Marco Antonio Ceschi

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 Tukeys 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.

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.

Metal halide hydrates as lewis acid catalysts for the conjugated friedel-crafts reactions of indoles and activated olefins

Metal halide hydrates such as SnCl2·2H2O, MnCl2·4H2O, SrCl2·6H2O, CrCl2·6H2O, CoCl2·6H2O e CeCl3·7H2O were investigated as mild Lewis acids catalysts for the conjugate Friedel-Crafts reaction between indoles and activated olefins. The reactions were carried out with aliphatic unsaturated ketones over a period of days at room temperature, while chalcones reacted only under reflux conditions. The reactions with nitrostyrenes were either performed in solvent or under solventless conditions. In all cases reasonable to good yields were obtained.

Lewis acid promoted Friedländer condensation reactions between anthranilonitrile and ketones for the synthesis of tacrine and its analogues

The scope of Lewis acid-promoted cyclodehydratation reactions between anthranilonitrile and several ketones, to afford tacrine and its derivatives, was expanded to include the use of various metal chloride salts not reported in the literature. The ability of the Lewis acids to effectively promote the cyclodehydratation between anthranilonitrile and cyclohexanone as the ketone was found to be the following order: InCl3 > AlCl3 ~ BF3.Et2O > FeCl3 > BiCl3 ~ SbCl3 ~ SnCl2.2H2O. The reactions were performed under both solvent and solvent-free conditions in good to excellent yields. Other Lewis acids screened, such as RuCl3, CeCl3, NiCl2, CoCl2.2H2O and CsCl were not effective.

InCl3/NaClO: a reagent for allylic chlorination of terminal olefins

Tricloreto de indio na presenca de hipoclorito de sodio promove a cloracao alilica de olefinas terminais em meio bifasico (diclorometano/agua) com bons rendimentos. Para estabelecer um procedimento geral, escolheu-se a carvona como composto modelo e otimizou-se a estequiometria, temperatura, e tempo de conversao para o respectivo cloreto alilico. Tratando-se b-pineno com tricloreto de indio/hipoclorito de sodio obteve-se seletivamente o cloreto perilico, um precursor importante para a obtencao de derivados de limoneno oxigenados no carbono C-7.

Preparation of (5R)-4,8-dimethylbicyclo[3.3.0]oct-1(8),3-dien-2-one from (-)-limonene oxide: a novel intermediate to the synthesis of 4-5-5 fused tricarbocyclic core present in terpenic natural products

Este trabalho refere-se a sintese enantiosseletiva da dienona (5R)-4,8-dimethylbicyclo[3.3.0]oct1(8),3-dien-2-one. Este intermediario, pode ser reconhecido como um bloco de construcao versatil para a sintese de uma grande variedade de compostos com esqueleto biciclo[3.3.0]octano. A estrategia sintetica empregada aqui faz uso da reatividade invertida de um precursor cianoidrina TMS-eter, como equivalente de ânion acila, para promover uma reacao de alquilacao intramolecular. A sintese formal do (-)-kelsoeno foi realizada pela preparacao do intermediario avancado (1R,5S,8R)-4,8dimethylbicyclo[3.3.0]oct-3-en-2-one, a partir da hidrogenacao seletiva do composto intitulado (5R)4,8-dimethylbicyclo[3.3.0]oct-1(8),3-dien-2-one. This paper describes the conversion of the readily available (-)-limonene oxide to the new (5R)4,8-dimethylbicyclo[3.3.0]oct-1(8),3-dien-2-one. This compound holds the prospect of serving as a useful chiral building block or intermediate to prepare a variety of compounds having a bicyclo[3.3.0]octane framework. The synthetic strategy made use of the umpolung reactivity of cyanohydrin TMS ether, as an acyl anion equivalent, in order to promote intramolecular alkylation. The formal synthesis of (-)-kelsoene was achieved by preparing a known advanced intermediate (1R,5S,8R)-4,8-dimethylbicyclo[3.3.0]oct-3-en-2-one via selective hydrogenation of the named compound (5R)-4,8-dimethylbicyclo[3.3.0]oct-1(8),3-dien-2-one.

Enantioselective synthesis of (R)-isocarvone from (S)-perillaldehyde

This work describes the enantioselective preparation of (R)-(+)-isocarvone, (S)-(-)-5-isopropenylcyclohex-2-enone and (S)-(-)-3-isopropenylcyclohexanone starting from (S)-(-)-perillaldehyde. These compounds hold the prospect of serving as useful chiral building blocks or intermediates in organic synthesis.

Lophine and pyrimidine based photoactive molecular hybrids. Synthesis, photophysics, BSA interaction and DFT study

Two photoactive molecular hybrids containing both lophine and pyrimidine moieties were synthesized by multicomponent reaction. The compounds present absorption in the UV-region (below 300 nm) and fluorescence emission in the violet region due to the lophine moiety. Experimental evidence indicates that photoinduced electron transfer (PET) occurs in the excited state of the hybrids. The observed photophysical features were successfully used to explore the interaction of the compounds with bovine serum albumin (BSA) in phosphate buffer solution (PBS) where a significant suppression mechanism was observed for both molecular hybrids. The DFT and TD-DFT calculations were performed at the ωB97XD level of theory. The results show low influence of the solvent on the wavelengths. However, the dipole moment undergoes a significant modification when the solvent is changed, showing a high polar behavior towards the excited state. Calculations also show us that the excitation is local, and that there is no charge transfer.

Design, synthesis, cholinesterase inhibition and molecular modelling study of novel tacrine hybrids with carbohydrate derivatives

A series of hybrids containing tacrine linked to carbohydrate-based moieties, such as d-xylose, d-ribose, and d-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50 scale. Most of the d-xylose derivatives (6a-e) were selective for AChE and the compound 6e (IC50 = 2.2 nM for AChE and 4.93 nM for BuChE) was the most active compound for both enzymes. The d-galactose derivative 8a was the most selective for AChE exhibiting an IC50 ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely 7a (d-ribose derivative) and 6b (d-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinskis rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II.