Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series

We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.     

Synthesis and biological activity of novel MIF antagonists

Two series of novel furan and indole compounds were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds from both series inhibited the enzymatic activity of MIF at levels equal to or significantly better than ISO-1 (an early MIF inhibitor). The majority of the compounds that robustly inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells were from the furan series (compounds 5, 9, 13, 15, and 16). In contrast, compounds that markedly inhibited the MIF-induced production of pro-inflammatory cytokines were predominantly from the indole series (compounds 26, 29, and 32).     

Synthesis of novel pyrazolo[1,5-a]pyrazin-4(5H)-one derivatives and their inhibition against growth of A549 and H322 lung cancer cells

A series of substituted pyrazolo[1,5-a]pyrazin-4(5H)-one was synthesized by the reaction of ethyl 1-(2-oxo-2-phenylethyl)-3-phenyl-1H-pyrazole-5-carboxylate derivatives and 2-(2-aminoethoxy)ethanol or 2-morpholinoethanamine in the condition of microwave-assisted one-step and solvent-free in a good yield. The structures of the compounds were determined by IR, ¹H NMR and mass spectroscopy. In addition, a representative single-crystal structure was characterized by using X-ray diffraction analysis. Preliminary biological evaluation showed that the compounds could inhibit the growth of A549 and H322 cells in dosage-dependent manners.     

Synthesis and evaluation of chromenyl barbiturates and thiobarbiturates as potential antitubercular agents

A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC₅₀) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC₉₀: 5.9 μg/mL) and cytotoxicity (CC₅₀: 14.27 μg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC₉₀: >20 μg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.     

Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor

A series of 3-aryl-5-acylpiperazinyl-pyrazoles (e.g., 3a-b) initially identified through a high-throughput screening campaign using the aequorin Ca²⁺ bioluminescence assay as novel, potent small molecule antagonists of the G protein-coupled human tachykinin NK₃ receptor (hNK3-R) is described. Preliminary profiling revealed poor plasma and metabolic stability for these structures in rodents. Further optimization efforts resulted in analogs with improved potency, stability, and pharmacokinetic properties as well as good brain permeability, for example, compounds 26 and 42. Unexpected cytotoxicity was observed in such N-Me pyrazole structures as compounds 41-42.     

Synthesis and in vitro cytotoxicity evaluation of some fluorinated hexahydropyrimidine derivatives

A series of trifluoromethylated hexahydropyrimidine and tetrahydropyrimidine derivatives were synthesized and their in vitro cytotoxic activities were determined in colon cancer cell line (COLO 320 HSR). Compounds 4f, 4g, 4k, 5, and 7 proved to be the most active in this series of compounds. They represent promising new leads for the development of highly potent and selective anticancer compounds. All the compounds are lipophilic due to the trifluoromethyl group, and are thus expected to penetrate the membrane in appreciable concentration.     

Ruthenium(II) carbonyl chloride complexes containing pyridine-functionalised bidentate N-heterocyclic carbenes: Synthesis, structures, and impact of the carbene ligands on catalytic activities

A series of new ruthenium(II) carbonyl chloride complexes with pyridine-functionalised N-heterocyclic carbenes [Ru(Py-NHC)(CO)₂Cl₂], [Py-NHC = 3-methyl-1-(2-pyridyl)imidazol-2-ylidene, 1 (1a and 1b); 3-methyl-1-(2-picoyl)imidazol-2-ylidene, 2 (2a and 2b); 3-methyl-1-(2-pyridyl)benzimidazolin-2-ylidene, 3 (3b); 3-methyl-1-(2-picoyl)benzimidazolin-2-ylidene, 4 (4a and 4b); 1-methyl-4-(2-pyridyl)-1,2,4-triazoline-5-ylidene, 5 (5a and 5b)] have been prepared by transmetallation from the corresponding silver carbene complexes and characterized by NMR, IR spectroscopy and elemental analysis. In these complexes with bidentate Py-NHC ligands, one CO ligand is trans to the Py ligand. In 1a, 2a, 4a, and 5a, the NHC ligand is trans to the other CO ligand, thus leaving the two Cl⁻ ligands trans to each other. In 1b, 2b, 3b, 4b, and 5b, the NHC ligands are trans to one Cl⁻ ligand, and the two Cl⁻ ligands are cis to each other. The structures for 1b, 2b, 3b and 4b have been determined by single-crystal X-ray diffraction. These complexes are efficient catalysts in the transfer hydrogenation of acetophenone and their catalytic activities are found to be influenced by electronic effect of the N-heterocyclic carbene ligands.     

Optimization of triazoles as novel and potent nonphlorizin SGLT2 inhibitors

Previous efforts have led to the identification of a potent, selective, and nonphlorizin based SGLT2 inhibitor 1. This Letter describes efforts to further optimize the potency, microsomal stability, solubility and pharmacokinetic properties of this series of SGLT2 inhibitors. From these efforts, compounds 28 and 32 have improved solubility and pharmacokinetic properties compared to compound 1     

Synthesis and characterization of cationic rhodium(I) dicarbonyl complexes

Treatment of Rh(acac)(CO)₂ (acac = acetoacetonate) with perchloric acid followed by addition of an α-diimine (α-diimine = 1,4-bis(Ar)-2,3-dimethyl-1,4-diaza-1,3-butadiene, Ar = 3,5-dimethylphenyl, 1; 3,5-di-tert-butylphenyl, 2; and 3,4,5-trimethoxyphenyl, 3; phenyl, 4; and 4-chlorophenyl, 5) generates a series of complexes of the type [Rh(α-diimine)(CO)₂][ClO₄] 6-10 with varying electronic properties of the supporting diimine ligand. X-ray crystal structures have been determined for the α-diimine ligands 1-5, and complexes 6, 8, and 10.     

Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene

To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.     

Discovery of novel ureas and thioureas of 3-decladinosyl-3-hydroxy 15-membered azalides active against efflux-mediated resistant Streptococcus pneumoniae

A series of novel ureas and thioureas of 3-decladinosyl-3-hydroxy 15-membered azalides, were discovered, structurally characterized and biologically evaluated. They have shown good antibacterial activity against selected Gram-positive and Gram-negative bacterial strains. These include N″ substituted 9a-(N′-carbamoyl-γ-aminopropyl)- (6a,c), 9a-(N′-thiocarbamoyl-γ-aminopropyl)- (7a,e), 9a-[N′-(β-cyanoethyl)-N′-(carbamoyl-γ-aminopropyl)]- (9a-c, 9g) 9a-[N′-(β-cyanoethyl)-N′-(thiocarbamoyl-γ-aminopropyl)]-derivatives (10d-f) of 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A (3).Among the synthesized compounds thiourea 7a and urea 9b have shown substantially improved activity comparable to azithromycin (1) and significantly better activity than the 3-decladinosyl-azithromycin (2) and the parent 3-cladinosyl analogues against efflux-mediated resistant S. pneumoniae.     

Synthesis and antimicrobial activity of some new N-glycosides of 2-thioxo-4-thiazolidinone derivatives

5-Arylidene-2-thioxo-4-thiazolidinones 3a-f react with each of 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl and α-d-galactopyranosyl bromides 4a,b in acetone in the presence of aqueous potassium hydroxide at room temperature to afford N-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl) or N-(2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl) 2-thioxo-4-thiazolidinone derivatives 5a-f. Similarly, the reaction of 5-cycloalkylidene-2-thioxo-4-thiazolidinones 7a,b with 4a gave the corresponding N-glucosides 8a,b. Also, 5-pyrazolidene rhodanines 10a-e react with 4a to afford the new N-glucosides 11a-e. Treatment of compounds 15 and 16 with 4a in the presence of few drops of triethylamine or in KOH solution accomplished the mono- and bis-nucleosides 17 and 18, respectively. Some selected products were tested for their antimicrobial activities.     

New organotin complexes with trans(cis)-1,4-cyclohexanedicarboxylic acid: Synthesis, characterization and crystal structures of mononuclears, 2D network polymers and a tetratin macrocycle

A series of new organotin carboxylates have been synthesized by reactions of trans(cis)-1,4-cyclohexanedicarboxylic acid with triorganotin chloride and diorganotin dichloride. All the complexes were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR, ¹¹⁹Sn NMR spectroscopy; furthermore, complexes 1, 3, 5, 8 and 9 were characterized by X-ray diffraction analyses. The structural analyses show that complex 1 possesses a monomer structure; complex 5 possesses a 1D zigzag chain structure; both the complexes 3 and 8 have 2D network structures and complex 9 has a tetratin 36-membered macrocyclic structure.     

Design, synthesis, and evaluation of bromo-retrochalcone derivatives as protein tyrosine phosphatase 1B inhibitors

A series of bromo-retrochalcones was designed, synthesized and evaluated as PTP1B inhibitors based on licochalcone A and E. Compounds 6, 12, 13, 14, 25, 36, 37, 39, and 41 showed potent inhibitory effects against PTP1B, and compound 37, the most potent among the series, had an IC₅₀ value of 1.9 μM, about two-fold better than that of the positive control, ursolic acid.     

The novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of N-aryl urea: synthesis, anti-inflammatory, antibacterial and antifungal activity evaluation

A series of novel 3,4-dihydropyrimidin-2(1H)-one urea derivatives of biological interest were prepared by sequential Bigineli’s reaction, reduction followed by reaction of resulting amines with different arylisocynates. All the synthesized (1-23) compounds were screened against the pro-inflammatory cytokines (TNF-α and IL-6) and antimicrobial activity (antibacterial and antifungal). Biological activity evaluation study reveled that among all the compounds screened, compounds 12 and 17 found to have promising anti-inflammatory activity (68-62% TNF-α and 92-86% IL-6 inhibitory activity at 10 μM). Interestingly compounds 3, 4, 5, 6, 15, 22 and 23 revealed promising antimicrobial activity at MIC of 10-30 μg/mL against selected pathogenic bacteria and fungi.     

Ketonethiosemicarbazones: structure-activity relationships for their melanogenesis inhibition

A series of 2-(1-phenylalkylidene)hydrazinecarbothioamides 2, 2-(1-phenylalkyl)hydrazinecarbothioamides 3, 2-(3,4-dihydronaphthalen-1(2H)-ylidene)hydrazinecarbothioamide (4), and 2-(1-(thiophen-2-yl)ethylidene)hydrazinecarbothioamide (5) were synthesized for their melanogenesis inhibition in melanoma B16 cells. The SAR of these ketonethiosemicarbazones revealed that the benzylidene hydrogen in aldehydethiosemicarbazones 1 can be replaced by hydrophobic moiety and substitutions with alkyl group for the terminal amino hydrogen of ketonethiosemicarbazones improved the activity appreciably. In addition, the double bond in thiosemicarbazones is an important factor for the increment of hydrophobicity. Thus hydrophobic ketonethiosemicarbazones are excellent inhibitors of melanogenesis like aldehydethiosemicarbazones.     

The effect of sulfur on CVD performance of Pd(II) β-diketonate precursors and the completion of a structural trans-influence series: synthesis and structural characterization of Pd(S,S-tmhd)2

The three complexes, Pd(tmhd)₂ (1), Pd(S-tmhd)₂ (2), and Pd(S,S-tmhd)₂ (3) (where tmhd, S-tmhd, and S,S-tmhd are the anions of 2,2,6,6-tetramethyl-3,5-heptanedione, 2,2,6,6-tetramethyl-5-thioxo-3-heptanone, and 2,2,6,6-tetramethyl-3,5-heptanedithione, respectively) were prepared and characterized by thermogravimetric analysis in order to assess their relative volatilities as a function of sulfur substitution. Complexes 1 and 2 volatilized with little residue, while 3 experienced significant decomposition during volatilization. The solid-state structure of 3 was determined in order to complete a structural trans-influence series with 1 and 2 and to assess possible reasons for its lower thermal stability. A large trans-influence was observed for the bond lengths in the coordination sphere across the series of complexes 1, 2, and 3. The longer Pd-S bond distances found in 3 may be a contributing factor to its unsuitability as a CVD precursor.     

Synthesis, structures and luminescent properties of new heterobimetallic Zn-4f Schiff base complexes

A series of new 3d-4f heterobimetallic Schiff base complexes of the general formula [Zn(μ-L²)Ln(NO₃)₃(H₂O)_n] (Ln = La 1, Nd 2, Gd 3, Er 4 and Yb 5; n = 1 or 2; H₂L² = N,N′-bis(3-methoxy-5-p-tolylsalicylidene)ethylene-1,2-diamine) are synthesized and characterized. Complexes 1, 2, 4 and 5 are structurally characterized by X-ray crystallography. The photophysical properties of these complexes are also investigated. At room temperature, complexes 1-5 exhibit similar solution absorption and emission spectra in the UV-Vis region. Furthermore, compounds 2, 4 and 5 exhibit solution emission corresponding to the lanthanide(III) ion in the near-infrared region at room temperature. The triplet state emission of the 3d-4f bimetallic complexes without energy transfer is also determined through the photophysical study of complex 3.     

Stereoselectivity of sodium borohydride reduction of saturated steroidal ketones utilizing conditions of Luche reduction

A series of keto steroids were reduced with sodium borohydride in the presence of cerium(III) chloride or samarium(III) iodide (Luche reduction). The ratios of axial and equatorial alcohols were determined by HPLC and the results were compared with those obtained by a standard sodium borohydride reduction. The best results were obtained with the 2-keto derivative 1, 7-keto derivatives 5 and 6, and 12-keto derivative 8 where the cerium(III) ion addition resulted in the inversion of the axial/equatorial ratios. The Luche reduction of the 20-keto derivative 11 improved the proportion of the (20S)-alcohol in a mixture of (20S)/(20R) alcohols up to 35% from 5% in a standard sodium borohydride reduction.