Spiro Heterocyclic Compounds as Potential Anti-Alzheimer Agents (Part 2): Their Metal Chelation Capacity, POM Analyses and DFT Studies.

BACKGROUND: One of the best methods to treat Alzheimer disease (AD) is through the effective use of cholinesterase inhibitors as vital drugs due to the identification of acetylcholine deficit in the AD patients. OBJECTIVE: The present study aims the investigation of spiro heterocyclic compounds as potential AD agents supported by their metal chelation capacity, POM analyses and DFT studies, respectively. METHODS: The cholinesterase inhibition and metal chelation ability were performed on ELISA microtiter assay. Whereas, the B3LYP method with 6-31+G(d,p) basis set was implemented to study HOMOLUMO energy calculations. The pharmacokinetic properties of the synthesized molecules were studied through Petra, Osiris and Molinspiration (POM). RESULTS: The six spiro (1-6) skeletons were tested for their inhibitory potential and metal-chelation capacity. Our findings revealed that the tested spiro skeletons exerted none or lower than 50% inhibition against both cholinesterases, while compound 4 proved to be the most active molecule with 57.21±0.89% of inhibition toward BChE. The spiro molecule 3 exhibited the highest metal-chelation capacity (9.12±5.26%). Molecular docking model for the most active molecule exhibited promising bindings with AChE and BChE's active site pertained to hydrophobic hydrogen bonds and positive ionizable interactions. The POM analyses gave the information about the flexibility at the site of coordination of spiro compounds (1-6). CONCLUSION: The screening of spirocompounds (1-6) against cholinesterases revealed that some of them show considerable potential to inhibit AChE and BChE. Herein, we propose that the spiro molecules after further derivatization could serve interesting AD inhibitor drugs.

Anti-tubercular activity of ruthenium (II) complexes with polypyridines.

A series of nine polypyridyl-ruthenium (II) complexes (N-ligands = 2,2'-bipyridines; 2,2'-6',2'-terpyridines, di-alkyloxy-2,2'-6,2-bipyridine-3,3'-di-carboxylates), were tested against Mycobacterium tuberculosis (MBT). The complex (11) showed remarkable activity against MBT as compared to other complexes, (1-10). The aquo ligand of complex (11), as opposed to other chloro and acetonitrile derivatives, appears to play a key role in the antitubercular potency of this new class of metal-based compounds.

4'-Methyl-3-(4-nitro-phen-yl)-4-phenyl-4,5,1',2',3',4'-hexa-hydro-spiro-[isoxazole-5,2'-naphthalen]-1'-one.

The title compound, C(25)H(20)N(2)O(4), is a new spiro-isoxazoline derivative. It contains a five-membered isoxazoline ring (A), a tetra-lone unit (E and D), a 4-nitro-phenyl substituent (B), and a phenyl ring (C). The isoxazoline ring (A) has an envelope conformation, while the cyclo-hexenone ring (D) has an inter-mediate sofa/half-chair conformation. The aromatic ring of the 4-nitro-phenyl substituent (B) is inclined at an angle of 78.97 (10)° to the phenyl ring (C). The rigid pharmacophore site, Osp(2)-C-C-Osp(3), is characterized by an O⋯O distance of 3.113 (2) Šand an O-C-C-O torsion angle of 97.8 (2)°. In the crystal structure, mol-ecules are linked by C-H⋯O contacts.