N-butyl Moieties Research Articles

Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors.

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC50 values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC50 =31.2nm), and it was more active than reference drug, tacrine (IC50 =100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC50 =8.0nm), also higher than tacrine (IC50 =16.3nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β-amyloid aggregation (at the concentration 10 μm-24.96% of inhibition, 25μm-72%, 50μm-78.44%, and 100μm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.

Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus

A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.

Design and evaluation of novel glutaminase inhibitors

A novel set of GAC (kidney glutaminase isoform C) inhibitors able to inhibit the enzymatic activity of GAC and the growth of the triple negative MDA-MB-231 breast cancer cells with low nanomolar potency is described. Compounds in this series have a reduced number of rotatable bonds, improved ClogPs, microsomal stability and ligand efficiency when compared to the leading GAC inhibitors BPTES and CB-839. Property improvements were achieved by the replacement of the flexible n-diethylthio or the n-butyl moiety present in the leading inhibitors by heteroatom substituted heterocycloalkanes.

Towards the sequence-specific multivalent molecular recognition of cyclodextrin oligomers.

Sequence-specific multivalent molecular recognition has been recognized to play a major role in biological processes. Furthermore, sequence-specific recognition motifs have been used in various artificial systems in the last years, e.g., to emulate biological processes or to build up new materials with highly specific recognition domains. In this article, we present the preparation of cyclodextrin (CD)-based strands and complementary and non-complementary strands modified with guest molecules and the investigation of their complexation behavior towards each other by isothermal titration calorimetry (ITC). As complementary binding motifs n-butyl and α-CD and adamantane and β-CD were selected. It was found that it is possible to realize sequence-specific molecular recognition by the use of host–guest chemistry, but the recognition motifs as well as the linkages have to be chosen very carefully. In the case of trivalent systems one adamantane moiety must be included to induce preferred formation of 1:1 adducts. Due to the too weak interaction between n-butyl and α-CD these systems have a negative chelate cooperativity and open adducts are preferentially formed. As soon as two adamantane moieties are present, the complementary systems have a positive chelate cooperativity and double-stranded structures are favored over open adducts. In this system the n-butyl moiety provides insufficient discrimination towards α- and β-CD and no sequence specificity is observed. By the combination of three adamantane moieties sequence specificity can be generated. Exclusively with the complementary CD sequence double-stranded structures are formed, with non-complementary strands aggregates of higher stoichiometry are generated.

Tetra-μ3-iodido-tetra-kis-[(tri-n-butyl-phosphane-κP)copper(I)

The title complex, [Cu4I4(C12H27P)4], crystallizes with six mol­ecules in the unit cell and with three independent one-third mol­ecule fragments, completed by application of the relevant symmetry operators, in the asymmetric unit. The tetranuclear copper core shows a tetrahedral geometry (site symmetry 3..). The I atoms also form a tetra­hedron, with I⋯I distances of 4.471 (1) Å. Both tetra­hedra show an orientation similar to that of a pair of self-dual platonic bodies. The edges of the I-tetra­hedral structure are capped to the face centers of the Cu-tetra­hedron and vice versa. The Cuface⋯I distances are 2.18 Å (averaged) and the Iface⋯Cu distances are 0.78 Å (averaged). As a geometric consequence of these properties there are eight distorted trigonal–bipyramidal polyhedra evident, wherein each trigonal face builds up the equatorial site and the opposite Cu⋯I positions form the axial site. As expected, the n-butyl moieties are highly flexible, resulting in large elongations of their anisotropic displacement parameters. Some C atoms of the n-butyl groups were needed to fix alternative discrete disordered positions.

New bis-di-organotin compounds derived from aminoacid-imine-hexadentate ligands. Multifunctional evaluation as corrosion inhibitors, antibacterials and asphaltene dispersants/inhibitors

A new class of bis-di-organotin (IV) compounds were synthesized in good yields (ca. 80%) by a one-step five molecules reaction in which intervene two molecular equivalents of leucine, one of 5,5′-methylene-bis-salicylaldehyde and either two of di-n-butyltin (IV) or diphenyltin (IV) oxides, that independently provided two bis-di-organotin derivatives. The structures of these two compounds were established by 1H, 13C and 119Sn NMR, as well as by IR and elemental analysis. In both cases the 119Sn chemical shifts are characteristic of pentacoordinated atoms in solution of non-coordinating solvent (CDCl3). Once characterized, the novel compounds were tested as corrosion inhibitors at 25, 50 and 100mgL−1 on mild steel surfaces in sour brine by linear polarization resistance and potentiodynamic curves. These experiments prove that these derivatives present top efficiencies of 54% and 68% for butyl and phenyl moieties, respectively. In addition, these two compounds were tested in vitro against Bacillus subtilis (Gram-positive, strain ATCC 6633), Escherichia coli (Gram-negative, strain DH5) and Pseudomonas fluorescens strains to assess their bactericidal activities, being more effective for the E. coli strain, at concentrations as low as 25mgL−1. Moreover, in order to correlate different activities and ascertain homologous action mechanisms, the two derivatives were tested for their asphaltene inhibition/dispersion activity. The results suggest that the presence of the four n-butyl moieties provide the needed amphiphillic balance to obtain better efficiencies in the tested activities.

On the mechanism of the reaction between ozone and alcohols: Ozonation kinetics of butanol-1 and its esters in CCl4

The ozonation kinetics of butanol-1, tributyl borate, butyl acetate, and butyl trichloroacetate was studied in the temperature range from −20 to 45°C. The reactivity of the α-methylene group of the n-butyl moiety decreases in going from the alcohol to its trichloroacetic ester. In butyl trichloroacetate, this group is deactivated to such an extent that the kinetic parameters of the ozonation of this ester are comparable to the parameters observed earlier for n-butane. This decrease in reactivity is due the fact that the preexponential factor in the rate constant of the initial formation of an ozone-substrate complex decreases on passing from the alcohol to its esters. The activation energy of this process is constant within the error of data processing. It is concluded that the high reactivity of alcohols toward ozone is due to the initial formation of the ozone-substrate complex involving the hydroxyl group of the latter.

Different coordination modes for disulfoxides towards diorganotin(IV) dichlorides. X-ray crystal structures of 1,2-cis-bis-(phenylsulfinyl)ethene (rac-,cis-cbpse) and adducts [{Ph2SnCl2(meso-bpse)}n] and [{n-Bu2SnCl2(pdtd)}2

The reactions of meso-1,2-bis(phenylsulfinyl)ethane (meso-bpse) with Ph2SnCl2, 2-phenyl-1,3-dithiane trans-1-trans-3-dioxide (pdtd) with n-Bu2SnCl2 and 1,2-cis-bis-(phenylsulfinyl)ethene (rac-,cis-cbpse) with Ph2SnCl2, in 1:1 molar ratio, yielded [{Ph2SnCl2(meso-bpse)}n], [{n-Bu2SnCl2(pdtd)}2] and [{Ph2SnCl2(rac,cis-cbpse)}x] (x = 2 or n), respectively. All adducts were studied by IR, Mossbauer and 119Sn NMR spectroscopic methods, elemental analysis and single crystal X-ray diffractometry. The X-ray crystal structure of [{Ph2SnCl2(meso-bpse)}n] revealed the occurrence of infinite chains in which the tin(IV) atoms appear in a distorted octahedral geometry with Cl atoms in cis and Ph groups in trans positions. The X-ray crystal structure of [{n-Bu2SnCl2(pdtd)}2] revealed discrete centrosymmetric dimeric species in which the tin(IV) atoms possess a distorted octahedral geometry with bridging disulfoxides in cis and n-butyl moieties in trans positions. The spectroscopic data indicated that the adduct containing the rac,cis-cbpse ligand can be dimeric or polymeric. The X-ray structural analysis of the free rac-,cis-cbpse sulfoxide revealed that the crystals belong to the C2/c space group.

Synthesis of Well-Defined Amphiphilic Block Copolymers Having Phospholipid Polymer Sequences as a Novel Biocompatible Polymer Micelle Reagent

To realize safer and effective drug administration, novel well-defined and biocompatible amphiphilic block copolymers containing phospholipid polymer sequences were synthesized. At first, the homopolymer of 2-methacryloyloxyethylphosphorylcholine (MPC) was synthesized in water by reversible addition-fragmentation chain transfer (RAFT) controlled radical polymerization. The "living" polymerization was confirmed by the fact that the number-average molecular weight increased linearly with monomer conversion while the molecular weight distribution remained narrow independent of the conversion. The poly(MPC) thus prepared is end-capped with a dithioester moiety. Using the dithioester-capped poly(MPC) as a macro chain transfer agent, AB diblock copolymers of MPC and n-butyl methacrylate (BMA) were synthesized. Associative properties of the amphiphilic block copolymer (pMPC(m)-BMA(n)) with varying poly(BMA) block lengths were investigated using NMR, fluorescence probe, static light scattering (SLS), and quasi-elastic light scattering (QELS) techniques. Proton NMR data in D2O indicated highly restricted motions of the n-butyl moieties, arising from hydrophobic associations of poly(BMA) blocks. Fluorescence spectra of N-phenyl-1-naphthylamine indicated that the probes were solubilized in the polymer micelles in water. The formation of polymer micelles comprising a core with poly(BMA) blocks and shell with hydrophilic poly(MPC) blocks was suggested by SLS and QELS data. The size and mass of the micelle increased with increasing poly(BMA) block length. With an expectation of a pharmaceutical application of pMPC(m)-BMA(n), solubilization of a poorly water-soluble anticancer agent, paclitaxel (PTX), was investigated. PTX dissolved well in aqueous solutions of pMPC(m)-BMA(n) as compared with pure water, implying that PTX is incorporated into the hydrophobic core of the polymer micelle. Since excellent biocompatible poly(MPC) sequences form an outer shell of the micelle, pMPC(m)-BMA(n) may find application as a promising reagent to make a good formulation with a hydrophobic drug.

Characterization of tolbutamide polymorphs (burger's forms II and IV) and polymorphic transition behavior

Burger's two polymorphs of tolbutamide (TB), an oral hypoglycemic agent, were obtained by spray-drying the drug dissolved in a mixed solvent of ethanol/dichloromethane (Form IV) and allowing Form IV to stand at constant temperatures and humidities (Form II). These polymorphs were characterized by various physical methods [e.g., powder X-ray diffractometry, differential scanning calorimetry, infrared spectrometry, and solid-state carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy] and compared with two other TB polymorphs Forms I and III. The 13C NMR spectra showed that the chemical shift and the peak shape of resonance associated with the toluene and n-butyl moieties of TB were different for each of the four polymorphs, whereas the carbonyl carbon was unchanged, indicating different conformations and molecular motions of the toluene and n-butyl moieties in the solid states. Form IV converted itself to Form II within 3 h when it was stored at 45 °C and 75% relative humidity (RH) and, in turn, Form II transformed to Form I at higher temperatures. The conversion of Form IV to Form II proceeded according to a zero-order equation (Polany–Winger equation), and that of Form II to Form I according to a first-order equation. The increase in RH accelerated the polymorphic transition of Form IV. Both the apparent dissolution rate and the solubility of Form IV were nearly identical with those of Form II, because the former changed to the latter during the dissolution, but their dissolution rates and solubility were higher than those of Forms I and III. These dissolution characteristics of TB polymorphs were reflected in the oral absorption behavior in dogs; that is, the bioavailability increased in the order Form I < Form III < Form II ≈ Form IV.