Synthesis and urease inhibition studies of some new quinazolinones

In this study, novel quinazolinones were designed, synthesized, characterized by FT-IR, ¹H-NMR, ¹³C-NMR spectral data, and LC–MS. New compounds inhibitory activities on urease were assessed. All of the compounds exhibited potent urease inhibitory activities. Especially in the synthesized compounds, 2-benzyl-3-({5-[(4-nitrophenyl)amino]-1,3,4-thiadiazol2-yl}methyl)quinazolin-4(3H)-one has the best inhibitory effect against Jack bean urease with IC₅₀ = 3.30 ± 0.09 μg/mL. And also, N-(4-nitrophenyl)-2-[(4-oxoquinazolin-3(4H)-yl)acetyl] hydrazinecarbothioamide, N-(4-fluorophenyl)-2-[(4-oxoquinazolin-3(4H)-yl)acetyl] hydrazinecarbothioamide, and 2-benzyl-3-({5-[(4-fluorophenyl)amino]-1,3,4-thiadiazol-2yl} methyl)quinazolin-4(3H)-one have best activities among the synthesized compounds.     

Probing BRD Inhibition Substituent Effects in Bulky Analogues of (+)-JQ1

A series of bulky organometallic and organic analogues of the bromodomain (BRD) inhibitor (+)-JQ1 have been prepared. The most potent, N-[(adamantan-1-yl)methyl]-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide, 2e , showed excellent potency with an K_D=ca. 130 nm vs. BRD4(1) and a ca. 2-fold selectivity over BRD4(2) (K_D=ca. 260 nm ). Its binding to the first bromodomain of BRD4 was determined by a protein cocrystal structure.     

An unusual reaction of propargylamines with CH2I2 and Et3Al

N-{2-[(1-R-Cyclopropyl)methyl]prop-2-enyl}-N,N-dimethylamines were prepared in 80-90% yields by the reaction (5 h, 23-25 C) of propargylamines R-C=C-CH₂NMe₂ (where R = alkyl, Ph) with a system of reactants CH2I2-Et₃Al taken in the molar ratio [propargylamine]: [Et₃Al]: [CH₂I₂] = 1: 6: 6. In the case of phenyl-substituted propargyl- amine, N-({1-[(1-phenylcyclopropyl)methyl]cyclopropyl}methyl)-N,N-dimethylamine is selectively formed in 76% yield upon the elongation of the reaction time to 4 days.     

Synthesis and stereochemistry of tetrahydro-4-aryl-3-[(dimethylamino)methyl]-2H-pyranols as potential analgesics

Diastereomeric cis- and trans-tetrahydro-4-aryl-3-[(dimethylamino)methyl]-2H-pyranols derived from 3-[(dimethylamino)methyl]tetrahydro-4H-pyran-4-one ( 5 ), have been prepared and their configurations were established on the basis of ir data. The biologically more potent trans isomer 3 was resolved into its optical antipodes and the absolute stereochemistry of one of the enantiomers 14 , was determined by X-ray crystallography. Some of the compounds showed analgesic activity comparable to codeine.     

A series of novel acyclic nucleosides. II. Synthesis of acyclic nucleosides bearing an imidazo[4,5-d] [1,3]oxazine ring

Novel acyclic nucleosides 3a,b,c where N-1 of acyclovir is replaced by oxygen atom were prepared. Thus, 1-[(2-acetoxyethoxy)methyl]-5-amino-4-ethoxycarbonylimidazole ( 9 ) was treated with ethoxycarbonyl isothiocyanate or benzoyl isothiocyanate to give 11e,f . Methylation of the latter with methyl iodide afforded S-methylisothiourea derivative 12f which was treated with alkali and subsequently the mixture was neutralized to give 5-amino-3-[(2-hydroxyethoxy)methyl]-3H-imidazo[4,5-d][1,3]oxazin-7-one ( 3a ). Compounds 3b,c were obtained by treatment of acetic anhydride or propionic anhydride with sodium 5-amino-1-[(2-hydroxyethoxy)methyl]imidazole-4-carboxylate ( 7 ) which was prepared via 5-amino-[(2-acetoxyethoxy)methyl]-imidazole-4-carboxamide ( 5 ). Evaluation of acyclic oxanosine analogs for cytotoxicity and activity against herpes simplex virus type 1 (HSV-1) revealed that all the derivatives tested were inactive, but cytotoxicity were similar or less as compared to that of acyclovir.     

Polymerization of ethylene with self-immobilizing bis(phenoxyimine) catalytic systems

The kinetic features of polymerization of ethylene with five methylaluminoxane-activated selfim-mobilizing bis(phenoxyimine) complexes of titanium chloride, namely, bis{2-[(4-allyloxyphenylimino)methyl]-6-tert-butylphenoxy}TiCl₂, bis{2-[(4-allyloxyphenylimino)methyl]-4,6-di-tert-butylphenoxy}TiCl₂, bis{2-[(4-allyloxyphenylimino)methyl]-6-cumylphenoxy}TiCl₂, bis{2-[(4-allyloxyphenylimino)methyl]-4,6-dicumylphenoxy}TiCl₂, and bis{2-[(4-allyloxyphenylimino)methyl]-6-1-(4-tert-butylphenyl)ethylphenoxy}TiCl₂ have been studied. The activity of these complexes in the polymerization of ethylene in the temperature range 20–80°C and an ethylene pressure of 0.3 MPa has been investigated both in the homogeneous and polymer matrix-bound states. The self-immobilizing catalytic systems possess high activity (up to 40000 kg_PE/mol_cat MPa h) and give rise to ultrahigh-molecular-weight PE (M = (2–7) × 10⁶) with an improved morphology of polymer particles.     

Azines and Azoles: CXX. Synthesis of Acyclic Analogs of N1-Ribosides of Barbituric Acid and Its 5-ylidene Derivatives

The reaction of 2,4,6-tris(trimethylsiloxy)pyrimidine with 2-oxabutane-1,4-diyl diacetate in methylene chloride in methylene chloride in the presence of SnCl₄ proceeds regioselectively to form 1-[(2-acetoxyethoxy)methyl]barbituric acid. The latter is readily deacetylated to a free acyclic analog of N-ribosides of barbituric acid. 1-[(2-Acetoxy- and 2-hydroxyethoxy)methyl]barbituric acids easily react with aromatic and heterocyclic aldehydes in water and organic solvents, forming 5-ylidenebarbituric acids. The structure of the products was proved by ¹H NMR and UV spectroscopy. Certain of the products exhibit a moderate antimicrobial and antiviral activity.     

Synthesis of a new class of uridine phosphorylase inhibitors

A new series of potent uridine phosphorylase inhibitors have been prepared from barbituric acid. Among them, 1-[(2-hydroxyethoxy)methyl]-5-)(m--benzyloxy)benzylbarbituric acid ( 37 , BBBA) is the most promising having a K_i value of 1.1 ± 0.2 nM with uridine phosphorylase from human liver. The new inhibitors are easily synthesized and are better inhibitors of human uridine phosphorylase than their uracil counterparts.     

Syntheses and crystal structures of two Schiff-base copper(II) complexes with urease inhibition

Two new copper(II) complexes, [CuL1(N₃)] (1) and [CuL2(NCS)] (2) (HL1 = 4-chloro-2-[(2-piperidin-1-ylethylimino)methyl]phenol, HL2 = 4-chloro-2-[(2-morpholin-4-ylethylimino)methyl]phenol), were prepared and structurally characterized by elemental analyses, infrared spectroscopy, and single-crystal X-ray diffraction. Complex 1 is an azide coordinated mononuclear complex, while complex 2 is a terminal thiocyanate coordinated mononuclear complex. The coppers in both complexes are four-coordinate, square-planar. Both complexes show potent urease inhibitory properties.     

Four NiII complexes with the new cyclam–methylimidazole ligand 1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐1,4,8,11‐tetraazacyclotetradecane

Although it has not proved possible to crystallize the newly prepared cyclam–methylimidazole ligand 1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐1,4,8,11‐tetraazacyclotetradecane (L^Im1), the trans and cis isomers of an Ni^II complex, namely trans‐aqua{1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐1,4,8,11‐tetraazacyclotetradecane}nickel(II) bis(perchlorate) monohydrate, [Ni(C₁₅H₃₀N₆)(H₂O)](ClO₄)₂·H₂O, (1), and cis‐aqua{1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐1,4,8,11‐tetraazacyclotetradecane}nickel(II) bis(perchlorate), [Ni(C₁₅H₃₀N₆)(H₂O)](ClO₄)₂, (2), have been prepared and structurally characterized. At different stages of the crystallization and thermal treatment from which (1) and (2) were obtained, a further two compounds were isolated in crystalline form and their structures also analysed, namely trans‐{1‐[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐1,4,8,11‐tetraazacyclotetradecane}(perchlorato)nickel(II) perchlorate, [Ni(ClO₄)(C₁₅H₃₀N₆)]ClO₄, (3), and cis‐{1,8‐bis[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐1,4,8,11‐tetraazacyclotetradecane}nickel(II) bis(perchlorate) 0.24‐hydrate, [Ni(C₂₀H₃₆N₆)](ClO₄)₂·0.24H₂O, (4); the 1,8‐bis[(1‐methyl‐1H‐imidazol‐2‐yl)methyl]‐1,4,8,11‐tetraazacyclotetradecane ligand is a minor side product, probably formed in trace amounts in the synthesis of L^Im1. The configurations of the cyclam macrocycles in the complexes have been analysed and the structures are compared with analogues from the literature.     

Exogenous bridging and nonbridging in Cu(II) complexes of Mannich base ligands: Synthesis and physical properties

Preparation of pentadentate ligands L¹, L², L³ and L⁴, where L¹ = 4-chloro-3-methyl-2[(prolin-1-yl)methyl]-6-[N-phenyl piperazin-1-yl)methyl]phenol, L² = 4-ethyl-2-[(prolin-1-yl)methyl]-6-[(N-phenyl piperazin-1-yl)methyl]phenol, L³ = 4-chloro-3-methyl-2-[(prolin-1-yl)methyl]-6-[N-methyl piperazin-1-yl]methyl phenol, L⁴ = 4-methoxy-2-[(prolin-1-yl)methyl]-6-[(N-phenyl piperazin-1-yl)methyl]phenol is described together with that of the corresponding Cu(II) complexes with various bridging motifs like OH, OAc and NO₂. The complexes are characterized by elemental analysis, electrochemical and electron paramagnetic spectral studies. Redox properties of the complexes in acetonitrile are highly quasireversible due to the chemical or/and stereochemical changes subsequent to electron transfer. The complexes show resolved copper hyperfine EPR at room temperature, indicating the presence of weak antiferromagnetic coupling between the copper atoms. Strengths of the antiferromagnetic interactions are in the order NO₂>OAc>OH.     

Ni(II) and Cu(II) complexes of new unsymmetrical N2O2 Schiff bases derived from 3-(2-aminobenzylimino)-1-phenylbutan-1-ol: synthesis,structure, antibacterial properties,and electrochemistry

Two new N₂O₂ unsymmetrical Schiff bases, H₂L¹ = 3-[({o-[(E)-(o-hydroxyphenyl)methylideneamino]phenyl}methyl)imino]-1-phenyl-1-buten-1-ol and H₂L² = 3-[({o-[(E)-(2-hydroxy-1-naphthyl)methylideneamino]phenyl}methyl)imino]-1-phenyl-1-buten-1-ol, and their copper(II) and nickel(II) complexes, [CuL¹] (1), [CuL²] (2), [NiL¹] (3), and [NiL²] (4), have been synthesized and characterized by elemental analyses and spectroscopic methods. The crystal structures of these complexes have been determined by X-ray diffraction. The coordination geometry around Cu(II) and Ni(II) centers is described as distorted square planar in all complexes with the CuN₂O₂ coordination more distorted than the Ni ones. The electrochemical studies of these complexes indicate a good correlation between the structural distortion and the redox potentials of the metal centers. The ligand and metal complexes were also screened for their in vitro antibacterial activity.     

Two Antioxidant Alkaloids from Portulaca oleracea L.

Two alkaloids, oleraceins F and G, were isolated from Portulaca oleracea L., and their structures were determined as methyl (2S)‐6‐[(β‐D ‐glucopyranosyl)oxy]‐2,3‐dihydro‐5‐hydroxy‐1‐[(2E)‐3‐(4‐hydroxy‐3‐methoxyphenyl)prop‐2‐enoyl]‐1H‐indole‐2‐carboxylate and methyl (2S)‐6‐[(β‐D ‐glucopyranosyl)oxy]‐2,3‐dihydro‐5‐hydroxy‐1‐[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enoyl]‐1H‐indole‐2‐carboxylate, based on their spectroscopic data. Oleraceins F and G exhibited scavenging activity against 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical, with EC₅₀ values of 21.00 and 37.69 μM , respectively.     

Neutral and cationic half‐sandwich arene d6 metal complexes containing pyridyl and pyrimidyl thiourea ligands with interesting bonding modes: Synthesis,structural and anti‐cancer studies

The reaction of [(p‐cymene)RuCl₂]₂ and [Cp*MCl₂]₂ (M = Rh/Ir) with benzoyl (2‐pyrimidyl) thiourea (L1) and benzoyl (4‐picolyl) thiourea (L2) led to the formation of cationic complexes bearing formula [(arene) M (L1)к² _(N,S) Cl]⁺ and [(arene) M (L2)к²_(N,S)Cl]⁺ [(arene) = p‐cymene, M = Ru, ( 1 , 4 ); Cp*, M = Rh ( 2 , 5 ) and Ir ( 3 , 6 )]. Precursor compounds reacted with benzoyl (6‐picolyl) thiourea (L3) affording neutral complexes having formula [(arene) M (L3)к¹_(S)Cl₂] [arene = p‐cymene, M = Ru, ( 7 ); Cp*, M = Rh ( 8 ), Ir ( 9 )]. X‐ray studies revealed that the methyl substituent attached to the pyridine ring in ligands L2 and L3 affects its coordination mode. When methyl group is at the para position of the pyridine ring (L2), the ligand coordinated metal in a bidentate chelating N, S‐ mode whereas methyl group at ortho position (L3), it coordinated in a monodentate mode. Further the anti‐cancer studies of the thiourea derivatives and its complexes carried out against HCT‐116, HT‐29 (human colorectal cancer), Mia‐PaCa‐2 (human pancreatic cancer) and ARPE‐19 (non‐cancer retinal epithelium) cell lines showed that the thiourea ligands are inactive but upon complexation, the metal compounds displayed potent and selective activity against cancer cells in vitro. Iridium complexes were found to be more potent as compared to ruthenium and rhodium complexes.     

Zinc (II), palladium (II) and cadmium (II) complexes containing 4‐methoxy‐N‐(pyridin‐2‐ylmethylene) aniline derivatives: Synthesis,characterization and methyl methacrylate polymerization

A series of Zn (II), Pd (II) and Cd (II) complexes, [(L) _n MX ₂ ] _m (L = L‐a–L‐c; M = Zn, Pd; X = Cl; M = Cd; X = Br; n, m = 1 or 2), containing 4‐methoxy‐N‐(pyridin‐2‐ylmethylene) aniline ( L‐a ), 4‐methoxy‐N‐(pyridin‐2‐ylmethyl) aniline ( L‐b ) and 4‐methoxy‐N‐methyl‐N‐(pyridin‐2‐ylmethyl) aniline ( L‐c ) have been synthesized and characterized. The X‐ray crystal structures of Pd (II) complexes [L ₁ PdCl ₂ ] (L = L‐b and L‐c) revealed distorted square planar geometries obtained via coordinative interaction of the nitrogen atoms of pyridine and amine moieties and two chloro ligands. The geometry around Zn (II) center in [(L‐a)ZnCl ₂ ] and [(L‐c)ZnCl ₂ ] can be best described as distorted tetrahedral, whereas [(L‐b) ₂ ZnCl ₂ ] and [(L‐b) ₂ CdBr ₂ ] achieved 6‐coordinated octahedral geometries around Zn and Cd centers through 2‐equivalent ligands, respectively. In addition, a dimeric [(L‐c)Cd(μ ‐ Br)Br] ₂ complex exhibited typical 5‐coordinated trigonal bipyramidal geometry around Cd center. The polymerization of methyl methacrylate in the presence of modified methylaluminoxane was evaluated by all the synthesized complexes at 60°C. Among these complexes, [(L‐b)PdCl ₂ ] showed the highest catalytic activity [3.80 × 10⁴ g poly (methyl methacrylate) (PMMA)/mol Pd hr^?1], yielding high molecular weight (9.12 × 10⁵ g mol^?1) PMMA. Syndio‐enriched PMMA (characterized using ¹H‐NMR spectroscopy) of about 0.68 was obtained with T_g in the range 120–128°C. Unlike imine and amine moieties, the introduction of N‐methyl moiety has an adverse effect on the catalytic activity, but the syndiotacticity remained unaffected.     

Four cytotoxic N4‐substituted thiosemicarbazones derived from 2‐hydroxynaphthalene‐1‐carboxaldehyde

The X‐ray crystal structures are reported of four novel and potentially O,N,S‐tridentate donor ligands that demonstrate antitumour activity. These ligands are 1‐[(4‐methyl­thio­semicarbazono)methyl]‐2‐naphthol, C₁₃H₁₃N₃OS, (III), 1‐[(4‐ethylthio­semicarbazono)­methyl]‐2‐naphthol, C₁₄H₁₅N₃OS, (IV), 1‐[(4‐phenyl­thio­semicarbazono)­methyl]‐2‐naphthol, C₁₈H₁₅N₃OS, (V), and 1‐[(4,4‐di­methyl­thio­semicarbazono)­methyl]‐2‐naphthol di­methyl sulfoxide solvate, C₁₄H₁₅N₃OS·C₂H₆OS, (VI). These chelators are N4‐substituted thio­semicarbazones, each based on the same parent aldehyde, namely 2‐­zhydroxynaphthalene‐1‐carboxaldehyde isonicotinoylhydrazone. Conformational variations within this series are discussed in relation to the optimum conformation for metal‐ion binding.     

The Synthesis of (±)-11-Deoxydaunomycinone via Regioselective Tandem Diels-Alder Reactions

The 2,5-dimethylidene-3,6-bis[(Z)-(2-nitrophenyl)sulfenylmethylidene]-7-oxabicyclo[2.2.1]heptane ( 13 ) can be used to generate polyfunctional and multicyclic molecules with high regio- and stereoselectivity via two successive Diels-Alder additions using two different dienophiles. This principle has been applied to the synthesis of (±)-11-deoxydaunomycinone ( 7 ), the aglycone of an important antitumor drug. The 2,3-didehydroanisole adds to 13 and gives the monoadduct 14 with high regioselectivity. No trace of bis-adduct is observed. The 1,4-epoxy-1,2,3,4-tetrahydro-5-methoxy-3-methylidene-2-[(Z)-(2-nitrophenyl)sulfenylmethylidene]anthracene ( 15 ) obtained on treating 14 with K₂CO₃ adds to methyl vinyl ketone to give [(1RS, 2SR, 5RS,12RS)-5,12-epoxy-1,2,3,4,5,12-hexahydro-7-methoxy-1-(2-nitrophenyl)sulfenyl-2-naphthacenyl]methyl ketone ( 16 ) with high regio- and stereoselectivity. The acid-catalyzed 7-oxanorbornadiene→phenol rearrangement of 16 is regioselective and gives (5-acetoxy-3,4-dihydro-7-methoxy-2-naphthacenyl) methyl ketone ( 20 ) which was transformed into (±)-7,11-dideoxydaunomycinone ((±)- 24 ), a known precursor of 7 .     

Crystal structures of two dinuclear cadmium(II) complexes with Schiff bases as ligands

Two new cadmium(II) complexes, Cd₂(L1)₂(NCS)₂ (1) and Cd₂(L2)₂(NCS)₂ (2), where L1 and L2 are the deprotonated forms of 2-[(3-dimethylaminopropylimino)methyl]-6-ethoxyphenol and 2-methoxy-6-[(pyridin-2-ylmethylimino)methyl]phenol, respectively, have been isolated as crystalline products and characterized by elemental analysis, IR spectroscopy, and single crystal X-ray diffraction method. Both compounds are structurally similar and are phenolate-O-bridged dinuclear cadmium(II) complexes. Each Cd(II) cation in the complexes is octahedrally coordinated. The Cd Cd distances in (1) and (2) are 3.618(2) d 3.571(2)     

Dinuclear Schiff-base copper(II) complexes with various bridging groups

Three new centrosymmetric dinuclear copper(II) complexes, [Cu₂Cl₂(L¹)₂] (1), [Cu₂(μ _1,3-NCS)₂(L²)₂] (2), and [Cu₂(μ _1,1-N₃)₂(L³)₂] (3), where L¹, L², and L³ are the deprotonated forms of the Schiff bases 1-[(2-propylaminoethylimino)methyl]naphthalen-2-ol (HL¹), 1-[(3-methylaminopropylimino)methyl]naphthalen-2-ol (HL²), and 2-[(2-isopropylaminoethylimino)methyl]phenol (HL³), respectively, have been prepared and characterized by elemental analysis, IR spectra, and single-crystal X-ray crystallography. Each Cu is coordinated by the three donors of the Schiff bases and by two bridging groups, forming a square-pyramidal geometry.     

Four oxoindole‐linked α‐alkoxy‐β‐amino acid derivatives

Four structures of oxoindolyl α‐hydroxy‐β‐amino acid derivatives, namely, methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐methoxy‐2‐phenylacetate, C₂₄H₂₈N₂O₆, (I), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐ethoxy‐2‐phenylacetate, C₂₅H₃₀N₂O₆, (II), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐[(4‐methoxybenzyl)oxy]‐2‐phenylacetate, C₃₁H₃₄N₂O₇, (III), and methyl 2‐[(anthracen‐9‐yl)methoxy]‐2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐phenylacetate, C₃₈H₃₆N₂O₆, (IV), have been determined. The diastereoselectivity of the chemical reaction involving α‐diazoesters and isatin imines in the presence of benzyl alcohol is confirmed through the relative configuration of the two stereogenic centres. In esters (I) and (III), the amide group adopts an anti conformation, whereas the conformation is syn in esters (II) and (IV). Nevertheless, the amide group forms intramolecular N—H...O hydrogen bonds with the ester and ether O atoms in all four structures. The ether‐linked substituents are in the extended conformation in all four structures. Ester (II) is dominated by intermolecular N—H...O hydrogen‐bond interactions. In contrast, the remaining three structures are sustained by C—H...O hydrogen‐bond interactions.