New HIV-1 replication inhibitors of the styryquinoline class bearing aroyl/acyl groups at the C-7 position: synthesis and biological activity

Novel variants of HIV-1 replication inhibitors of the styrylquinoline class harboring aroyl/acyl group at the C-7 position have been synthesized. In sharp contrast with styrylquinolines bearing a carboxylic acid group at C-7, these compounds proved to be inactive toward HIV-1 integrase in in vitro assays.     

Main characteristics of the boundary layer macrofauna in the English Channel

Four hundred and thirty two suprabenthic hauls with a modified Macer-GIROQ sledge were taken over the period 1988–1996. Fifteen sites within the English Channel were sampled from the Roscoff and Plymouth waters to the Dover Strait, including the Bay of Morlaix, Bay of Saint Brieuc, the Bay of Seine and the Seine Estuary. The main characteristics of the Benthic Boundary Layer (BBL) macrofauna in the English Channel were elucidated from these data. BBL macrofauna was found over the whole water column sampled (10–150 m). Firstly, the number of species collected was very high (up to 116 species for five hauls) except in the Seine estuary. Numerically, mysids were the dominant group of organisms collected with the sledge, followed by amphipods, cumaceans, isopods and decapods. Abundance and biomass of the fauna were very high in the Seine estuary, especially in the mesohaline and oligohaline zones (maximum >216000 ind. 100 m^-3; >200 g AFDW 100 m^-3) where the specialised mysids Neomysis integer and Mesopodopsis slabberi occurred in very high abundance. At other sites, the abundance and biomass were moderate (100–10000 ind. 100 m^-3; 15–2000 mg AFDW 100 m^-3). Abundance reached its maximum when mysids or swarms of amphipods of the genus Apherusa were collected, and during the reproduction of the amphipods of the genus Ampelisca, as in June in the Bay of Morlaix. The number of species, abundance and biomass showed seasonal changes in all sites with, in general, lowest values in winter or spring, and highest values in autumn. For the open sea sites, two main geographical gradients were identified: i) in spring, a higher number of species in the western part of the Channel compared with the eastern part of the Channel and, in autumn, a higher number of species in the eastern part of the Channel compared with the western part, and ii) an increasing density gradient from west to east at spring and a decreasing gradient from west to east during the autumn. The suprabenthic fauna of the Channel can be considered as a unique community including three kinds of species: (i) good swimmer species which were common at all the time and all sites: e.g. Anchialina agilis, Gastrosaccus spp., Haplostylus spp. and Apherusa spp., (ii) species present at all sites only at night: e.g. Atylus vedlomensis, Megaluropus agilis, Melphipidella macra, Orchomenella nana, Pseudocuma longicornis, Schistomysis ornata and Synchelidium maculatum, and iii) species collected at one or a limited number of sites only at night: e.g. Ampelisca spp. at Pierre Noire and Diastylis spp. at site F. The Seine estuary supports a typical suprabenthic estuarine community. Elements of the suprabenthic fauna also showed significant daily rhythms which took several forms depending on the species under consideration.     

Linker-modified quinoline derivatives targeting HIV-1 integrase: synthesis and biological activity

A novel series of HIV-1 integrase inhibitors was synthesized and tested in both in vitro and ex vivo assays. These inhibitors are featured by the presence of a quinoline subunit and an ancillary aromatic ring linked by functionalized spacers such as amide, hydrazide, urea and 1-hydroxyprop-1-en-3-one moiety. Amide derivatives are the most promising ones and could serve as leads for further developments.     

Sensitive and specific LC-ESI-MS/MS method for the determination of a styrylquinoline, BA011FZ041, a potent HIV anti-integrase agent, in rat plasma

A LC-MS/MS method was validated for the determination of BA011FZ041, a styrylquinoline derivative. After addition of BA011FZ055 as internal standard (IS), the method involved solid phase extraction (SPE), LC separation with an ether-phenyl column and quantification by MS/MS after positive ESI. The calibration curve, ranging from 1 to 500 ng/mL was fitted to a 1/x-weighted quadratic regression model. Lower limit of quantification (LLOQ) was 1 ng/mL using 100 microL of plasma. Intra- and inter-assay precision and accuracy values were within the regulatory limits. The method was successfully applied to the determination of BA011FZ041 in rat plasma and PBMCs after i.v. dosing.     

Tautomers of styrylquinoline derivatives containing a methoxy substituent: computation of their population in aqueous solution and their interaction with RSV integrase catalytic core

8-Hydroxy-2-[2-(3-hydroxy-4-methoxyphenyl)ethenyl]-7-quinoline carboxylic acid and 8-hydroxy-2-[2-(3-methoxy-4-hydroxyphenyl)ethenyl]-7-quinoline carboxylic acid inhibit the processing and strand transfer reactions catalyzed by HIV-1 integrase with an IC50 of 2 microM. Some of their spectral properties are briefly reported. Their fluorescence is so weak that it is of no use in an experimental determination of the binding to the protein and we resorted to computer simulation. Both styrylquinoline derivatives, in their monoanionic form, have several dozens of tautomers and each of these forms has four planar rotamers. In this work computer simulations have been performed to determine which tautomer is the most abundant in aqueous solution and which binds to the Rous sarcoma virus (RSV) integrase catalytic core. As the substituents on the quinoline moiety are the same as on salicylic acid, the energies of hydroxy benzoic acid tautomers were also computed both in vacuo and embedded in a continuous medium which had the dielectric constant of bulk water, using the recent CPCM technique. The CPCM method was then applied to the two integrase inhibitors to estimate the tautomer population in water. The binding site of the compounds on the RSV integrase catalytic core was determined through a docking protocol, consisting of coupling a grid search method with full energy minimization. The designed method is a way leading to identification of potent integrase inhibitors using in silico experiments.