Synthesis of new lophine-carbohydrate hybrids as cholinesterase inhibitors: cytotoxicity evaluation and molecular modeling.

In this study, we synthesized nine novel hybrids derived from d-xylose, d-ribose, and d-galactose sugars connected by a methylene chain with lophine. The compounds were synthesized by a four-component reaction to afford the substituted imidazole moiety, followed by the displacement reaction between sugar derivatives with an appropriate N-alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound 9a (a d-galactose derivative) being the most potent inhibitor (IC50 = 0.17 µM). According to the molecular modeling results, all the compounds indicated that the lophine moiety existed at the bottom of the BuChE cavity and formed a T-stacking interaction with Trp231, a residue accessible exclusively in the BuChE cavity. Noteworthily, only one compound exhibited activity against AChE (8b; IC50 = 2.75 µM). Moreover, the in silico ADME predictions indicated that all the hybrids formulated in this study were drug-likely, orally available, and able to reach the CNS. Further, in vitro studies demonstrated that the two most potent compounds against BuChE (8b and 9a) had no cytotoxic effects in the Vero (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines.

Novel series of tacrine-tianeptine hybrids: Synthesis, cholinesterase inhibitory activity, S100B secretion and a molecular modeling approach.

Tianeptine was linked to various 9-aminoalkylamino-1,2,3,4-tetrahydroacridines using EDC·HCl/HOBt to afford a series of tacrine-tianeptine hybrids. The hybrids were tested for their ability to inhibit AChE and BuChE and IC50 values in the nanomolar concentration scale were obtained. AChE molecular modeling studies of these hybrids indicated that tacrine moiety interacts in the bottom of the gorge with the catalytic active site (CAS) while tianeptine binds to peripheral anionic site (PAS). Furthermore, the compounds 2g and 2e were able to reduce the in vitro basal secretion of S100B, suggesting its therapeutic action in some cases or stages of Alzheimer's disease.

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors.

A novel series of tacrine-lophine hybrids was synthesized and tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC50 in the nanomolar concentration scale. The key step is the one-pot four component condensation reaction of 9-aminoalkylamino-1,2,3,4-tetrahydroacridines, benzil, different substituted aromatic aldehydes and NH4OAc, using InCl3 as the best catalyst. Tacrine-lophine hybrids were found to be potent and selective inhibitors of cholinesterases. As an extension of the four component approach to tetrasubstituted imidazoles, a new series of bis-(2,4,5-triphenyl-1H-imidazoles) or bis(n)-lophines was tested against AChE and BuChE.

Synthesis and AChE inhibitory activity of new chiral tetrahydroacridine analogues from terpenic cyclanones.

This work describes the enantioselective synthesis of a new series of terpenic chiral 9-aminotetrahydroacridine analogues. Several chiral ketones were synthesized from natural monoterpenes in an optically active form and subjected to the cyclodehydration reactions with anthranilonitrile in the presence of BF(3).Et(2)O as catalyst. The 9-aminotetrahydroacridine analogues were tested as acetylcholinesterase (AChE) inhibitors. Based on qualitative structure-activity relationship some trends are suggested.

Synthesis of phosphate monomers and bonding to dentin: esterification methods and use of phosphorus pentoxide.

OBJECTIVES: The aim of this study was to synthesize an acidic monomer using an alternative synthetic pathway and to evaluate the influence of the acidic monomer concentration on the microtensile bond strength to dentin. METHODS: The intermediary 5-hydroxypentyl methacrylate (HPMA) was synthesized through methacrylic acid esterification with 1,5-pentanediol, catalyzed by p-toluenesulfonic acid. To displace the reaction balance, the water generated by esterification was removed by three different methods: anhydrous sodium sulfate; molecular sieves or azeotropic distillation. In the next step, a phosphorus pentoxide (4.82 mmol) slurry was formed in cold acetone and 29 mmol of HPMA was slowly added by funnel addition. After the reaction ended, solvent was evaporated and the product was characterized by 1HNMR and FTIR. The phosphate monomer was introduced in a self-etch primer at concentrations of 0, 15, 30, 50, 70 and 100 wt%. Clearfil SE Bond was used as commercial reference. Microtensile bond strength to dentin was evaluated 24h after the bonding procedures, followed by fracture analysis (n=20). Data was submitted to ANOVA and Tukey's post hoc test. RESULTS: The highest yield was obtained (62%) when azeotropic distillation was used, while the reaction with molecular sieves was not feasible. The phosphoric moiety attachment to the monomer was successfully performed with a quantitative yield that reached around 100%. The acidic monomer concentration significantly affected the bond strength and the highest mean (55.1+/-12.8 MPa) was obtained when 50% of acidic monomer was used. CONCLUSION: The synthesis pathways described in the present study appear to be a viable alternative for developing phosphate monomers.

2,3-Epithiopropyl methacrylate as functionalized monomer in a dental adhesive.

OBJECTIVES: The aim of this study was to investigate new dentin bonding agents formulated with 2,3-epithiopropyl methacrylate (ETMA) comonomer blends. METHODS: Synthesis and characterization of ETMA were performed. Adhesive resins with three different ETMA concentrations (0.1, 1 and 10 wt.%) were prepared. To comparison a blend with only Bis-GMA/HEMA and with 1% of GMA were used as controls. FTIR analysis was used to verify the degree of conversion. Blend copolymerization was investigated by (1)H NMR spectroscopy analysis. To investigate immediate properties of experimental adhesives, microtensile bond strength to human dentin and SEM fractographic analysis were studied. RESULTS: ETMA was synthesized with 90% yield through a one step synthetic route. Degree of conversion for the experimental and control resins was not significantly different. Different monomers showed copolymerization among them, not presenting traces of ETMA release in 0.1 and 1% groups. Bonding agents containing ETMA had statistically higher microtensile bond strength values than the no ETMA adhesive (p<0.05). CONCLUSIONS: Dental adhesive resin-ETMA mixtures produced increased bond strengths without harming the other properties investigated.