Diarylidene-N-Methyl-4-Piperidones and Spirobibenzopyrans as Antioxidant and Anti-Inflammatory Agents.

Curcumin has antioxidant properties resulting from its radical scavenging ability and inhibition of inflammation-associated factors. However, its lack of solubility, instability, and poor bioavailability are impediments to its therapeutic use. As potential alternatives, we synthesized and performed chemical analysis of thirty diarylidene-N-methyl-4-piperidone (DANMP), diheteroarylidene-N-methyl-4-piperidone (DHANMP), and spirobibenzopyran (SBP) derivatives, one of which was also characterized by single crystal X-ray diffraction. All compounds were evaluated for antioxidant activity via 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and for drug-like properties in silico. A subset of five compounds was investigated in terms of aqueous solubilities, which were significantly improved compared to that of curcumin. In vitro assessments of cellular and anti-inflammatory effects were conducted via real time polymerase chain reaction (RT-PCR) and Griess assays to evaluate the presence of inflammatory/activated (M1) markers and production of nitric oxide (NO) species, which are associated with inflammation. The five compounds reduced levels of markers and NO to extents similar to or better than curcumin in inflamed cells, and showed no adverse effects on cell viability. We show that these compounds possess anti-inflammatory properties and may be used as curcumin-substitutes with improved characteristics.

Antiplasmodial and Antimalarial Activity of 3,5-Diarylidenetetrahydro-2H-pyran-4(3H)-ones via Inhibition of Plasmodium falciparum Pyridoxal Synthase.

A series of 22 different 3,5-diarylidenetetrahydro-2H-pyran-4(3H)-ones (DATPs) were synthesized, characterized, and screened for their in vitro antiplasmodial activities against chloroquine (CQ)-sensitive Pf3D7, CQ-resistant PfINDO, and artemisinin-resistant PfMRA-1240 strains of Plasmodium falciparum. DATP 19 (3,5-bis(4-hydroxy-3,5-dimethoxybenzylidene)tetrahydro-2H-pyran-4(3H)-one) was found to be the most potent (IC50 1.07 µM) against PfMRA-1240, whereas 21 (3,5-bis(3,4,5-trimethoxybenzylidene)tetrahydro-2H-pyran-4(3H)-one) showed IC50 values of 1.72 and 1.44 µM against Pf3D7 and PfINDO, respectively. Resistance indices (RI) as low as 0.2 to 0.5 for 10 (3,5-bis(4-nitrobenzylidene)tetrahydro-2H-pyran-4(3H)-one) and 20 (3,5-bis(3-nitrobenzylidene)tetrahydro-2H-pyran-4(3H)-one), and <1 for most other DATPs reveals their greater potency against resistant strains than the sensitive one. The single-crystal XRD data for DATP 21 are reported. In silico support was obtained through docking studies. Killing all three strains within 4-8 h, these DATPs showed rapid kill kinetics toward the trophozoite stage. Furthermore, DATP 18 (3,5-bis(quinolin-4-ylmethylene)tetrahydro-2H-pyran-4(3H)-one) inhibited PfPdx1 enzyme activity with IC50 20.34 µM, which is about twofold lower than that (IC50 43 µM) for an already known inhibitor 4PEHz. At an oral dose of 300 mg/kg body weight, DATPs 19 and 21 were found to be nontoxic to mice, and at 100 mg/kg body weight, DATP 19 was found to suppress parasitaemia, which led to an increase in median survival time by three days relative to untreated control mice in a malaria curative study.

Azobenzene-based unnatural amino acid scaffolds via a Pd(II)-catalyzed C(sp3)-H arylation strategy.

Azobenzene-based unnatural amino acid motifs were synthesized via Pd(II)-catalyzed diastereoselective C(sp3)-H arylation of amino acid carboxamides with iodoacetanilides and Mills azo coupling.

Well-Defined Ni(0) and Ni(II) Complexes of Bicyclic (Alkyl)(Amino)Carbene (Me BICAAC): Catalytic Activity and Mechanistic Insights in Negishi Cross-Coupling Reaction.

Negishi cross-coupling reaction of organozinc compounds as nucleophiles with aryl halides has drawn immense focus for C-C bond formation reactions. In comparison to the well-established library of Pd complexes, the C-C cross-coupling of this particular approach is largely primitive with nickel-complexes. Herein, we describe the syntheses of Ni(II) complexes, [(Me BICAAC)2 NiX2 ] (X=Cl (1), Br (2), and I (3)) by employing the bicyclic (alkyl)(amino)carbene (Me BICAAC) ligand. The reduction of complexes 1-3 using KC8 afforded the two coordinate low valent, Ni(0) complex, [(Me BICAAC)2 Ni(0)] (4). Complexes 1-4 have been characterized by spectroscopic techniques and their solid-state structures were also confirmed by X-ray crystallography. Furthermore, complexes 1-4 have been applied in a direct and convenient method to catalyze the Negishi cross-coupling reaction of various aryl halides with 2,6-difluorophenylzinc bromide or phenylzinc bromide as the coupling partner in the presence of 3 mol % catalyst. Comparatively, among all-pristine complexes, 1 exhibit high catalytic potential to afford value-added C-C coupled products without the use of any additive. The UV-vis studies and HRMS measurements of controlled stochiometric reactions vindicate the involvement of Ni(I)-NI(III) cycle featured with a penta-coordinated Ni(III)-aryl species as the key intermediate for 1 whereas Ni(0)/Ni(II) species are potentially involved in the catalytic cycle of 4.

Organocatalyzed umpolung addition for synthesis of heterocyclic-fused arylidene-imidazolones as anticancer agents.

A strategy of "Nature-to-new" with iterative scaffold-hopping was considered for investigation of privileged ring/functional motif-elaborated analogs of natural aurones. An organocatalyzed umpolung chemistry based method was established for molecular-diversity feasible synthesis of title class of chemotypes i.e. (Z)-2-Arylideneimidazo[1,2-a]pyridinones and (Z)-2-Arylidenebenzo[d]imidazo[2,1-b]thiazol-3-ones. Various biophysical experiments indicated their important biological properties. The analogs showed characteristic anticancer activities with efficiency more than an anticancer drug. The compounds induced apoptosis with arrest in the S phase of the cell cycle regulation. The compounds' significant effect in up/down-regulation of various apoptotic proteins, an apoptosis cascade, and the inhibition of topoisomerases-mediated DNA relaxation process was identified. The analysis of the structure-activity relationship, interference with biological events and the drug-likeness physicochemical properties of the compounds in the acceptable window indicated distinctive medicinal molecule-to-properties of the investigated chemotypes.

Chiral Bent-Shaped Molecules Exhibiting Unusually Wide Range of Blue Liquid-Crystalline Phases and Multistimuli-Responsive Behavior.

Recently, an unprecedented observation of polar order, thermochromic behavior, and exotic mesophases in new chiral, bent-shaped systems with a -CH3 moiety placed at the transverse position of the central core was reported. Herein, a homologous series of compounds with even-numbered carbon chains from n=4 to 18 were synthesized, in which -Cl was substituted for -CH3 at the kink position and a drastic modification in the phase structure of the bent-shaped molecule was observed. An unusual stabilization of the cubic blue phase (BP) over a wide range of 16.4 °C has been witnessed. Two homologues in this series (1-12 and 1-14) exhibit an interesting phase sequence consisting of BPI/II, chiral nematic, twist grain boundary, smectic A, and smectic X (SmX) phases. The higher homologues (1-16 and 1-18) stabilize the SmX phase enantiotropically over the entire temperature range. Crystal structure analysis confirmed the bent molecular architecture, with a bent angle of 148°, and revealed the presence of two different molecular conformations in an asymmetric unit of compound 1-4. A DFT study corroborated that the -Cl moiety at the central core of the molecule led to an increase in the dipole moment along the transverse direction, which, in turn, facilitated the unusual stabilization of frustrated structures. Crystal polymorphism has been evidenced in three homologues (1-10, 1-12, and 1-14) of the series. On the application of mechanical pressure through grinding, compound 1-10 transformed from a bright yellow crystalline solid to a dark orange-green amorphous solid, which reversed upon dropwise addition of dichloromethane, indicating reversible mechanochromism in this class of compounds. In addition, excellent thermochromic behavior has been observed for compound 1-10 with a controlled temperature-color combination.

Reactions of a BICAAC with hydroboranes: propensity for Lewis adduct formation and carbene insertion into the B-H bond.

The reactivity of a bicyclic (alkyl)(amino)carbene (BICAAC) towards different boranes has been examined in the present work. The reactions with boranes BX3·SMe2 (X = H, Cl, Br), BF3·OEt2 and BCl3 yield Lewis adducts [BICAAC·BH3] (1), [BICAAC·BHCl2] (2), [BICAAC·BH2Cl] (3), [BICAAC·BF3] (4), [BICAAC·BCl3] (5) and [BICAAC·BBr3] (6) respectively, whereas more hydridic boranes, 9-borabicyclo[3.3.1]nonane (9-BBN) and catecholborane (HBcat), enable the insertion of the carbene carbon into the B-H bond to form [BICAAC(H)-(9-BBN)] (7) and [BICAAC(H)-Bcat] (8). These complexes are the first examples of BICAAC-boron compounds and have been characterized using IR, multinuclear NMR spectroscopy, HRMS spectrometry and single crystal X-ray diffraction. Computational analyses were also performed to gain insight into the mechanism of B-H bond activation and adduct formation. Furthermore, the reactions of the BICAAC with boranes have been compared with the known reactions of CAACs and NHCs.

Group 13 element containing conformationally rigid "N-E-N" heteroatomic bridged [3.3](2,6)pyridinophanes (E = B, Al).

The first examples of group 13 element containing pyridinophanes have been assembled using heteroatom N-E-N bridges (E = B, Al). The presence of B and Al as acceptor atoms in the bridges and their coordination with pyridine nitrogen has a very strong influence on the conformational rigidity of the pyridinophanes.

Quantitative characterization of new supramolecular synthons involving fluorine atoms in the crystal structures of di- and tetrafluorinated benzamides.

Strong hydrogen bonds play a significant role in crystal packing. In particular, the involvement of interactions involving fluorine in controlling the crystal packing requires appropriate attention, especially in the presence of other strong hydrogen bonds. In the present study, a detailed quantitative assessment has been performed of the nature, energetics and topological properties derived from the electron density in model compounds based on fluorinated benzamides (a total of 46 fluorine-substituted benzamides containing multiple fluorine atoms) in the solid state. The primary motivation in the design of such molecules is to enhance the acidity of the interacting H atoms in the presence of an increasing number of F atoms on the molecular scaffold, resulting in increased propensity towards the formation of intermolecular interactions involving organic fluorine. This exercise has resulted in the identification of new and frequently occurring supramolecular synthons involving F atoms in the packing of molecules in the solid state. The energetics associated with short and directional intermolecular Csp2-H...F-Csp2 interactions with significantly high electrostatic contributions is noteworthy, and the topological analysis reveals the bonding character of these ubiquitous interactions in crystal packing in addition to the presence of Csp2-F...F-Csp2 contacts.

Hg(ii) and Pd(ii) complexes with a new selenoether bridged biscarbene ligand: efficient mono- and bis-arylation of methyl acrylate with a pincer biscarbene Pd(ii) precatalyst.

Two equivalents of 1-benzyl-3-bromoethylbenzimidazolium bromide couple with Na2Se to produce the first selenoether bridged bis-benzimidazolium salt (LH2)Br2. The nitrate (LH2)(NO3)2 and tetrafluoroborate (LH2)(BF4)2 salts were also synthesized from (LH2)Br2. The reaction of Hg(OAc)2 with (LH2)Br2 gave the first pseudo pincer carbene mercury complex, [Hg(L-κ2C)][HgBr4] (C1). Different complexes of Pd(ii) with selenoether bridged carbene were obtained using (LH2)Br2 and (LH2)(NO3)2. Syntheses of these complexes were dependent on the counter anion and the temperature. Thus, the pincer type ionic complex [PdBr(L-κ3CSeC)]Br (C2) was isolated at 80 °C and the pseudo pincer type neutral complex cis-[PdBr2(L-κ2C)] (C3) was isolated at room temperature from (LH2)Br2 and Pd(OAc)2 in DMSO. The nitrate precursor (LH2)(NO3)2 on palladation with Pd(OAc)2 afforded [Pd(L-κ4CBzCSeC)]NO3 (C4) showing an unprecedented intramolecular metallation at the ortho position of the benzyl wingtip of the benzimidazole moiety. The ligand salts and metal complexes have been characterized using HRMS, heteronuclear NMR and IR spectroscopy. Single crystal X-ray structures of the ligand salts (LH2)Br2 and (LH2)(BF4)2 and complexes C1-C4 have also been elucidated. Complex C2 showed good activity for C-C coupling in the mono-Heck reaction of methyl acrylate and arylbromides. Interestingly, the less common bis-arylation was also observed with deactivated arylbromides as the result of double-Heck coupling.

New 'aggregation induced emission (AIE)' active cyclometalated iridium(III) based phosphorescent sensors: high sensitivity for mercury(II) ions.

Design and syntheses of 'aggregation induced emission (AIE)' active blue-emitting bis-cyclometalated iridium(III) complexes with appended diphosphine ligands [Ir(F2ppy)2(L1/L2)2(Cl)] (F2ppy = 2-(2',4'-difluoro) phenylpyridine; L1 = 1,2-bis(diphenylphosphino)ethane; L2 = bis(diphenylphosphino)propane) have been realized on a suitable route. The free phosphorous donor atom present on the appended diphosphine is shown to provide selective binding to the mercuric ion (Hg(2+)). The selective binding ability of the probe molecule towards mercuric ions results in a detectable signal due to complete quenching of their AIE properties. The quenching effect of the probe molecule has been explored and found to be the result of the degradation of the probe iridium(III) complex triggered by the presence of mercuric ions due to an interplay of a soft-soft interaction between the free phosphorous atom of the probe molecule and mercuric ions. These complexes were modelled to obtain deeper understanding of excited state properties and the results were tentatively correlated with the experimental data.

One-pot synthesis of strong solid state emitting mono-cyclometalated iridium(III) complexes: study of their aggregation induced enhanced phosphorescence.

Strong solid-state greenish-blue emitting, mono-cyclometalated iridium complexes, [Ir(ppy)(PPh(3))(2)(H)(Cl)], 2a and [Ir(F(2)ppy)(PPh(3))(2)(H)(Cl)], 2b [ppyH = 2-phenylpyridine; F(2)ppyH = 2-(2',4'-difluoro)phenylpyridine], have been synthesized by a convenient route. The 'aggregation induced enhanced phosphorescence (AIEP)' activity exhibited by these complexes has been rationalized.

Selective and unusual fluoride ion complexation by a steroidal receptor using OH...F- and CH...F- interactions: a new motif for anion coordination?

[structure: see text] A novel cholaphane has been synthesized from a naturally occurring bile acid in just two steps. It has an ability to bind two fluoride ions selectively utilizing the glycolate motif in chloroform. This "inside-out" cyclodextrin analogue encapsulates fluoride through O-H...F(-) and C-H...F(-) interaction.