Synthesis, biological evaluation and molecular modeling studies of quinolonyl diketo acid derivatives: new structural insight into the HIV-1 integrase inhibition.

New quinolonyl diketo acid compounds bearing various substituents at position 6 of the quinolone scaffold were designed and synthesized as potential HIV-1 integrase inhibitors. These new compounds were evaluated for their antiviral and anti-integrase activity and showed inhibitory potency similar to that of 6-bromide analog 2. Molecular modeling and docking studies were performed to rationalize these data and to provide a detailed understanding of the mechanism of inhibition for this class of compounds.

Preparation of a polyacrylonitrile/multi-walled carbon nanotubes composite by surface-initiated atom transfer radical polymerization on a stainless steel wire for solid-phase microextraction.

We report on the fabrication and performances of a solid-phase microextraction (SPME) fiber based on a stainless steel wire coated with a covalently attached polyacrylonitrile (PAN)/multi-walled carbon nanotubes (MWCNTs) composite. This new coating is obtained by atom transfer radical polymerization (ATRP) of acrylonitrile mixed with MWCNTs. ATRP is initiated from 11-(2-bromo-2-methylpropionyloxy)-undecyl-phosphonic acid molecules grafted on the wire surface via the phosphonic acid group. The extraction performances of the fibers are assessed on different classes of compounds (polar, non-polar, aromatic, etc.) from water solutions by headspace extraction. The optimization of the parameters affecting the extraction efficiency of the target compounds was studied as well as the reproducibility and the repeatability of the fiber. The fibers sustain more than 200 extractions during which they remain chemically stable and maintain good performances (detection limits lower than 2 microg/l, repeatability, etc.). Considering their robustness together with their easy and inexpensive fabrication, these fibers could constitute promising alternatives to existing products.

Structural and theoretical studies of [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid as HIV-1 integrase inhibitor.

Ethyl [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl]-4-hydroxy-2-oxo-3-butenoate 1 and [6-bromo-1-(4-fluorophenylmethyl)-4(1H)-quinolinon-3-yl)]-4-hydroxy-2-oxo-3-butenoïc acid 2 were synthesized as potential HIV-1 integrase inhibitors and evaluated for their enzymatic and antiviral activity, acidic compound 2 being more potent than ester compound 1. X-ray diffraction analyses and theoretical calculations show that the diketoacid chain of compound 2 is preferentially coplanar with the quinolinone ring (dihedral angle of 0-30 degrees ). Docking studies suggest binding modes in agreement with structure-activity relationships.

New pyridinone derivatives as potent HIV-1 nonnucleoside reverse transcriptase inhibitors.

Several 5-ethyl-6-methyl-4-cycloalkyloxy-pyridin-2(1H)-ones were synthesized and evaluated for their anti HIV-1 activities against wild-type virus and clinically relevant mutant strains. A racemic mixture (10) with methyl substituents at positions 3 and 5 of the cyclohexyloxy moiety had potent antiviral activity against wild-type HIV-1. Subsequent stereoselective synthesis of a stereoisomer displaying both methyl groups in equatorial position was found to have the best EC(50). Further modulations focused on position 3 of the pyridinone ring improved the antiviral activity against mutant viral strains. Compounds bearing a 3-ethyl (22) or 3-isopropyl group (23) had the highest activity against wild-type HIV-1 and displayed low-nanomolar potency against several clinically relevant mutant strains.

Magneto-responsive organogels prepared through surface-initiated atom transfer radical polymerization on iron nanoparticles.

Iron nanoparticles (Fe(np)) with average diameter 50 nm have been synthesized by addition of NaBH4 to FeCl3 solution then radical initiator, (11-(2-bromo-2-methyl)propionyloxy)undecyltrichlorosilane (1) has been immobilized on to Fe(np). Surface-initiated atom transfer radical polymerization (SI-ATRP) of different monomers such as styrene, methyl methacrylate, methacrylonitrile and N-vinylimidazol have been carried out from initiator-grafted Fe(np) and the amount of grafted polymers was determined by thermogravimetric analysis (TGA). Immobilization of PMMA has been monitored by TGA of samples taken from the reaction mixture after 4, 9 and 21 hours. Activators regenerated by electron transfer (ARGET) ATRP of methyl methacrylate and styrene were conducted from initiator-grafted Fe(np) in the presence of phenol and Na-phenoxide respectively and the yields of immobilized polymers were found lower than those we observed in the case of conventional ATRP. The concentration of Fe(np) (c(m)) in the reaction mixture was found to influence significantly the appearance of products; at higher c(m) values SI-ATRP of styrene resulted in the formation of magneto-responsive gels. Transmission electron microscope investigation of bare Fe(np) and magnetic gel revealed that the particles are well-dispersed in the gel while non-grafted Fe(np) form aggregates. XRD measurements were used to determine the composition of magnetic nanoparticles. It was found that the crystalline phase of Fe(np) is mostly reduced iron and the fraction of iron-oxide (hydroxide) species is below the detection limit of XRD. Immobilized polymers have been degrafted by digestion of Fe(np) in HCl and trifluoroacetic acid and the residual polymeric material were identified by FTIR and 1H-NMR spectroscopy. A plausible mechanism for the formation of magnetic gel was given in which polymer network is built up through interparticle termination reactions and Fe(np) act as functional cross-linkers.

Surface-initiated ATRP of PMMA, PS and diblock PS-b-PMMA copolymers from stainless steel modified by 11-(2-bromoisobutyrate)-undecyl-1-phosphonic acid.

A new ATRP initiator, 11-(2-bromoisobutyrate)-undecyl-1-phosphonic acid, has been synthesized and grafted as a film on a mechanically polished stainless steel (ASI304) substrate. Molecular integrity of the grafted initiator in the film, alkyl chain ordering, wettability were determined by X-ray photoelectron spectroscopy, infrared, and water contact angles. Polystyrene, poly(methyl methacrylate) and diblock copolymer (polystyrene-b-poly(methyl methacrylate)) brushes have been grafted from the flat stainless steel surfaces through surface-initiated atom transfer radical polymerization (ATRP) and characterized to check the effectiveness of the new initiator for future uses in surface-initiated ATRP.

A novel approach to magneto-responsive polymeric gels assisted by iron nanoparticles as nano cross-linkers.

A new route for the preparation of magneto-responsive polymeric gels involving iron nanoparticles as nano cross-linkers has been described.

Kinetic Control in the Cleavage of Unsymmetrical Disilanes.

A series of 12 phenyl-substituted arylpentamethyldisilanes 1a-l have been synthesized in order to examine the regioselectivity of their nucleophilic Si,Si bond cleavage reactions under Still's conditions (MeLi/HMPA/0 degrees C). It has been found that the sensitivity of these reactions to the electronic effects of the substituents in the phenyl ring could be described by the Hammett-type equation log(k(A)/k(B)) = 0.4334 + 2.421(Sigmasigma); (correlation coefficient R = 0.983). The k(A)/k(B) ratio represents the relative rate of attack at silicon atom A (linked to the aryl ring) or at silicon atom B (away from the aryl ring) of the unsymmetrical disilanes. Thus, the present investigation shows that the earlier belief according to which the nucleophilic cleavage of unsymmetrical disilanes always produces the more stable silyl anionic species (thermodynamic control) should be abandoned, or at least seriously amended: kinetic factors appear to exert a primary influence on the regioselectivity of such reactions. Since the two major kinetic factors (i.e., electrophilic character of and steric hindrance at a given silicon atom) have opposite effects on the orientation of the reaction, it may happen that kinetic and thermodynamic control lead to the same result. For some of the unsymmetrical disilanes studied, the major reaction path was not the Si,Si bond cleavage; instead, Si-aryl bond breaking occurred, producing the corresponding aryl anions.