Dihydro-alkylthio-benzyl-oxopyrimidines as Inhibitors of Reverse Transcriptase: Synthesis and Rationalization of the Biological Data on Both Wild-Type Enzyme and Relevant Clinical Mutants

A series of novel S-DABO analogues, characterized by different substitution patterns at positions 2, 5, and 6 of the heterocyclic ring, were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays, with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC50wt = 25 pM). The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach, leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules

Development of o

The ortho-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type-I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para-position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells. [Image: see text

Insights on the properties of levofloxacin-adsorbed Sr- and Mg-doped calcium phosphate powders

Several types of biodegradable materials have been investigated for the treatment of osteomyelitis. Calcium phosphate (CaP) ceramics are among the most performing materials due to their resemblance to human hard tissues in terms of mineralogical composition, and proven ability to adsorb and deliver a number of drugs. This research work was intended to study the suitability of modified CaP powders loaded with a fluoroquinolone as drug delivery systems for osteomyelitis treatment. Levofloxacin (LEV) was chosen due to the well-recognized antistaphylococcal activity and adequate penetration into osteoarticular tissues. Substituted CaP powders (5 mol% Sr2+ or 5 mol% Mg2+) were synthesised through aqueous precipitation. The obtained powders were characterised by X-ray diffraction, SEM and FTIR analysis. The X-ray diffraction patterns confirmed the presence of HA and beta-tricalcium phosphates (beta-TCP) phases in doped compositions, especially in the case of Mg-doped system. The fixation of LEV at the surface of the particles occurred only by physisorption. Both the in vitro microbiological susceptibility, against Staphylococcus spp, and biocompatibility of LEV-loaded CaP powders have not been compromised