Novel arylcarbamate-N-acylhydrazones derivatives as promising BuChE inhibitors: Design, synthesis, molecular modeling and biological evaluation.

A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC50 values of 0.07-2.07 µM, highlighting the compound 10c (IC50 = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC50 = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CH⋯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.

Synthesis and antifungal activity of new hybrids pyrimido[4,5-d]pyridazinone-N-acylhydrazones.

Paracoccidioidomycosis is an endemic mycosis in Latin America for which there is a high mortality rate and limited treatment options. There are no specific drugs to treat the systemic disease. Thus, there is a need for further studies focused on the development of specific drugs. In this work we synthesized new hybrids pyrimido[4,5-d]pyridazinone-N-acylhydrazone (5a-p) by simple methodologies with good yields. The antifungal activity of compounds was evaluated against P. brasiliensis (Pb18) and Candida spp. Compounds 5a, 5f, 5i, 5 k, 5m and 5n showed significant inhibition against Pb18 with MIC of 0.125 to 64 µg mL-1. Compound 5a is the most promising, showing potent fungicidal profile with MFC of 0.5 µg mL-1, synergic effect with amphotericin B, besides showing no toxicity against HeLa and Vero cells.

Strong hyperconjugative interactions limit solvent and substituent influence on conformational equilibrium: the case of cis-2-halocyclohexylamines.

The presence of strong stereoelectronic interactions involving the substituents in cis-2-substituted cyclohexanes may lead to results different from those expected. In this work, we studied the conformational behavior of cis-2-fluoro- (F), cis-2-chloro- (Cl), cis-2-bromo- (Br) and cis-2-iodocyclohexylamine (I) by dynamic NMR and theoretical calculations. The experimental data pointed to an equilibrium strongly shifted toward the ea conformer (equatorial amine group and axial halogen), with populations greater than 90% for F, Cl and Br in both dichloromethane-d 2 and methanol-d 4. Theoretical calculations (M06-2X/6-311++G(2df,2p)) were in agreement with the experimental, with no influence of the solvent or the halogen on the equilibrium. A principal component analysis of natural bond orbital energies pointed to the σ*C-X and σC-H orbitals and the halogen lone pairs (LPX) as the most significant for the hyperconjugative interactions that influenced the equilibrium. The σC-H → σ*C-X hyperconjugation and the interactions involving the LPX counterbalance each other, explaining the non-influence of the halogen on the conformational equilibrium. These interactions are responsible for the strong preference for the ea conformer in cis-2-halocyclohexylamines, being strong enough to restrain the shift in the equilibrium due to other factors such as steric repulsion or solvent effects.

NMR spectroscopy and theoretical calculations in the conformational analysis of 1-methylpyrrolidin-2-one 3-halo-derivatives.

This study reports the results of ab initio and density functional theory (DFT) electronic structure calculations as well as (3)J(HH) experimental and calculated coupling constant data obtained in the investigation of the conformational equilibrium of 3-halo-derivatives of 1-methylpyrrolidin-2-one. The five-membered ring assumes an envelope conformation owing to the plane of formation of the O═C-N-R bond, with C4 forming the "envelope lid". When the conformation changes, the "lid" alternates between positions above and below the amide plane. The α-carbonyl halogen assumes two positions: a pseudo-axial and a pseudo-equatorial. In the gaseous phase, the calculations indicate that the pseudo-axial conformer is more stable and preferable going down the halogen family. Natural bond orbital analysis showed that electronic delocalization is significant only for the iodo derivative. In the other derivatives, the electrostatic repulsion between oxygen and the halogen determines the conformational equilibrium. When the solvated molecule was taken into account, the pseudo-equatorial conformer population increased with the relative permittivity of the solvent. This variation was strong in the fluoro derivative, and the preference was inverted. In the chlorine derivative, the two populations became closer in methanol and acetonitrile. In the bromine and iodine derivatives, the percentage of pseudo-equatorial conformer increased only slightly owing to the dipole moment of the conformation: the pseudo-equatorial conformation has a greater dipole moment and thus is stable in media with high relative permittivity.

Conformational analysis of cis-2-halocyclohexanols; solvent effects by NMR and theoretical calculations.

Conformational problems often involve very small energy differences, even low as 0.5 kcal mol(-1). This accuracy can be achieved by theoretical methods in the gas phase with the appropriate accounting of electron correlation. The solution behavior, on the other hand, comprises a much greater challenge. In this study, we conduct and analysis for cis-2-fluoro-, cis-2-chloro-, and cis-2-bromocyclohexanol using low temperature NMR experiments and theoretical calculations (DFT, perturbation theory, and classical molecular dynamics simulations). In the experimental part, the conformers' populations were measured at 193 K in CD(2)Cl(2), acetone-d(6), and methanol-d(4) solutions; the preferred conformer has the hydroxyl group in the equatorial and the halogen in the axial position (ea), and its population stays at about 60-70%, no matter the solvent or the halogen. Theoretical calculations, on the other hand, put the ae conformer at a lower energy in the gas phase (MP2/6-311++G(3df,2p)). Moreover, the theoretical calculations predict a markedly increase in the conformational energy on going from fluorine to bromine, which is not observed experimentally. The solvation models IEF-PCM and C-PCM were tested with two different approaches for defining the atomic radii used to build the molecular cavity, from which it was found that only with explicit consideration of hydrogens can the conformational preference be properly described. Molecular dynamic simulations in combination with ab initio calculations showed that the ea conformer is slightly favored by hydrogen bonding.

Effect of sulfur oxidation on the transmission mechanism of 4J(HH) NMR coupling constants in 1,3-dithiane.

Long-range 4J(HH) couplings in 1,3-dithiane derivatives are rationalized in terms of the effects of hyperconjugative interactions involving the S=O group. Theoretical and experimental studies of 4J(HH) couplings were carried out in 1,3-dithiane-1-oxide (2), cis-1,3-dithiane-1,3-dioxide (3), 1,3-dithiane-1,1,3-trioxide (4), and 1,3-dithiane-1,1,3,3-tetraoxide (5) compounds. Hyperconjugative interactions were studied with the natural bond orbital, NBO, method. Hyperconjugative interactions involving the LP(O), oxygen lone pair and sigma*(C2-S1) and sigma*(S1-C6) antibonding orbitals yield an increase of 4J(H(eq)-H(eq)) couplings. Long-range 4J(H(ax)-H(ax)) couplings were also observed between hydrogen atoms in axial orientation, which are rationalized as originating in hyperconjugative interactions involving the bonding sigma(C6-H(ax)) and antibonding sigma*(S=O) orbitals. The symmetry for orbital interactions is possible only when the S=O group is in the axial orientation.

Novel 4-methoxynaphthalene-N-acylhydrazones as potential for paracoccidioidomycosis and tuberculosis co-infection.

Aim: 17 new 4-methoxynaphthalene-N-acylhydrazones were synthesized in order to evaluate their biological action against important pathogens. Methods: In vitro susceptibility assays of compounds were performed against Paracoccidioidesbrasiliensis and Mycobacterium tuberculosis. Results: Compounds 4a, 4b and 4k were the most potent against P. brasiliensis, two with minimum inhibitory concentrations of ≤1 µg ml-1 and exhibited pharmacological synergy with amphotericin B. The compounds also showed activity against M. tuberculosis, with 4c and 4k being the more promising. Compound 4k showed good synergistic antimycobacterium activity with ethambutol. None of the compounds tested showed toxicity. Conclusion: We highlight the compound 4k, as a potential agent for the treatment of patients co-infected with paracoccidioidomycosis and tuberculosis.

New 4-methoxy-naphthalene derivatives as promisor antifungal agents for paracoccidioidomycosis treatment.

AIM: Novel 4-methoxy-naphthalene derivatives were synthesized based on hits structures in order to evaluate the antifungal activity against Paracoccidioides spp. METHODS: Antifungal activity of compounds was evaluated against P. brasiliensis and most promising compounds 2 and 3 were tested against eight clinically important fungal species. RESULTS: Compound 3 was the more active compound with MIC 8 to 32 µg.ml-1 for Paracoccidioides spp without toxicity monkey kidney and murine macrophagecells. Carbohydrazide 3 showed good synergistic antifungal activity with amphotericin B against P. brasiliensis specie. Titration assay of carbohydrazide 3 with PbHSD enzyme demonstrates the binding ligand-protein. Molecular dynamics simulations show that ligand 3 let the PbHSD protein more stable. CONCLUSION: New carbohydrazide 3 is an attractive lead for drug development to treat paracoccidioidomycoses.

The conformational analysis of 2-halocyclooctanones.

The establishment of the most stable structures of eight membered rings is a challenging task to the field of conformational analysis. In this work, a series of 2-halocyclooctanones were synthesized (including fluorine, chlorine, bromine and iodine derivatives) and submitted to conformational studies using a combination of theoretical calculation and infrared spectroscopy. For each compound, four conformations were identified as the most important ones. These conformations are derived from the chair-boat conformation of cyclooctanone. The pseudo-equatorial (with respect to the halogen) conformer is preferred in vacuum and in low polarity solvents for chlorine, bromine and iodine derivatives. For 2-fluorocyclooctanone, the preferred conformation in vacuum is pseudo-axial. In acetonitrile, the pseudo-axial conformer becomes the most stable for the chlorine derivative. According to NBO calculations, the conformational preference is not dictated by electron delocalization, but by classical electrostatic repulsions.

Infrared and theoretical calculations in 2-halocycloheptanones conformational analysis.

2-Halocycloheptanones (Halo=F, Cl, Br and I) were synthesized and their conformational analysis was performed through infrared spectroscopy data. The corresponding conformers geometries and energies were obtained by theoretical calculations at B3LYP/aug-cc-pVDZ level of theory in the isolated state and in solution. It was observed, by both approaches, that the conformational preferences were very sensitive to the solvent polarity, since its increase led to an increase in the population of the more polar conformer. An analysis of these conformational equilibria showed they suffer also the influence of stereoelectronic effects, like hyperconjugation and steric effects. These results were interpreted using natural bond orbital (NBO) analysis, which indicated that the electronic delocalization to the orbital π*(C=O) is directly involved in the stability increase of conformers I and II. The relative effect of the period of the halogen can also be noted, with changes in the conformational preferences and in the energies involved in the interactions of NBO.

The prediction of (1)H chemical shifts in amines: a semiempirical and ab initio investigation.

Twenty one conformationally fixed amines and their N,N-dimethyl derivatives were obtained commercially or synthesized. These included cis and trans 4-t-butyl cyclohexylamine, 2-exo and 2-endo norbornylamine, 2-adamantylamine, 4-phenylpiperidine, 1-napthylamine and tetrahydro-1-napthylamine. The (1)H NMR spectra of these amines were measured in CDCl(3) solution, assigned and the (1)H chemical shifts given. This data was used to investigate the effect of the amino group on the (1)H chemical shifts in these molecules. These effects were analyzed using the CHARGE model. This calculates the electric field and steric effects of the amino group for protons more than three bonds removed, together with functions for the calculation of two-bond and three-bond effects. The rotational isomerism about the C--N bond of the amino group was investigated by ab initio calculations of the potential energy surface (PES) about this bond at the HF/3-21G level. The resulting conformers were then minimized at the B3LYP/6-311 + + G (d,p) level. These geometries were then used to calculate the (1)H chemical shifts in the above compounds by CHARGE and the ab initio gauge-invariant atomic orbital (GIAO) method at the B3LYP/6-311 + + G(d,p) level and the shifts were compared with those observed. The compounds investigated gave 170 (1)H chemical shifts ranging from 0.60 to 8.2 ppm. The rms errors (obs.-calc.) were ca 0.1 ppm (CHARGE) and ca 0.2 ppm (GIAO). Large deviations of ca 1.0 ppm were observed for the NH protons in the GIAO calculations. The complex spectra of alkyl and aryl amines can thus be successfully predicted by both ab initio and semiempirical methods except for the NH protons, for which the ab initio calculations are not sufficiently accurate.