Stefano Sabatini

A 1,8-naphthyridone derivative targets the HIV-1 Tat-mediated transcription and potently inhibits the HIV-1 replication.

The emergence of multidrug resistant HIV-1 strains and the inability of the HAART to eradicate HIV-1 virus from infected patients demand new drugs able to interfere with an alternative step of the replicative cycle. The naphthyridone 3 (HM13N), described in the present study, is a promising anti-HIV agent due to its ability to inhibit the HIV-1 Tat-mediated transcription and the potent antiviral activity observed in acutely, chronically, and latently infected cells. The absence of any tendency to select for resistance mutations in vitro adds to the potential clinical value of this type of compounds, especially as these compounds are drug-like and obey the Lipinski rules.

From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump

Overexpression of efflux pumps is an important mechanism by which bacteria evade effects of substrate antimicrobial agents and inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus multidrug efflux pump, the activity of which confers decreased susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant (MDR) phenotype. In this work, a series of 1,4-benzothiazine derivatives were designed and synthesized as a minimized structural template of phenothiazine MDR efflux pump inhibitors (EPIs) in an effort to identify more potent S. aureus NorA EPIs. Almost all derivatives evaluated showed good activity in combination with ciprofloxacin against S. aureus ATCC 25923; some were capable of completely restoring ciprofloxacin activity in a norA-overexpressing strain (SA-K2378). Compounds 6k and 7j displayed good activity against SA-1199B, a strain that also overexpresses norA, in an ethidium bromide (EtBr) efflux inhibition assay.

Evolution from a natural flavones nucleus to obtain 2-(4-Propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump.

Overexpression of efflux pumps is an important mechanism by which bacteria evade the effects of substrate antimicrobial agents. Inhibition of such pumps is a promising strategy to circumvent this resistance mechanism. NorA is a Staphylococcus aureus efflux pump that confers reduced susceptibility to many structurally unrelated agents, including fluoroquinolones, resulting in a multidrug resistant phenotype. In this work, a series of 2-phenyl-4(1H)-quinolone and 2-phenyl-4-hydroxyquinoline derivatives, obtained by modifying the flavone nucleus of known efflux pump inhibitors (EPIs), were synthesized in an effort to identify more potent S. aureus NorA EPIs. The 2-phenyl-4-hydroxyquinoline derivatives 28f and 29f display potent EPI activity against SA-1199B, a strain that overexpresses norA, in an ethidium bromide efflux inhibition assay. The same compounds, in combination with ciprofloxacin, were able to completely restore its antibacterial activity against both S. aureus SA-K2378 and SA-1199B, norA-overexpressing strains.

Pyrazolo[4,3-c][1,2]benzothiazines 5,5-Dioxide: A Promising New Class of Staphylococcus aureus NorA Efflux Pump Inhibitors

The increasing resistance to antibacterials commonly employed in the clinic and the growth of multidrug resistant strains suggest that the development of new therapeutic approaches should be of primary concern. In this context, EPIs may restore life to old drugs. In the present work, the EPI activity of the COX-2 inhibitor celecoxib was confirmed and a new class of pyrazolo[4,3-c][1,2]benzothiazine 5,5-dioxide analogues acting as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump was identified.

Discovery of novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus.

Four novel inhibitors of the NorA efflux pump of Staphylococcus aureus, discovered through a virtual screening process, are reported. The four compounds belong to different chemical classes and were tested for their in vitro ability to block the efflux of a well-known NorA substrate, as well as for their ability to potentiate the effect of ciprofloxacin (CPX) on several strains of S. aureus, including a NorA overexpressing strain. Additionally, the MIC values of each of the compounds individually are reported. A structure-activity relationship study was also performed on these novel chemotypes, revealing three new compounds that are also potent NorA inhibitors. The virtual screening procedure employed FLAP, a new methodology based on GRID force field descriptors.

Structure-activity relationship study on anti-HIV 6-desfluoroquinolones

On the basis of our recent findings that 6-aminoquinolones inhibit the HIV Tat-mediated transactivation, we have designed a broad series of derivatives identifying novel potent agents such as the 6-desfluoroquinolones 24 (HM12) and 27 (HM13), which showed pronounced anti-HIV activity in acutely, chronically, and latently HIV-1 infected cell cultures. We demonstrate here that highly potent molecules can be obtained by optimizing the substituent in the various positions of the quinolone nucleus.

From 6-aminoquinolone antibacterials to 6-amino-7-thiopyranopyridinylquinolone ethyl esters as inhibitors of Staphylococcus aureus multidrug efflux pumps.

The thiopyranopyridine moiety was synthesized as a new heterocyclic base to be inserted at the C-7 position of selected quinolone nuclei followed by a determination of antibacterial activity against strains of Staphylococcus aureus. Selected thiopyranopyridinylquinolones showed significant antimicrobial activity, including strains having mutations in gyrA and grlA as well as other strains overexpressing the NorA multidrug (MDR) efflux pump. Most derivatives did not appear to be NorA substrates. The effect of the thiopyranopyridinyl substituent on making these quinolones poor substrates for NorA was investigated further. Several quinolone ester intermediates, devoid of any intrinsic antibacterial activity, were tested for their abilities to inhibit the activities of NorA (MFS family) and MepA (MATE family) S. aureus MDR efflux pumps. Selected quinolone esters were capable of inhibiting both MDR pumps more efficiently than the reference compound reserpine. Moreover, they also were able to restore, and even enhance, the activity of ciprofloxacin toward some genetically modified resistant S. aureus strains.

Novel 1,4-benzothiazine derivatives as large conductance Ca2+-activated potassium channel openers.

The design and synthesis of a novel class of 1,4-benzothiazines targeted for the large-conductance calcium-activated potassium channels (BK) are presented. In vitro functional characterization of BK channel opening activity was assessed by measuring the relaxation of isolated rat aortic rings precontracted with KCl 20 mM. The results of this study show that the 1,4-benzothiazine heterocyclic nucleus is a suitable backbone for designing novel BK-openers; indeed, some of these new 1,4-benzothiazine derivatives had a vasorelaxant potency comparable or superior to that of reference BK-activator NS-1619 (1).

Solution structure investigations of olefin Pd(II) and Pt(II) complex ion pairs bearing α-diimine ligands by 19F, 1H-HOESY NMR

Complexes [M(η1,η2-C8H12OMe)((2,6-(R)2C6H3)NC(R′)C(R′)N((2,6-(R)2C6H3))]PF6 (where M=Pd, R=H and R′2=Me2 (1), M=Pd, R=Me and R′2=Me2 (2), M=Pd, R=Et and R′2=Me2 (3), M=Pd, R=iPr and R′2=Me2 (4), M=Pd, R=iPr and R′2=An (5), M=Pt, R=iPr and R′2=An (6)) were synthesized by the reaction of [M(η1,η2-C8H12OMe)Cl]2 with the appropriate α-diimine ligand in the presence of NH4PF6. Their ion pair structure in solution was investigated by detecting dipolar interactions between protons belonging to the cation and fluorine nuclei of the anion (interionic contacts) in the 19F, 1H-HOESY NMR spectra. In complexes 1–4, the anion in solution is located close to the peripheral protons of the α-diimine ligand and it interacts with the R′ protons and with the R protons that point toward the R′ groups. The steric protection of apical position exerted by the R substituents is clearly illustrated by the absence of interionic contacts between any protons of the cycloctenylmethoxy-moiety and the anion for R≥Me in 1–4. In complexes 5 and 6 the interactions between the anion and the peripheral N,N protons also predominate but other anion–cation orientations are significantly present and, consequently, the interionic structure is less specific.

A Broad Anti-influenza Hybrid Small Molecule That Potently Disrupts the Interaction of Polymerase Acidic Protein-Basic Protein 1 (PA-PB1) Subunits.

In continuing our efforts to identify small molecules able to disrupt the interaction of the polymerase acidic protein-basic protein 1 (PA-PB1) subunits of influenza virus (Flu) RNA-dependent RNA polymerase, this paper is devoted to the optimization of a dihydrotriazolopyrimidine derivative, previously identified through structure-based drug discovery. The structure modifications performed around the bicyclic core led to the identification of compounds endowed with both the ability to disrupt PA-PB1 subunits interaction and anti-Flu activity with no cytotoxicity. Very interesting results were obtained with the hybrid molecules 36 and 37, designed by merging some peculiar structural features known to impart PA-PB1 interaction inhibition, with compound 36 that emerged as the most potent PA-PB1 interaction inhibitor (IC50 = 1.1 μM) among all the small molecules reported so far. Calculations showed a very favored H-bonding between the 2-amidic carbonyl of 36 and Q408, which seems to justify its potent ability to interfere with the interaction of the polymerase subunits.