Synthesis of Aliphatic Polyanhydrides with Controllable and Reproducible Molecular Weight.

Polyanhydrides have been synthesized for decades by melt-polycondensation of diacid monomers and 5 to >10 times mole excess acetic anhydride to diacid monomers to form polymers with a polydispersity ranging from 2.5 to 6 and low reproducibility. Hydrophobic segments in polyanhydrides are beneficial to hinder the characteristic hydrolytic cleavage of an anhydride bond that provides stable polyanhydrides at room temperature. The objective of this work is to synthesize aliphatic polyanhydrides with various hydrophobic segments, controllable and reproducible molecular weight, and low polydispersity that are essential for potential use as drug carriers. A series of polyanhydrides of suberic, azelaic, sebacic, and dodecanedioic acids with controlled molecular weight, reduced polydispersity, and standard deviation of molecular weights, have been synthesized. All synthesized polyanhydrides were thoroughly characterized by NMR, Fourier transform infrared spectroscopy, and gel permeation chromatography. Molecular weights of the synthesized polyanhydrides are highly controllable, depending on the degree of activation of the dicarboxylic acid monomers, i.e., the amount of acetic anhydride used during synthesis. Polyanhydrides have been synthesized in triplicate by melt-polycondensation, using various mole ratios of acetic anhydride to diacids. The standard deviation of the molecular weights of the polyanhydrides is minute when using 1 equivalent of acetic anhydride during the activation of dicarboxylic acids, whereas if excess acetic anhydride is used, the standard deviation is very high. The effect of safe and natural inorganic catalysts, Calcium oxide, Zinc oxide, and Calcium carbonate on polymerization is also studied. As-synthesized poly(sebacic acid) can offer convenience to use in controlled drug delivery applications. In vitro drug release study using Temozolamide (TMZ), a medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma, shows 14% TMZ release after the first hour and 70% release over one day from the poly(sebacic acid) wafers.

Poly(ester-anhydrides) Derived from Esters of Hydroxy Acid and Cyclic Anhydrides.

The alternating architecture and hydrophobic side chains hinder hydrolytic cleavage and anhydride interchange in poly(sebacic acid-ricinoleic acid) (P(SA-RA)), which provides stable polyanhydrides at room temperature. In this report, a series of polyanhydrides were designed to investigate the effect of ester bonds, hydrophobic side chains, phenyl moieties, and their distance from anhydride bonds on their stability and properties. Polyanhydrides with alternating architecture are constructed by the polymerization of ester-diacids prepared from ricinoleic or other hydroxy acids with anhydrides such as succinic, maleic, and phthalic anhydrides. The hydrophobic side chains are designed closer to anhydride bonds to investigate hindrance to hydrolytic cleavage and anhydride interchange. Polyanhydrides were obtained by the activation of ester-diacid using acetic anhydride followed by melt condensation. The reactions were monitored by NMR, Fourier transform infrared (FTIR), and gel permeation chromatography (GPC). The synthesized poly(ester-anhydride)s with a shorter chain length compared to P(SA-RA) were stable at room temperature. The hydrolytic degradation studies reveal that the phenyl moiety present in poly(ricinoleic acid phthalate) (PRAP) and poly(hydroxystearic acid phthalate) (PHSAP) reduces the hydrolysis of anhydride bonds. Poly(hydroxyoctanoic acid succinate) (PHOAS) demonstrates the highest molecular weight of all tested polymers. The results reveal that the presence of hydrophobic side chains, phenyl moieties, and their distance from anhydride bonds significantly improves the stability. These stable polyanhydrides can provide convenience to use in control drug-delivery applications. The in vitro drug release study using ibuprofen shows that polymers with aromatic units such as PRAP and PHSAP establish sustained release, which presents more than 50 and 40% of ibuprofen over a period of 28 days.

Unprecedented formation of palladium(II)-pyrazole based thiourea from chromone thiosemicarbazone and [PdCl2(PPh3)2]: Interaction with biomolecules and apoptosis through mitochondrial signaling pathway.

Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh3)(C9H8NO2S-pz)] (1) and [PdCl(PPh3)(C14H10NO2S-pz)] (2) [pz = pyrazole (C3H2N2)] have been obtained unexpectedly from chromone thiosemicarbazones (L1 and L2) and [PdCl2(PPh3)2]. The compounds have been fully characterized by physicochemical studies. The single crystal X-ray diffraction and spectral studies revealed square planar geometry for the complexes. The conversion of chromone thiosemicarbazone into pyrazole based thiourea might have happened through coordination to palladium(II) ion after enolization, Michael addition and ring opening followed by cyclization. To the best of our knowledge, this is the first report for the conversion of chromone thiosemicarbazone into pyrazole based thiourea moiety. Plausible mechanism was proposed based on the spectroscopic studies. Calf thymus (CT) DNA binding of the compounds was explored using various spectroscopic and molecular docking methods. DNA cleavage studies suggested that complexes 1 and 2 had the capacity to cleave the supercoiled DNA (pUC19) to its naked form. In vitro cytotoxic property of the ligands and complexes has been evaluated against three human cancer cells such as A549, HepG-2 and U937. Complex 2 exhibited potent cytotoxic activity against HepG-2 cells with the IC50 value of 10.4 µM. In addition, mechanistic studies showed that complex 2 induced apoptosis through mitochondrial signaling pathway in HepG-2 cells. Beneficially, complex 2 showed less toxicity against human lung (IMR90) normal cells and hence it emerges as a potential candidate for further studies.

A New Class of ß-Pyrrolidino-1,2,3-Triazole Derivatives as ß-Adrenergic Receptor Inhibitors: Synthesis, Pharmacological, and Docking Studies.

New 1,4-disubstituted ß-pyrrolidino-1,2,3-triazoles were synthesized using a reusable copper-iodide-doped neutral alumina catalyst. Synthesis of diversely substituted triazoles and recyclability of CuI catalyst explains the broad scope of this protocol. The synthesized compounds were screened for their antimicrobial and anticancer properties. Most of the compounds showed significant antimicrobial activities against all the tested microorganisms compared to standard drugs. Furthermore, compounds 5a, 5e, 5g, 5h, 5i, and 5j showed moderate to potent activities against A549 and HepG-2 cells. In addition, compounds 5g and 5h displayed potential cytotoxicity activity against A549 cells with IC50 values of 72 ± 3.21 and 58 ± 2.31 µM, respectively. The molecular docking study revealed that some of the synthesized compounds exhibited comparable binding as co-crystalized ligands with the DNA topoisomerase IV and anaplastic lymphoma kinase receptors.

Rhodium(iii)-catalysed decarbonylative annulation through C-H activation: expedient access to aminoisocoumarins by weak coordination.

Rhodium-catalysed decarbonylative annulation of isatoic anhydrides with alkynes through C-H activation for the synthesis of aminoisocoumarins was developed. This enables the gram-scale transformation to iodoisocoumarin which is a vital building block in transition-metal-catalysed cross couplings. These compounds exhibit blue-emitting luminescence properties.

Ru(II)-Catalyzed Regiospecific C-H/O-H Oxidative Annulation to Access Isochromeno[8,1-ab]phenazines: Far-Red Fluorescence and Live Cancer Cell Imaging.

A facile ruthenium(II)-catalyzed regiospecific C-H/O-H oxidative annulation methodology was developed to construct isochromeno[8,1-ab]phenazines. This methodology delivers various advantages, such as scope for diverse substrates, tolerance to a range of functional groups, stability under air, and yields regioselective products. This methodology was successfully applied to synthesize far red (FR) fluorescent probes for live cancer cell imaging. The synthesized compounds displayed notable fluorescence properties in solution and thin-film. Their application in live cancer cell imaging was investigated using various cancer cell lines. The synthesized compound showed prominent FR fluorescence, with high quantum yield, and exhibited better cell-imaging properties, with excellent biocompatibility.

Synthesis of Ni(II) complexes bearing indole-based thiosemicarbazone ligands for interaction with biomolecules and some biological applications.

A series of new Ni(II) complexes containing indole-based thiosemicarbazone ligands was synthesized and characterized by elemental analyses, and UV-visible, FT-IR, 1H & 13C NMR and mass spectroscopic techniques. The Ni(II) complexes (1-4) bear the general formula [Ni{C10H9N2NHCSNH(R)}2] where R = hydrogen (1), 4-methyl (2), 4-phenyl (3) and 4-cyclohexyl (4). Molecular structure of ligands (L3 and L4) and complexes (2, 3 and 4) was confirmed by single crystal X-ray crystallography. Four coordinated Ni(II) complexes showed square planar geometry. The interaction of the Ni(II) complexes with calf thymus DNA (CT-DNA) has been evaluated by absorption spectroscopic and ethidium bromide (EB) competitive binding studies, which revealed the intercalative interaction of the complexes with CT-DNA. Gel electrophoresis experiments showed the cleavage of DNA by the complexes without any external agent. Further, the interaction of the complexes with bovine serum albumin (BSA) was investigated using UV-visible, fluorescence and synchronous fluorescence spectroscopic methods, which showed that the complexes could bind strongly with BSA. Molecular docking was employed to understand the binding of the Ni(II) complexes with the molecular target B-DNA, human DNA topoisomerase I and BSA. All the Ni(II) complexes possess high antioxidant activity against 2-2-diphenyl-1-picrylhydrazyl (DPPH) radical and antihaemolytic activity. In addition, in vitro cytotoxicity of the Ni(II) complexes against lung cancer (A549), human breast cancer (MCF7) and mouse embryonic fibroblasts (L929) cell lines was investigated. Complex 4 has high cytotoxicity. The mode of cell death effected by complex 4 has been explored using Hoechst 33258 staining. Nickel(II) complexes of thiosemicarbazone ligands were synthesized and their DNA/protein binding, DNA cleavage and cytotoxicity abilities were studied.

Isolation and characterization of 2-hydroxy-9,10-anthraquinone from Streptomyces olivochromogenes (ERINLG-261) with antimicrobial and antiproliferative properties

Abstract Currently Streptomyces is one of the most important antibiotic producing microorganisms against several diseases. In the present study Streptomyces olivochromogenes ERINLG-261 was isolated from the soil samples of the Mudumalai hills, Western Ghats, India. Morphological, physiological, biochemical and 16S rRNA studies strongly suggested that this isolate belonged to the genus Streptomyces. ERINLG-261 showed good antimicrobial activity against different bacteria and fungi in Micromonospora fermentation medium. The active ethyl acetate extract was packed in column chromatography over silica gel which led to the isolation of 2-hydroxy-9,10-anthraquinone as the active principle. The isolated compound showed good antimicrobial activity against tested bacteria and fungi in minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) studies. The compound showed moderate in vitro antiproliferative activity against A549 and COLO320 cells. The compound was subjected to molecular docking studies for the inhibition of Topoisomerase, TtgR and Beta-lactamase enzymes which are targets for antimicrobials. Docking results of the compound showed low docking energy with these enzymes indicating its usefulness as antimicrobial agent. This is the first report of antimicrobial and antiproliferative activity of 2-hydroxy-9,10-anthraquinone isolated from Streptomyces olivochromogenes along with molecular docking studies.

Synthesis of cinnolines via Rh(iii)-catalysed dehydrogenative C-H/N-H functionalization: aggregation induced emission and cell imaging.

Rhodium catalysed dehydrogenative C-H/N-H functionalization was developed to construct phthalazino[2,3-a]-/indazolo[1,2-a]cinnolines by reacting N-phenyl phthalazine/indazole with alkynes. The synthesized compounds exhibit prominent fluorescence properties in solid and aggregation states. Their application in cell imaging was investigated using various cancer cell lines.

1-Ethyl-4'-(1H-indol-3-ylcarbon-yl)-1'-methyl-2,2''-dioxodi-spiro-[indoline-3,2'-pyrrolidine-3',3''-indoline]-4'-carbo-nitrile dimethyl sulfoxide monosolvate.

In the title compound, C31H25N5O3·C2H6OS, the three indole/indoline units are all essentially planar with maximum deviations of 0.0172 (3), 0.053 (2) and 0.07 (2) Å. The pyrrolidine ring adopts an envelope conformation with the C atoms bearing the 1-ethyl-2-oxo-indole substituent (in which the five-membered ring adopts a twisted conformation) as the flap. The dimethyl sulfoxide solvent mol-ecule is disordered over two positions, with an occupancy factor ratio of 0.871 (4):0.129 (4). The solvent components are linked to the heterocyclic mol-ecule via C-H⋯O and C-H⋯S hydrogen bonds. In the crystal, the solvent components are linked to the heterocyclic molecule via C-H⋯O and C-H⋯S inter-actions, forming R 2 (2)(10) ring motifs. The mol-ecules are further connected into a chain along the a-axis direction via N-H⋯O hydrogen bonds.

3'-[(1H-Indol-3-yl)carbon-yl]-1'-methyl-2-oxo-4'-(thio-phen-2-yl)-spiro-[indoline-3,2'-pyrrolidine]-3'-carbo-nitrile.

In the title compound, C26H20N4O2S, the central pyrrolidine ring adopts a twist conformation on the C-C bond involving the spiro C atom. Its mean plane makes dihedral angles of 78.83 (14), 65.91 (15) and 44.49 (18)° with the mean planes of the adjacent oxindole ring system, the indole system and the thio-phene ring, respectively. The indole and indoline units are essentially planar, with maximum deviations of 0.019 (3) and 0.090 (3) Å, respectively. In the oxindole fused-ring system, the pyrrole ring adopts an envelope conformation with the spiro C atom as the flap. In the crystal, pairs of N-H⋯O hydrogen bonds link the mol-ecules, forming inversion dimers with an R (2) 2(8) ring motif. The dimers are linked by further N-H⋯O hydrogen bonds, forming a two-dimensional network lying parallel to (100).

4'-(1H-Imidazol-2-yl)-3'-[(1H-indol-3-yl)carbon-yl]-1'-methyl-2-oxo-spiro-[indoline-3,2'-pyrrolidine]-3'-carbo-nitrile 0.15-hydrate.

In the title compound, C25H20N6O2·0.15H2O, the dihedral angles between the least-squares planes of the indole and pyrrolidine rings and between the oxindole and imidazole rings are 77.66 (7) and 45.31 (7)°, respectively. The pyrrolidine ring and the fused five-membered pyrrolidine ring of the oxindole moiety exhibit twisted conformations. The amide N atom is involved in both intra- and inter-molecular hydrogen bonding, having a bifurcated character. The mol-ecular structure is characterized by an intra-molecular N-H⋯O hydrogen bond, which generates an S(7) ring motif while an inter-molecular N-H⋯O hydrogen bond links the organic and solvent water mol-ecules. In the crystal, N-H⋯N hydrogen bonds generate a zigzag chain running parallel to c-axis direction. The H atoms of the solvent water mol-ecule were not located.

rac-Dimethyl 5-oxo-2-[(2,4,4-trimethyl-pentan-2-yl)amino]-4,5-dihydro-pyrano[3,2-c]chromene-3,4-dicarboxyl-ate.

The title compound, C(24)H(29)NO(7), is asymmetric with a chiral centre located in the pyran ring and crystallizes as a racemate. The coumarin ring system and the fused pyran ring make a dihedral angle of 10.46 (8)°. A short intra-molecular N-H⋯O hydrogen bond between the amino group and the vicinal carbonyl group generates an S(6) ring. Inter-molecular C-H⋯O inter-actions contribute to the stability of the crystal structure.

Synthesis of novel spirooxindole derivatives by one pot multicomponent reaction and their antimicrobial activity.

A series of novel spirooxindoles have been synthesized through 1,3-dipolar cycloaddition of an azomethine ylide generated from isatin and sarcosine or l-proline with the dipolarophile 1,4-naphthoquinone followed by spontaneous dehydrogenation. Synthesised compounds were evaluated for their antimicrobial activities against eight bacteria and three fungi. All the spirooxindole derivatives exhibited significant antibacterial activity against Staphylococcus aureus, S. aureus (MRSA), Enterobacter aerogens, Micrococcus luteus, Proteus vulgaris, Klebsiella pneumonia, Salmonella typhimurium, Salmonella paratyphi-B and anti-fungal activity against Malassesia pachydermatis, Candida albicans and Botyritis cinerea organisms. Among 23 compounds screened, 1'-acetyl-2,5'-dimethyl-2,3-dihydrospiro[benzo[f]isoindole-1,3'-indoline]-2',4,9-trione was found to be more active against tested bacteria and fungi.

rac-Diethyl 5-oxo-2-[(2,4,4-trimethyl-pentan-2-yl)amino]-4,5-dihydro-pyrano[3,2-c]chromene-3,4-dicarboxyl-ate.

The title compound, C(26)H(33)NO(7), comprises a racemic mixture of asymmetric mol-ecules containing one stereogenic centre. The dihedral angle between the mean planes of the fused pyran ring and the coumarin ring system is 8.12 (14)°. The mol-ecular structure features a short N-H⋯O contact, which generates an S(6) ring motif. The crystal packing are stabilized by C-H⋯O inter-actions.

rac-Dimethyl 2-(tert-butyl-amino)-5-oxo-4,5-dihydro-pyrano[3,2-c]chromene-3,4-dicarboxyl-ate.

The title compound, C(20)H(21)NO(7), is asymmetric with a chiral centre located in the pyran ring and crystallizes as a racemate. The mol-ecular framework is somewhat bent; the coumarin moiety and the pyran ring are inclined by 7.85 (5)°. The mol-ecular structure is characterized by an intra-molecular N-H⋯O hydrogen bond, which generates an S(6) ring motif, and the crystal packing is stabilized by inter-molecular C-H⋯O hydrogen bonds. The 3-carboxyl-ate O atom is involved in both of them, having a bifurcated character.