Comparison of 19 aminoquinolines supports the hypothesis that chloroquine and related antimalarials act by complexing ferriprotoporphyrin IX (Fe(III)PPIX), inhibiting its conversion to beta-hematin (hemozoin) and hence its detoxification. The study suggests that a basic amino side chain is also essential for antiplasmodial activity. 2- And 4-aminoquinolines are unique in their strong affinity for Fe(III)PPIX, and attachment of side chains to the amino group has relatively little influence on the strength of complex formation. Association with Fe(III)PPIX is necessary, but not sufficient, for inhibiting beta-hematin formation. Presence of a 7-chloro group in the 4-aminoquinoline ring is a requirement for beta-hematin inhibitory activity, and this is also unaffected by side chains attached to the amino group. In turn, beta-hematin inhibitory activity is necessary, but not sufficient, for antiplasmodial activity as the presence of an aminoalkyl group attached to the 4-amino-7-chloroquinoline template is essential for strong activity. We thus propose that the 4-aminoquinoline nucleus of chloroquine and related antimalarials is responsible for complexing Fe(III)PPIX, the 7-chloro group is required for inhibition of beta-hematin formation, and the basic amino side chain is required for drug accumulation in the food vacuole of the parasite.

Resveratrol is a polyphenolic nutraceutical that exhibits pleiotropic activities in human subjects. The efficacy, safety, and pharmacokinetics of resveratrol have been documented in over 244 clinical trials, with an additional 27 clinical trials currently ongoing. Resveretrol is reported to potentially improve the therapeutic outcome in patients suffering from diabetes mellitus, obesity, colorectal cancer, breast cancer, multiple myeloma, metabolic syndrome, hypertension, Alzheimer's disease, stroke, cardiovascular diseases, kidney diseases, inflammatory diseases, and rhinopharyngitis. The polyphenol is reported to be safe at doses up to 5 g/d, when used either alone or as a combination therapy. The molecular basis for the pleiotropic activities of resveratrol are based on its ability to modulate multiple cell signaling molecules such as cytokines, caspases, matrix metalloproteinases, Wnt, nuclear factor‐κB, Notch, 5′‐AMP‐activated protein kinase, intercellular adhesion molecule, vascular cell adhesion molecule, sirtuin type 1, peroxisome proliferator‐activated receptor‐γ coactivator 1α, insulin‐like growth factor 1, insulin‐like growth factor‐binding protein 3, Ras association domain family 1α, pAkt, vascular endothelial growth factor, cyclooxygenase 2, nuclear factor erythroid 2 like 2, and Kelch‐like ECH–associated protein 1. Although the clinical utility of resveratrol is well documented, the rapid metabolism and poor bioavailability have limited its therapeutic use. In this regard, the recently produced micronized resveratrol formulation called SRT501, shows promise. This review discusses the currently available clinical data on resveratrol in the prevention, management, and treatment of various diseases and disorders. Based on the current evidence, the potential utility of this molecule in the clinic is discussed.

Antiplasmodial activities versus the chloroquine sensitive D10 strain of Plasmodium falciparum of a series of N(1),N(1)-diethyl-N(2)-(4-quinolinyl)-1,2-ethanediamines with 11 different substituents at the 7-position on the quinoline ring have been investigated in vitro. Electron-withdrawing groups at the 7-position have been shown to lower the pK(a) of both the quinoline ring nitrogen atom and the tertiary amino nitrogen in the alkyl side chain. The quinoline nitrogen pK(a) ranges from 6.28 in the nitro derivative to 8.36 in the amino derivative, while the tertiary amino nitrogen has a pK(a) ranging between 7.65 in the trifluoromethyl derivative and 10.02 in the amino derivative. Calculation suggests that the resulting pH trapping of these compounds in the parasite food vacuole ranges between about 7% of that observed in chloroquine for the NO(2) derivative and 97% in the amino derivative. A direct proportionality between antiplasmodial activity normalized for pH trapping and beta-hematin inhibitory activity was observed. Activity could not be correlated with any other observed physical parameter. The beta-hematin inhibitory activity of these derivatives appears to correlate with both the hematin-quinoline association constant and the electron-withdrawing capacity of the group at the 7-position (Hammett constant). For the compounds under investigation, the hematin association constant is in turn influenced by the lipophilicity of the group at the 7-position.

Changes in epsilon (393) (the Soret band) of aqueous ferriprotoporphyrin IX [Fe(III)PPIX] with concentration indicate that it dimerizes, but does not form higher aggregates. Diffusion measurements support this observation. The diffusion coefficient of aqueous Fe(III)PPIX is half that of the hydrated monomeric dicyano complex. Much of the apparent instability of aqueous Fe(III)PPIX solutions could be attributed to adsorption onto glass and plastic surfaces. However, epsilon (347) was found to be independent of the aggregation state of the porphyrin and was used to correct for the effects of adsorption. The UV-vis spectrum of the aqueous dimer is not consistent with that expected for a mu-oxo dimer and the (1)H NMR spectrum is characteristic of five-coordinate, high-spin Fe(III)PPIX. Magnetic susceptibility measurements using the Evans method showed that there is no antiferromagnetic coupling in the dimer. By contrast, when the mu-oxo dimer is induced in 10% aqueous pyridine, characteristic UV-vis and (1)H NMR spectra of this species are observed and the magnetic moment is consistent with strong antiferromagnetic coupling. We propose a model in which the spontaneously formed aqueous Fe(III)PPIX dimer involves noncovalent interaction of the unligated faces of two five-coordinate H(2)O/HO-Fe(III)PPIX molecules, with the axial H(2)O/OH(-) ligands directed outwards. This arrangement is consistent with the crystal structures of related five-coordinate iron(III) porphyrins and accounts for the observed pH dependence of the dimerization constant and the spectra of the monomer and dimer. Structures for the aqueous dimer are proposed on the basis of molecular dynamics/simulated annealing calculations using a force field previously developed for modeling metalloporphyrins.