Correction: Conformationally restricted benzothienoazepine respiratory syncytial virus inhibitors: their synthesis, structural analysis and biological activities.

[This corrects the article DOI: 10.1039/C8MD00033F.].

Conformationally restricted benzothienoazepine respiratory syncytial virus inhibitors: their synthesis, structural analysis and biological activities.

Atropisomeric drug substances are known to have different biological properties. Compounds containing the N-benzoylbenzazepine motif have been shown to exhibit energetically restricted rotation around the Ar(CO)N axis. Herein we report, for the first time, the synthesis, physical characterisation and anti-viral profiles of a series of C-4 and C-5 methylated thieno-benzazepines. NMR analysis reveals that incorporation of a single additional substituent at either of these loci influences the conformational dynamics of the azepine ring system. In the case of the C-5 alkyl analogues, the influence of the new stereocentre is so pronounced that its absolute configuration determines which unique atropisomer is obtained following the generation of the benzazepine nucleus. Screening of the alkylated derivatives for their anti-respiratory syncytial virus (RSV) activity indicates that the desired viral pathogenicity is strongly associated with the conformation adopted by the modified tricyclic scaffolds. This is particularly evident in the case of the C-5 homologues in which one atropisomer was found to be potently active and the other essentially inert. These results provide compelling evidence that we have determined the bioactive conformation shared by RSV inhibitors that employ the thienobenazapine nucleus as their core molecular architecture. Furthermore, the understanding obtained from these studies may make it possible to design improved agents against RSV infection in the future.

Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor.

Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective antiviral activity against laboratory-adapted or clinical isolates of RSV-A (50% inhibitory concentration [IC50], <0.09 to 0.71 nM) and RSV-B (IC50, 1.3 to 50.6 nM), which were determined by inhibition of cytopathic effects in HEp-2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV-infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and minigenome assay in HEp-2 cells (IC50, 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections.

Discovery of novel benzothienoazepine derivatives as potent inhibitors of respiratory syncytial virus.

The development of novel non-nucleoside inhibitors of the RSV polymerase complex is of significant clinical interest. Compounds derived from the benzothienoazepine core, such as AZ-27, are potent inhibitors of RSV viruses of the A-subgroup, but are only moderately active against the B serotype and as yet have not demonstrated activity in vivo. Herein we report the discovery of several novel families of C-2 arylated benzothienoazepine derivatives that are highly potent RSV polymerase inhibitors and reveal an exemplary structure, compound 4a, which shows low nanomolar activity against both RSV A and B viral subtypes. Furthermore, this compound is effective at suppressing viral replication, when administered intranasally, in a rodent model of RSV infection. These results suggest that compounds belonging to this chemotypes have the potential to provide superior anti-RSV agents than those currently available for clinical use.

Discovery of Narrow Spectrum Kinase Inhibitors: New Therapeutic Agents for the Treatment of COPD and Steroid-Resistant Asthma.

The discovery of a novel series of therapeutic agents that has been designed and optimized for treating chronic obstructive pulmonary disease is reported. The pharmacological strategy was based on the identification of compounds that inhibit a defined subset of kinase enzymes modulating inflammatory processes that would be effective against steroid refractory disease and exhibit a sustained duration of action after inhaled delivery.

Mixed valence Mn(II)/Mn(III) [3 x 3] grid complexes: structural, electrochemical, spectroscopic, and magnetic properties.

Mn(II)9 grid complexes with a [Mn9(mu-O)12] core, obtained by self-assembly of a series of tritopic picolinic dihydrazone ligands with Mn(II) salts, have been oxidized by both chemical and electrochemical methods to produce mixed oxidation state systems. Examples involving [Mn(III)3Mn(II)6] and [Mn(III)4Mn(II)5] combinations have been produced. Structures are reported for [Mn9(2poap-2H)6](NO3)6.14H2O (1), [Mn9(2poap-2H)6](ClO4)10.10H2O (3), and [Mn9(Cl2poap-2H)6](ClO4)9.14H2O.3CH3CN (10). Structural studies show distinct contraction of the corner grid sites on oxidation, with overall magnetic properties consistent with the resulting changes in electron distribution. Antiferromagnetic exchange in the outer ring of eight metal centers creates a ferrimagnetic subunit, which undergoes antiferromagnetic coupling to the central metal, leading to S=1/2 (3) and S2/2 (10) ground states. Two moderately intense absorptions are observed on oxidation of the Mn(II) grids in the visible and near-infrared (1000 nm, 700 nm), associated with charge transfer transitions (LMCT, IVCT respectively). Compound 1 crystallized in the monoclinic system, space group P2 1/n, with a=21.308(2) A, b=23.611(2) A, c=32.178(3) A, beta=93.820(2) degrees . Compound 3 crystallized in the tetragonal system, space group I, with a=b=18.44410(10) A, c = 24.9935(3) A. Compound 10 crystallized in the triclinic system, space group P, with a=19.1150(10) A, b=19.7221(10) A, c=26.8334(14) A, alpha=74.7190(10) degrees, beta=77.6970(10) degrees, gamma=64.7770(10) degrees. The facile oxidation of the Mn(II)9 grids is highlighted in terms of their potential use as molecular based platforms for switching and data storage.

Self-assembly of a unique hexadecanuclear [4 x (2 x 2)]-Pb16 'grid of grids' type structure.

A new ligand containing a linear sequence of four-tridentate chelating subunits built around alkoxide and pyrimidine bridging groups undergoes a spontaneous self-assembly process with Pb(CF3SO3)2 to produce a unique hexadecanuclear [4 x (2 x 2)] 'grid of grids' type structure with external dimensions of 26 A.

Synthesis, structure and magnetism of a unique dodecanuclearcopper(II) 'picture frame' held in a 4 x 4 grid-like assembly.

The synthesis, structure and preliminary magnetic studies of a novel dodecanuclearcopper(II) grid-like assembly are reported.