Predicting Blood–Brain Partitioning of Small Molecules Using a Novel Minimalistic Descriptor-Based Approach via the 3D-RISM-KH Molecular Solvation Theory

Compartmentalization of drug molecules between plasma and brain is important for desired activities. The difficulty in obtaining the blood–brain permeability of drug (like) substances experimentally resulted in the development of several theoretical quantitative structure–activity relationships toward predicting the capability of a given substrate to pass across a tight junction, known as the blood–brain barrier, both qualitatively and quantitatively. Here, we report a novel method based on the molecular solvation theory for predicting blood–brain barrier permeability coefficients of molecules of diverse structures using a minimum set of descriptors derived from solvation energetics. Our finding points to the importance of solvation free energy based descriptors in modeling blood–brain barrier permeability quantitatively

De bezonken actualiteit van een nieuwe wereldatlas

Contains fulltext : 179868.pdf (publisher's version ) (Open Access)14 december 199

Synthesis and properties of rhenium(I) bridged boron-dipyrromethene dyad

We synthesized the hexa-coordinated Re(I) bridged BODIPY dyad 1 in decent yield by thermal reaction of benzimidazole substituted BODIPY 2 with Re(CO)5Cl. The dyad 1 was characterized by 1H, 13C, 11B, 19F NMR, ESI-MS, FTIR, UV-vis and electrochemical techniques. In Re(I) bridged dyad 1, the Re(I) ion is hexa-coordinated and coordinates with nitrogen atoms of two benzimidazole units, three axial carbonyl ligands and one chloride atom. The presence of three carbonyl groups in dyad 1 was verified by 13C NMR and IR spectroscopy. The absorption and steady-state fluorescence spectra of Re(I) bridged BODIPY dyad showed a slightly broad and hypsochromically shifted absorption and emission bands compared to BODIPY 2. The electrochemical studies indicated that, the Re(I) bridge BODIPY dyad 1 was easy to reduce compared to BODIPY 2 supporting the electron deficient nature dyad upon Re(I) ion binding. The molecular structure of dyad 1 was further elucidated by DFT computational studies

Ratiometric fluorescence off-on-off sensor for Cu²⁺ in aqueous buffer by a lower rim triazole linked benzimidazole conjugate of calix[4]arene

A benzimidazole appended triazole linked 1,3-diconjugate of calix[4]arene (L) has been synthesized and characterized. The conjugate L has been found to recognize Cu2+ among the thirteen different metal ions studied by exhibiting ratiometric fluorescence changes through newly generated excimer band at ∼380 nm. Fluorescence off–on–off behavior has been clearly demonstrated on the basis of the binding variability of Cu2+ to L. The binding has been elicited through the changes observed in the fluorescence, ESI MS and 1H NMR titrations. All the other metal ions studied do not show any new band and further do not interfere with the recognition of Cu2+ by L, even when these are present in the same medium. The structural features of both the mono- and di-nuclear complexes were established by DFT computational calculations and found to display highly distorted geometry about the copper centers that deviate from both the tetrahedral and the square planar

Interaction of a dinuclear fluorescent Cd(II) complex of calix[4]arene conjugate with phosphates and its applicability in cell imaging

A triazole-linked hydroxyethylimino conjugate of calix[4]arene (L) and its cadmium complex have been synthesized and characterized, and their structures have been established. In the complex, both the Cd²⁺ centers are bound by an N₂O₄ core, and one of it is a distorted octahedral, whereas the other is a trigonal anti-prism. The fluorescence intensity of the di-nuclear Cd(II) complex is quenched only in the presence of phosphates and not with other anions studied owing to their binding affinities and the nature of the interaction of the phosphates with Cd²⁺. These are evident even from their absorption spectra. Different phosphates exhibit changes in both their fluorescence as well as absorption spectra to varying extents, suggesting their differential interactions. Among the six phosphates, H₂PO₄⁴⁻ has higher fluorescence quenching even at low equivalents of this ion, whereas P₂O₇⁴⁻ shows only 50% quenching even at 10 equivalents. The fluorescence quenching is considerable even at 20 ppb (0.2 μM) of H₂PO₄⁻, whereas all other phosphates require a concentration of 50–580 ppb to exhibit the same effect on fluorescence spectra. Thus, the interaction of H₂PO₄⁻ is more effective by ∼30 fold as compared to that of P₂O₇⁴⁻. Fluorescence quenching by phosphate is due to the release of L from its original cadmium complex via the formation of a ternary species followed by the capture of Cd²⁺ by the phosphate, as delineated based on the combination of spectral techniques, such as absorption, emission, ¹H NMR and ESI MS. The relative interactive abilities of the six phosphates differ from each other. The removal of Cd²⁺ is demonstrated to be reversible by the repeated addition of the phosphate followed by Cd²⁺. The characteristics of the ternary species formed in each of these six phosphates have been computationally modeled using molecular mechanics. The computational study revealed that the coordination between cadmium and –CH₂–CH₂–OH breaks and new coordination is established through the phosphate oxygens, and as a result the Cd²⁺ center acquires a distorted octahedral geometry. The utility of the complex was demonstrated in HeLa cells

Selective recognition of cysteine in its free and protein-bound states by the Zn<SUP>2+</SUP> complex of a triazole-based calix[4]arene conjugate

Zinc-ed in: A highly fluorescent zinc complex of triazole-linked calix[4]arene (see scheme), [ZnL], for the selective recognition of Cys and other protein-bound/free thiols in the blood-serum milieu by mimicking the Zn<SUP>2+</SUP>-induced redox switch has been developed

Structural comparisons of the binding cores formed by 1,3-di-Amide derivatives of p-tert-Butylcalix[4]arene: arms stabilization through Intra-molecular interactions including N-H***O, O-H***Cl and π***Cl types

his paper deals with the development of a receptor with selectively functionalized at the lower rim of p-tert-butyl calix[4]arene linked through amide bond, resulting in the diamide derivatives (L 1 , L 2 and L 3 ) suitable for sensing ions and molecules. All the derivatives were thoroughly characterized by analytical and spectral methods. These derivatives were structurally characterized by single crystal X-ray diffraction and the conformational features of the calix[4]arene as well as the pendants are discussed. The L 1 and L 2 exhibited intramolecular hydrogen bond interaction between the N-H and the lower rim phenolic oxygen in addition to the circular hydrogen bonding between the phenolic O-H and the ether oxygen of the adjacent strand. The corresponding H-bond is absent when no 'H' is present on amide-N as in case of L 3 . Such intramolecular N-H***O interactions observed with the pendant results in a conformational bend responsible for the orientation of the arms and there by the nature of the binding core formed. Thus the binding cores formed differ largely between L 3 and the other two

Phenylene-Diimine-Capped Conjugate of Lower Rim 1,3-Calix[4]Arene As Molecular Receptor for Mg²⁺ via Arm Conformational Changes Followed by Aggregation and Mimicking the Species by Molecular Mechanics

A phenylene-diimine-capped conjugate of lower rim 1,3-calix[4]­arene (<b>L</b>) was synthesized, characterized, and shown to selectively bind to Mg²⁺ using its capped arms. This results in a selective recognition of Mg²⁺ through eliciting fluorescence enhancement of ∼70 fold with a detection limit of 40 ± 5 ppb. However, in the presence of blood serum, the lowest detection limit is 209 ± 10 ppb (0.2 μM). The binding of Mg²⁺ to <b>L</b> is authenticated by absorption and ¹H NMR data. The Job’s plot derived on the basis of the absorption data showed 1:1 stoichiometry between the receptor and Mg²⁺. The 1:1 species was further confirmed through ESI MS, that is, being supported by the isotope peak pattern authenticating the presence of Mg²⁺ in the complex. The <b>L</b> binds Mg²⁺ octahedrally using the tetradentate <b>L</b>^2– and two additional acetic acid moieties by bringing conformational changes as studied on the basis of MM computations. The conformational changes that occur in the capped arms upon Mg²⁺ binding were supported experimentally by NOESY. AFM and SEM studies showed that spherical particles of <b>L</b> are modified into flower and chain type aggregates upon complexation with Mg²⁺, confirming the supramolecular behavior of the species formed

Fluorescence and piezoresistive cantilever sensing of trinitrotoluene by an upper rim tetra-benzimidazole conjugate of calix[4]arene and the delineation of the features of the complex by molecular dynamics

A new benzimidazole-functionalized calix[4]arene receptor (R) was synthesized and characterized. The receptor R shows better selectivity toward trinitrotoluene (TNT) compared to the other nitro explosives in solution, which also retains its effectiveness for solid-phase detection. The chemical interactions of the molecule with different nitro explosive analytes were studied by fluorescence spectroscopy and by a molecular dynamics approach. The molecular dynamics studies show a 1:3 complex between R and TNT, and hence high sensitivity was imparted by fluorescence studies. The detection of explosive vapors in ambient conditions was tested by using a sensitive coating layer of R on an SU-8/CB-based piezoresistive cantilever surface. The developed device showed large sensitivity toward TNT compared to cyclotrimethylenetrinitramine (RDX) and pentaerythritol tetranitrate (PETN) in the solid state at their respective vapor pressures at room temperature. The detection sensitivity of the device was estimated to be 35 mV for TNT at ambient conditions. Moreover, the sensor does not show a response when exposed to humidity. These results demonstrate that R can be used as one of the coating materials for a cantilever for the detection of TNT using piezoresistivity measurement. R can also detect the explosives in solution with high sensitivity and selectivity by fluorescence spectroscopy