Improved bioavailability of poorly water-soluble drug curcumin in cellulose acetate solid dispersion.

Curcumin (Cur), one of the most widely used natural active constituents with a great variety of beneficial biological and pharmacological activities, is a practically water-insoluble substance with a short biologic half-life. The aim of this study was to develop a sustained-release solid dispersion by employing water-insoluble carrier cellulose acetate for solubility enhancement, release control, and oral bioavailability improvement of Cur. Solid dispersions were characterized by solubility, in vitro drug release, Fourier transform infrared spectroscopy, X-ray diffractometry, and differential scanning calorimetry studies. The in vivo performance was assessed by a pharmacokinetic study. Solid-state characterization techniques revealed the amorphous nature of Cur in solid dispersions. Solubility/dissolution of Cur was enhanced in the formulations in comparison with pure drug. Sustained-release profiles of Cur from the solid dispersions were ideally controlled in vitro up to 12 h. The optimized formulation provided an improved pharmacokinetic parameter (C(max) = 187.03 ng/ml, t(max) = 1.95 h) in rats as compared with pure drug (C(max) = 87.06 ng/ml, t(max) = 0.66 h). The information from this study suggests that the developed solid dispersions successfully enhanced the solubility and sustained release of poorly water-soluble drug Cur, thus improving its oral bioavailability effectively.

Oxidative cyclization of 2-aryl-3-arylamino-2-alkenenitriles to N-arylindole-3-carbonitriles mediated by NXS/Zn(OAc)2.

A variety of 2-aryl-3-arylamino-2-alkenenitriles were converted to N-arylindole-3-carbonitriles in a one-pot manner through NBS- or NCS-mediated halogenation followed by Zn(OAc)(2)-catalyzed intramolecular cyclization. It is postulated that the process involves the formation of arylnitrenium ion intermediates, which undergo the electrophilic aromatic substitution to give the cyclized N-arylindole product.

Oxidative aromatic C-N bond formation: convenient synthesis of N-amino-3-nitrile-indoles via FeBr3-mediated intramolecular cyclization.

A variety of functionalized N-amino-3-nitrile-indole derivatives are obtained via an intramolecular hetero-cyclization of 2-aryl-3-substituted hydrazono-alkylnitriles using FeBr(3) as a single electron oxidant. This approach allows the N-moiety on the side-chain to be annulated to the benzene ring during the final synthetic step via direct oxidative aromatic C-N bond formation.

1-(4-Bromo-phen-yl)-2-methyl-1H-indole-3-carbonitrile.

In the title compound, C(16)H(11)BrN(2), the dihedral angle between the indole ring system and the phenyl ring is 58.85 (11)°.

6-Meth-oxy-2-methyl-1-phenyl-1H-indole-3-carbonitrile.

In the title compound, C(17)H(14)N(2)O, the dihedral angle between the indole ring system and the phenyl ring is 64.48 (7)°. The crystal packing features weak C-H⋯π inter-actions.

1-(4-Meth-oxy-phen-yl)-2-methyl-1H-indole-3-carbonitrile.

In the title compound, C(17)H(14)N(2)O, the dihedral angle between the indole ring system and the benzene ring is 58.41 (4)°. The crystal packing features π-π stacking [shortest centroid-centroid separation = 3.8040 (9) Å] and C-H⋯π inter-actions.

2-Benzyl-6-chloro-1-(4-methyl-phen-yl)-1H-indole-3-carbonitrile.

In the title compound, C(23)H(17)ClN(2), the dihedral angle between the indole ring and the attached tolyl ring is 86.97 (8)°. Weak C-H⋯N(nitrile) hydrogen bonding, and C-H⋯π(aromatic) and short Cl⋯π(aromatic) [3.628 (1) Å] inter-actions consolidate the crystal packing.

A solid-phase approach to DDB derivatives.

Since the discovery of 2,2'-dimethoxycarbonyl-4,4-dimethoxy-5,6,5',6'-biomethylenedioxy-biphenyl (DDB) as a potent anti-HBV agent, we have studied the structure-activity relationships of 4,4'-dimethoxy-5,6,5',6'-dimethenedioxy-2-alkyloxycarbonyl-2'-(4-substituted benzyl piperazin-1-yl)carbonyl-biphenyl as anti-HBV agents. Therefore, it is rational to extend this study to the 3,3'-disustituted-4,4'-dimethoxy-5,6,5',6'-dimethenedioxy-2-alkyloxycarbonyl-2'-Serine derivatives. Thus, in an attempt to develop an efficient method for the preparation of a large number of DDB derivatives, the reaction between a DDB acid chloride and serine derivatives on solid support was studied. The structure of resulted compounds was confirmed by LC-MS and (1)H NMR analysis. Compounds 2a, 2d, 2f, 2j showed in vitro anti-HBV activity without significant toxicity up to 100 microM.