Analogues of 2'-hydroxychalcone with modified C4-substituents as the inhibitors against human acetylcholinesterase.

A series of C4-substituted tertiary nitrogen-bearing 2'-hydroxychalcones were designed and synthesised based on a previous mixed type acetylcholinesterase inhibitor. Majority of the 2'-hydroxychalcone analogues displayed a better inhibition against acetylcholinesterase (AChE) than butyrylcholinesterase (BuChE). Among them, compound 4c was identified as the most potent AChE inhibitor (IC50: 3.3 µM) and showed the highest selectivity for AChE over BuChE (ratio >30:1). Molecular docking studies suggested that compound 4c interacts with both the peripheral anionic site (PAS) and catalytic anionic site (CAS) regions of AChE. ADMET analysis confirmed the therapeutic potential of compound 4c based on its blood-brain barrier penetrating. Overall, the results suggest that this 2'-hydroxychalcone deserves further investigation into the therapeutic lead for Alzheimer's disease (AD).

Current approaches in antiviral drug discovery against the Flaviviridae family.

Viruses belonging to the Flaviviridae family primarily spread through arthropod vectors, and are the major causes of illness and death around the globe. The Flaviviridae family consists of 3 genera which include the Flavivirus genus (type species, yellow fever virus) as the largest genus, the Hepacivirus (type species, hepatitis C virus) and the Pestivirus (type species, bovine virus diarrhea). The flaviviruses (Flavivirus genus) are small RNA viruses transmitted by mosquitoes and ticks that take over host cell machinery in order to propagate. However, hepaciviruses and pestiviruses are not antropod-borne. Despite the extensive research and public health concern associated with flavivirus diseases, to date, there is no specific treatment available for any flavivirus infections, though commercially available vaccines for yellow fever, Japanese encephalitis and tick-born encephalitis exist. Due to the global threat of viral pandemics, there is an urgent need for new drugs. In many countries, patients with severe cases of flavivirus infections are treated only by supportive care, which includes intravenous fluids, hospitalization, respiratory support, and prevention of secondary infections. This review discusses the strategies used towards the discovery of antiviral drugs, focusing on rational drug design against Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Yellow Fever virus (YFV) and Hepatitis C virus (HCV). Only modified peptidic, nonpeptidic, natural compounds and fragment-based inhibitors (typically of mass less than 300 Da) against structural and non-structural proteins are discussed.

2-(2-Meth-oxy-phen-oxy)-3-nitro-pyridine.

In the title compound, C(12)H(10)N(2)O(4), the pyridine and benzene rings are almost orthogonal, forming a dihedral angle of 86.63 (6)°. Each of the nitro [O-N-C-C torsion angle = -6.45 (19)°] and meth-oxy [C-O-C-C torsion angle = 179.69 (11)°] groups is almost coplanar with the ring to which it is connected. Mol-ecules are consolidated in the crystal structure via C-H⋯O inter-actions, forming a three-dimensional network.

Tetra-µ-acetato-κO:O'-bis-[(2-phen-oxy-pyrimidine-κN)copper(II)](Cu-Cu).

The complete dinuclear mol-ecule of the title complex, [Cu(2)(CH(3)COO)(4)(C(10)H(8)N(2)O)(2)], is generated by a centre of inversion. The Cu(II) atom is in a distorted octa-hedral coordination geometry defined by four O atoms derived from four bridging acetate ligands, a terminally connected pyrimidine N atom and a Cu atom.

2-(4-Methyl-phen-oxy)-5-nitro-pyridine.

The title mol-ecule, C(12)H(10)N(2)O(3), is twisted, the dihedral angle between the rings being 61.16 (13)°. The nitro group is approximately coplanar with the pyridine ring to which it is attached [O-N-C-C torsion angle = -178.1 (3)°]. Supra-molecular chains along [010] and mediated by C-H⋯O and π-π [centroid(pyrid-yl)-(benzene) distance = 3.8259 (18) Å] contacts feature in the crystal packing.

2-(Naphthalen-2-yl-oxy)-5-nitro-pyridine.

A nearly orthogonal relationship is found for the ring systems in the title compound, C(15)H(10)N(2)O(3), with the dihedral angle between the rings being 86.13 (11)°. The nitro group is approximately coplanar with the pyridine ring to which it is connected [the O-N-C-C torsion angle = -1.8 (4)°]. This coplanarity allows for the close approach of these residues in the crystal structure enabling the formation of N-O⋯π(pyridine) inter-actions [3.547 (4) Å]. Further consolidation of the crystal packing is afforded by weak π-π inter-actions [centroid-centroid distances = 3.9576 (16) and 3.9822 (16) Å].

2-(2-Meth-oxy-phen-oxy)pyrazine.

A significant twist is observed in the title molecule, C(11)H(10)N(2)O(2), as seen in the dihedral angle between the pyrazine and benzene rings of 72.79 (8)°. The meth-oxy group is almost coplanar with the benzene ring to which it is attached [C-O-C-C torsion angle = 175.83 (15)°]. Centrosymmetric dimers are formed in the crystal structure which are held together by weak π-π inter-actions between pyrazine rings [centroid-centroid distance = 3.8534 (10) Å].

2-(3-Meth-oxy-phen-oxy)pyrimidine.

In the title compound, C(11)H(10)N(2)O(2), the benzene ring faces towards one of the pyrimidine N atoms, and is almost orthogonal to the plane through the pyrimidine ring [dihedral angle = 84.40 (14)°]. In the crystal, the presence of C-H⋯π and π-π [centroid-centroid separation = 3.7658 (18) Å] inter-actions leads to a supra-molecular array in the ac plane. The layers thus formed inter-digitate along the b axis.

2-(Pyrimidin-2-yl-oxy)phenol.

The pyrimidine and benzene rings in the title compound, C(10)H(8)N(2)O(2), form a dihedral angle of 71.03 (7)°, with the roughly orthogonal benzene ring being folded towards one of the pyrimidine N atoms. In the crystal, pairs of O-H⋯N hydrogen bonds connect mol-ecules related by twofold symmetry into dimeric aggregates. These associate into a supra-molecular chain propagating along the b axis by way of C-H⋯π contacts. The chains are cross-linked by π-π inter-actions that occur between pyrimidine rings [ring centroid-centroid distances = 3.5393 (9) and 3.5697 (9) Å].

2-(4-Meth-oxy-phen-oxy)pyrazine.

In the title compound, C(11)H(10)N(2)O(2), the aromatic rings are almost orthogonal to each other [dihedral angle = 86.97 (8)°], with the benzene ring orientated to face one of the pyrazine N atoms. In the crystal, centrosymmetrically related pairs are connected via pairs of C-H⋯π inter-actions and the dimeric units thus formed pack into undulating layers that stack along the a axis.

2-(4-Meth-oxy-phen-oxy)-3-nitro-pyridine.

In the title mol-ecule, C(12)H(10)N(2)O(4), the pyridine and benzene rings are almost orthogonal [dihedral angle = 86.69 (11)°], with the pyridine N atom directed towards the centre of the benzene ring. The -NO(2) [O-N-C-C = -26.1 (3)°] and -OMe [C-O-C-C = 166.5 (2)°] substituents are not coplanar with their respective aromatic rings. In the crystal, supra-molecular layers in the ab plane are formed via C-H⋯π inter-actions involving methyl H atoms and the pyridine and benzene rings. Short N-O⋯π contacts (where the π-system is derived from the pyridine ring) occur between layers in the c-axis direction.