distribution. It crystallized from methyl isobutyl ketone in colorless acicular plates which melted at 127 to 130 C. The empirical formula was C₄₂H₇₅NO₁₄ with a molecular weight of 820. Electrometric titration in 66% dimethylformamide showed an apparent pKa of 8.4. Nuclear magnetic resonance, infrared, and ultraviolet absorption indicated a close resemblance of the compound to known erythromycins, although its chromatographic behavior and solubility differed from those of the known erythromycins. Its antimicrobial spectrum was similar to erythromycin A, but the minimal inhibitory concentrations were much higher.     

New carboxamides bearing benzenesulphonamides: Synthesis,molecular docking and pharmacological properties

Ten new derivatives of benzenesulphonamide bearing carboxamide functionality were synthesized and investigated for their in vitro antimicrobial, antioxidant and in vivo anti-inflammatory activities. Compound 9d inhibited carrageenan induced rat-paw oedema at 93.81, 88.79 and 86.09% at 1 h, 2 h and 3 h administration respectively. In the antimicrobial activity, compound 9a (6.54, 6.69 and 6.64 mg/mL) was most potent against S. aureus, B. subtilis and C. albicans respectively, compound 9e (6.45 and 6.46 mg/mL) was most active against P. aeruginosa and A. niger respectively while compound 9i (6.24 mg/mL) was most active against E. coli. Only compound 9a (IC₅₀ 0.3052 mg/mL) had comparable activity with Vitamin C (IC₅₀ 0.2090 mg/mL) in the antioxidant assay.     

Synthesis,properties and structure of hexaaquo-tris(N,N-dimethylformamide)-lanthanide trifluoromethanesulfonates

The compounds of general formula [Ln(DMF)₃- (H₂O)₆](CF₃SO₃)₃ (Ln = LaEu, Tb, Dy) were synthesized and characterized by microanalysis, conductance measurements, IR absorption (Nd³⁺) and emission (Eu³⁺) spectra. The crystal structure of the neodymium compound was determined by X-ray diffraction techniques. The compound crystallizes in the triclinic system, space group P1, a = 8.589(4), b = 11.222(2), c = 12.271(2) Å, α = 56.83(2), β = 62.13(2), γ = 75.14(2)°, V = 875.2 ų, M = 918.4, Z = 1, D_c = 1.73 g cm⁻³, λ(Mo Kα) = 0.71073 Å, μ = 1.65 mm⁻¹, F(000) = 456, R = 0.056, R_w = 0.057, for 2979 independent reflections with I > 3σ(I). Nd³⁺ is coordinated to the oxygen atoms of six independent water molecules at a mean distance NdO = 2.52(1) Å, and to the oxygen atoms of three independent DMF groups at a mean distance NdO = 2.40(2) Å. The coordination polyhedron is a tricapped trigonal prism of point symmetry C_3v.     

Liriodendronine,an oxoaporphine pigment from discolored sapwood of Liriodendron tulipifera

A new violet oxoaporphine alkaloid. liriodendronine, has been isolated from the discolored sapwood of Liniodendron tulipifera and its structure determined by spectroscopic methods and by conversion into a corunnine-type compound, 2-O,N-dimethylliriodendronine. UV studies demonstrated that the compound exists primarily as a quinone-methide in a neutral medium, a dianion in base, an isoquinolinium ion in weak acid, and as an antiaromatic conjugate acid in conc H₂SO₄.     

Discovery of N-substituted 7-azaindoline derivatives as potent,orally available M1 and M4 muscarinic acetylcholine receptors selective agonists

We designed and synthesized novel N-substituted 7-azaindoline derivatives as selective M₁ and M₄ muscarinic acetylcholine receptors (mAChRs) agonists. Hybridization of compound 2 with the HTS hit compound 5 followed by optimization of the N-substituents of 7-azaindoline led to identification of compound 1, which showed highly selective M₁ and M₄ mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species.     

Photoluminescent metal-organic framework with hex topology constructed from infinite rod-shaped secondary building units and single e,e-trans-1,4-cyclohexanedicarboxylic dianion

Hydrothermal reaction produced a three-dimensional zinc 1,4-cyclohexanedicarboxylate formulated as Zn₅(μ³-OH)₂(trans-chdc)₄ (chdc = 1,4-cyclohexanedicarboxylic dianion) in high purity and good yield, which is constructed from infinite rod-shaped Zn-O-C secondary building units interconnected by -C₆H₁₂-cyclohexane rings of the ligands. The topology of the framework can be regarded as hex type. Though it is synthesized from 1,4-cyclohexanedicarboxylic acid with mixed conformations (trans and cis), interestingly, the ligands in the compound Zn₅(μ³-OH)₂(trans-chdc)₄ are uniformly in e,e-trans conformation. This may be related to its synthetic conditions. Photoluminescence measurement reveals that the compound exhibits intense violet-blue fluorescent emission at room temperature. Origin of the emission can be assigned to intraligand transitions by comparison of the fluorescent emission bands for the free ligand chdcH₂ and the compound Zn₅(μ³-OH)₂(trans-chdc)₄.