Synthesis and in vitro study of antiproliferative benzyloxy dihydropyrimidinones.

In this study, we report on antiproliferative benzyloxy dihydropyrimidinones (DHPMs) produced by the Biginelli reaction of benzyloxy benzaldehyde, urea, and diverse 1,3-diones. The reaction was catalyzed by lanthanum triflate and completed within 1-1.5 h, with 74-97% yield. The antiproliferative assay was carried out for all synthesized dihydropyrimidinones against six human solid tumor cell lines. Six compounds showed good antiproliferative activity with GI50 values below 5 µM. Among all the synthesized compounds, the most potent derivative showed good antiproliferative activity against all cell lines with GI50 values in the range of 1.1-3.1 µM. These DHPMs comply with druglikeness. Furthermore, ADMET prediction and the effect of P-glycoprotein on the antiproliferative activity were also studied. Overall, our method allows eco-friendly access to benzyloxy DHPMs as potential anticancer drugs.

Electron Precise Group 5 Dimetallaheteroboranes [{CpV(µ-EPh)}2{µ-η2:η2-BH3E}] and [{CpNb(µ-EPh)}2{µ-η2:η2-B2H4E}] (E = S or Se).

Synthesis and structural elucidation of various electron precise group 5 dimetallaheteroboranes have been described. Room temperature reaction of [Cp2VCl2] with Li[BH3(EPh)], generated from the treatment of LiBH4·THF and Ph2E2 (E = S or Se), for 1 h in toluene, followed by thermolysis, led to the formation of bimetallic complexes [{CpV(µ-EPh)}2{µ-η2:η2-BH3E}], 1 and 2 (1: E = S and 2: E = Se), and [{CpV(µ-SePh)}2{µ-η2:η2-BH(OC4H8)Se}], 3. One of the striking features of these compounds is that they represent a rare class of distorted tetrahedral clusters having bridging hydrogens. Evaluating the skeletal electron pairs and bonding types, compounds 1, 2, and 3 may be considered as isoelectronic with our earlier reported [(CpV)2(B2H6)2]. In an attempt to synthesize the Nb analogues of 1-3, room temperature reactions of [CpNbCl4] and Li[BH3(EPh)] (E = S or Se) were carried out that afforded compounds [{CpNb(µ-EPh)}2{µ-η2:η2-B2H4E}], 4 and 5 (4: E = S and 5: E = Se). The solid-state X-ray structures of both 4 and 5 exemplify electronically saturated [M2B3] systems, and their geometries are analogous to that of [(Cp*MoCl)2B3H7]. For the extension of this work, reaction of [Cp*TaCl4] (Cp* = η5-C5Me5) with Li[BH3(SePh)] was carried out that yielded a tantalaselenaborane cluster [(Cp*Ta)2(µ-Se)B3H6Se(C6H5)] (6). All the new compounds have been characterized using 1H, 11B{1H}, 13C{1H} NMR, UV-vis absorption, and IR spectroscopy, mass spectrometry, and X-ray diffraction studies.

Palladium catalyzed carbonylative annulation of the C(sp2)-H bond of N,1-diaryl-1H-tetrazol-5-amines and N,4-diaryl-4H-triazol-3-amines to quinazolinones.

Pd(ii) catalyzed direct C-H carbonylative annulation of N,1-diaryl-1H-tetrazol-5-amines and N,4-diaryl-4H-1,2,4-triazol-3-amines gave the corresponding triazole and tetrazole fused quinazolinones in good yields. This methodology offers a convenient method for the synthesis of these important heterocyclic scaffolds in a highly atom economical process. On the mechanistic aspect weakly nucleophilic triazole and tetrazole moieties function as both directing as well as intramolecular nucleophiles. The catalytically active C-H activated intermediate dimeric Pd complex was isolated and characterized which on exposure to CO gas gave the corresponding tetrazole fused quinazolinone derivative. On the basis of isolation of the intermediate and observed kinetic isotope effects, a mechanism has been proposed for the C-H activated direct carbonylative annulation reaction.

Sulfamide-Lattice Restructuring To Form Dimensionally Controlled Molecular Arrays and Gel-Forming Systems.

A design approach that incorporates structural requirements for the formation of a 1D assembly, fibril stability, and fibril-fibril interactions for gelation was attempted by using amino acid-based sulfamides with the general structure Aa-NH-SO2 -NH-Aa (Aa=amino acid). A preference for 1D assembly alone was not a sufficient condition for gelation, which became evident from studies involving sulfamide esters 1-5. Reducing the crystallization tendency without hindering unidirectional growth was executed through diacids of the sulfamide precursors with various amines that form an envelope around the sulfamide core through salt bridges. This strategy was fruitful, and gels of a wide variety of solvents could be formed by varying the acid and amine components. The use of dodecylamine or benzylamine, which could stabilize the molecular layers through alkyl-chain segregation or π-π interactions improved the gelation tendency, whereas the nature of the amino acid side chain, especially the rotational freedom and hydrophobicity, had a direct role in dictating the solvent preference. Crystallographic studies of these two-component systems gave molecular-level insight into the assembly and showed the importance of anisotropy in the distribution of secondary interactions in gelation.

Triamide macrocyclic chloride receptors via a one-pot tandem reduction-condensation-cyclization reaction.

A pyridine containing triamide macrocycle and its substituted analog have been synthesized in one pot from the corresponding monomer without the use of coupling reagents. The macrocycle can selectively bind chloride ions. The ease of synthesis and chloride-binding properties of the macrocycle make it a highly attractive scaffold for ion-encapsulation, ion-transport and water purification.

Correction: Triamide macrocyclic chloride receptors via a one-pot tandem reduction-condensation-cyclization reaction.

Correction for 'Triamide macrocyclic chloride receptors via a one-pot tandem reduction-condensation-cyclization reaction' by Harekrushna Behera, et al., Org. Biomol. Chem., 2017, DOI: .

Cation-Transporting Peptides: Scaffolds for Functionalized Pores?

Protein pores that selectively transport ions across membranes are among nature's most efficient machines. The selectivity of these pores can be exploited for ion sensing and water purification. Since it is difficult to reconstitute membrane proteins in their active form for practical applications it is desirable to develop robust synthetic compounds that selectively transport ions across cell membranes. One can envision tuning the selectivity of pores by incorporating functional groups inside the pore. Readily accessible octapeptides containing (aminomethyl)benzoic acid and alanine are reported here that preferentially transport cations over halides across the lipid bilayer. Ion transport is hypothesized through pores formed by stable assemblies of the peptides. The aromatic ring(s) appear to be proximal to the pore and could be potentially utilized for functionalizing the pore interior.

Effect of distal sugars and interglycosidic linkage on the N-glycoprotein linkage region conformation: synthesis and X-ray crystallographic investigation of ß-1-N-alkanamide derivatives of cellobiose and maltose as disaccharide analogs of the conserved chitobiosylasparagine linkage.

The linkage region constituents, 2-deoxy-2-acetamido-ß-D-glucopyranose (GlcNAc) and L-asparagine (Asn) are conserved in the N-glycoproteins of all eukaryotes. Elucidation of the structure and conformation of the linkage region of glycoproteins is important to understand the presentation and dynamics of the carbohydrate chain at the protein/cell surface. Earlier crystallographic studies using monosaccharide models and analogs of N-glycoprotein linkage region have shown that the N-glycosidic torsion, ϕN, is more influenced by the structural variation in the sugar part than that of the aglycon moiety. To access the influence of distal sugar as well as interglycosidic linkage (α or ß) on the N-glycosidic torsion angles, cellobiosyl and maltosyl alkanamides have been synthesized and structural features of seven of these analogs have been characterized by X-ray crystallography. Comparative analysis of the seven disaccharide analogs with the reported monosaccharide analogs showed that the ϕN value of cellobiosyl analogs deviate ~9° with respect to GlcßNHAc. In the case of maltosyl analogs, deviation is more than 18°. These deviations indicate that the N-glycosidic torsion is influenced by addition of distal sugar as well as with respect to inter glycosidic linkage (α or ß); it is less influenced by changes occurring at the aglycon. The χ2 value of alkanamide derived from glucose, cellobiose and maltose exhibit a large range of variations (from 1.6° to -109.9°). This large span of χ2 value suggests the greater degree of rotational freedom around C1'-C2' bond which is restricted in GlcNAc alkanamides. The present finding explicitly proved the importance of molecular architecture in the N-glycoproteins linkage region to maintain the linearity, planarity and rigidity. These factors are necessary for N-glycan to serve role in inter- as well as intramolecular carbohydrate-protein interactions.

Synthesis and structure of trans-bis(1,4-dimesityl-3-methyl-1,2,3-triazol-5-ylidene)palladium(II) dichloride and diacetate. Suzuki-Miyaura coupling of polybromoarenes with high catalytic turnover efficiencies.

trans-Bis(1,4-dimesityl-3-methyl-1,2,3-triazol-5-ylidene)palladium(II) dichloride has been shown to be an excellent catalyst for the multiple Suzuki-Miyaura coupling reactions of polybromoarenes to the corresponding fully substituted polyarylarenes. The reactions proceeded in excellent yields and with high turnover numbers. With 1,4-dibromobenzene the catalyst was found to be active for up to 13 consecutive cycles with a turnover number of 1260. The polyarylarenes were obtained in pure form after crystallization once without recourse to chromatographic purification. The single-crystal X-ray structures of the chloro (1) as well as the corresponding acetato (2) complexes are also reported and compared with the corresponding complexes of 1,4-diphenyl-3-methyl-1,2,3-triazol-5-ylidene as the ligand.

Salen complexes of zirconium and hafnium: synthesis, structural characterization, controlled hydrolysis, and solvent-free ring-opening polymerization of cyclic esters and lactides.

Dinuclear salen compounds of zirconium and hafnium are efficient initiators for the solvent-free ring-opening polymerization of cyclic ester monomers and lactides. There is a correlation between the theoretical and experimental number-average molecular weights (M(n)'s) in these polymerizations. Polymerization of ß-butyrolactone gives poly(3-hydroxybutyrate) with a good M(n) and molecular weight distribution.

1,1'-Binaphthyl-2,2'-diyl benzyl-phos-phoramidate.

In the title compound, C(27)H(20)NO(3)P, the P atom exhibits a somewhat distorted PNO(3) tetra-hedral geometry, with the O-P-O angle for the binaphthyl fragment being 102.82 (6)°. The dihedral angle between the naphthyl ring systems is 59.00 (2)°. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R(2) (2)(8) loops.

Delocalization Effects and Tunable Emission in a Class of Charged Cyclazines with Nitrogen on the Periphery.

A new class of cyclazine analogues with periphery reminiscent of an aza[10]annulene framework, tethered internally by an sp3 carbon, is presented. In depth structure analysis based on NMR and X-ray diffraction data gave a deeper insight into the effect of electron delocalization on their structure and properties. A characteristic change in chemical shift positions suggested an aromatic ring current in these systems. Attractive emission properties in solid and solution states involving charge transfer is another highlight.

Stereocontrolled facile synthesis and antimicrobial activity of oximes and oxime ethers of diversely substituted bispidines.

A small library of diversely substituted 2,4,6,8-tetraaryl-3,7-diazabicyco[3.3.1]nonan-9-ones, their oximes and O-methyloximes were achieved in a stereocontrolled manner by an easiest synthetic strategy as single isomers with high yields. Stereochemistry of all the synthesized compounds was established by their 1D/2D NMR spectral studies, further, witnessed by single-crystal XRD analysis. Accordingly, the compounds exist in a chair-boat conformation with equatorial orientation of the substituents in the chair part and boat-axial orientation in the boat part. Finally, all the synthesized oximes and oxime ethers were evaluated for their in vitro antimicrobial activity against a panel of pathogenic bacteria and fungi, and as a result of the structure-activity correlations, some lead molecules were known for further optimization.

Stereospecific synthesis of oximes and oxime ethers of 3-azabicycles: A SAR study towards antimicrobial agents.

Libraries of 1-methyl-2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones/oximes/O-methyloximes 1-14/15-28/29-42 and 7-methyl-2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones/oximes/O-methyloximes 43-48/49-54/55-60 were synthesized and their stereochemistry was established by 1D/2D NMR spectral and single crystal XRD studies. All the synthesized oximes and oxime ethers were screened for their in vitro antimicrobial activity against a panel of pathogenic bacteria (Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa) and fungi (Candida albicans, Candida parapsilosis, Aspergillus niger and Cryptococcus neoformans) using Gentamicin and Fluconazole as standards, respectively. From the SAR profile, the lead molecules were identified.

Triethyl-ammonium 1,1'-binaphthyl-2,2'-diyl phosphate.

In the crystal structure of the title compound, C(6)H(16)N(+)·C(20)H(12)O(4)P(-), an N-H⋯O inter-action links the cation to the anion. The N atom in the triethyl-ammonium cation exhibits a trigonal-bipyramidal coordination geometry and forms an N-H⋯O inter-action with one phosphate O atom of the 1,1'-binaphthyl-2,2'-diyl phosphate ligand. A bifurcated C-H⋯O inter-action with the other phosphate O atom links molecules along the a axis. The dihedral angle between the two naphthyl ring systems is 58.92 (3)°. The refined Flack parameter value of 0.50 (10) indicates inversion twinning.

p-Tolyl-methanaminium cyclo-hexane-1,2-diyl phosphate.

In the title mol-ecular salt, C(8)H(12)N(+)·C(6)H(10)O(4)P(-), the cation and anion are connected by N-H⋯O hydrogen bonds. The C atoms of the cyclo-hexane ring are disordered over two sets of sites in a 0.51 (4):0.49 (4) occupancy ratio to generate two superimposed chair conformations. One of the terminal phosphate O atoms is also disordered in a 0.62 (2):0.38 (2) ratio.

Synthesis, stereochemistry and antimicrobial studies of novel oxime ethers of aza/diazabicycles.

Two series of bicyclic oxime ethers viz, 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one O-benzyloximes 13-24 and 2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1]nonan-9-one O-benzyloximes 31-36 were synthesized and stereochemistry was established by their spectral (1D and 2D NMR) and crystal studies. Synthesized oxime ethers were screened for their in vitro antimicrobial activity against a set of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, Escherichia coli and Klebsiella pneumoniae) and fungi (Candida albicans, Candida-51, Rhizopus sp., Aspergillus niger and Aspergillus flavus) by twofold serial dilution method, respectively, using Ciprofloxacin and Amphotericin B as standards. Most of the molecules expressed promising antimicrobial profile against the tested pathogens and even a few compounds 16, 21, 22, 33 and 34 were better than standard drugs.

Synthesis, spectral, crystal and antimicrobial studies of biologically potent oxime ethers of nitrogen, oxygen and sulfur heterocycles.

Three series of oxime ethers viz, 2,6-diarylpiperidin-4-one O-benzyloximes 5a-o, 2,6-diaryltetrahydropyran-4-one O-benzyloximes 7a-e and 2,6-diaryltetrahydrothiopyran-4-one O-benzyloximes 11a-b and 12a-c were synthesized and stereochemistry is established by their spectral and single crystal analysis. A SAR study has been carried out for the above oxime ethers against a panel of antibacterial (Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi and Escherichia coli) and antifungal agents (Candida albicans, Candida-51, Rhizopus sp., Aspergillus niger, Aspergillus flavus and Cryptococcus neoformans), respectively, using Ciprofloxacin and Amphotericin B as standards. Most of the chloro/methyl/methoxy substituted compounds exerted moderate to good activity against all the tested organisms; moreover, some compounds (5i, 5l, 5n, 5o, 7c2, 7d1, 7d2, 7e, 11b and 12c) exhibited promising activity than standard drugs.

Nb and Ta benzotriazole or benzoxazole phenoxide complexes as catalysts for the ring-opening polymerization of glycidol to synthesize hyperbranched polyglycerols.

A series of novel mononuclear (1a-7a and 1b-6b) as well as tetranuclear (8a and 9a) niobium (Nb) and tantalum (Ta) complexes of benzotriazole or benzoxazole phenoxide pro-ligands bearing different substituents at the ortho and para positions of the phenol rings were synthesized and characterized. The reaction of NbCl5 or TaCl5 with one equivalent of benzotriazole or benzoxazole phenoxide pro-ligands (L1H-L6H) in dry toluene or chloroform produced the corresponding chloride (1a-6a and 1b-6b) and ethoxy (7a) mononuclear Nb and Ta complexes in high yields. Furthermore, from the mononuclear Nb complexes (1a or 4a), a new structural form of tetrameric niobium complexes (8a and 9a) was synthesized through a controlled hydrolysis reaction. The molecular structures of complexes 1b, 4b, 7a, 8a and 9a were unambiguously confirmed by single crystal X-ray diffraction analyses. Furthermore, all these complexes (1a-9a and 1b-6b) were tested as catalysts for the ring-opening polymerisation (ROP) of glycidol to synthesize hyperbranched polyglycerols (HPG) by using 1,1,1-tris(hydroxymethyl)propane (TMP) as an initiator. The degree of branching (DB) observed was 0.30-0.54, which is an indication of hyperbranched structures. In particular, for the niobium complex with electron-withdrawing substituents on the benzoxazole phenoxide pro-ligand (5a), we achieved superior behavior for the ROP of glycidol in terms of activity, control of molecular weight (Mn) and molecular weight distributions (MWDs) (92% of glycidol to HPG, Mn = 10.52 kg mol-1, MWDs <1.33, DB = 0.53 and Tg = -57 °C). A highly hydrophilic nature was observed for the synthesized HPG polymer by water contact angle measurement (20° to 35°).

Bite-Angle-Regulated Coordination Geometries: Tetrahedral and Trigonal Bipyramidal in Ni(II) with Biphenyl-Appended (2-Pyridyl)alkylamine N,N'-Bidentate Ligands.

Two simple biphenyl-appended (2-pyridyl)alkylamine N-bidentate ligands, Le and Lm, having ethylene and methylene spacers between donor groups, with bite angles Le ≈ 100° and Lm ≈ 80°, dictate pseudotetrahedral and trigonal-bipyramidal geometries in six high-spin Ni(II)-halide complexes, [Ni(Le)X2] and [Ni(Lm)2X](ClO4) (where X = Cl-, Br-, I-), respectively. The structures in the solid state, determined using X-ray crystallography, and in solution, determined using spectroscopic methods (UV-vis-NIR and paramagnetic 1H NMR), which complement each other, are described.