Petra,Osiris, and Molinspiration Together as a Guide in Drug Design: Predictions and Correlation Structure/Antibacterial Activity Relationships of New N-Sulfonyl Monocyclic β-Lactams

We report in this article the design and calculated molecular properties of 18 new mono-cyclic β-lactams 4–21, on the basis of one hypothetical antibacterial pharmacophore structure designed to interact with both of Gram-positive bacteria and Gram-negative bacteria. The in vitro biological evaluation of these compounds allowed us to point out new potential non-nucleoside hits, with MIC values in the range of 2–8 μg/mL active against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. A correlation structure/antibacterial activities relationship of these monocyclic β-lactams is described.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Microbial Screening of Copolymers of N‐Vinylimidazole with Phenacyl Methacrylate: Synthesis and Monomer Reactivity Ratios

N‐vinylimidazole (VIM), and phenacyl methacrylate (PAMA) copolymerized with different feed ratios using 1,4‐dioxane as a solvent and α,α'‐azobisisobutyronitrile (AIBN) as an initiator at 60°C. Structure and composition of copolymers for a wide range of monomer feed were determined by elemental analysis (content of N for VIM‐units) and by Fourier transform infrared spectroscopy through recorded analytical absorption bands for VIM (670 cm^?1 for C‐N of imidazole ring) and PAMA (1730 cm^?1 for C?O of ester group) units, respectively. Monomer reactivity ratios for VIM (M₁)‐PAMA (M₂) pair were determined by the application of conventional linearization methods such as Fineman‐Ross (F‐R) and Kelen‐Tüdös (KT) and a nonlinear error invariable model method using a computer program RREVM. The molecular weights (_w and _n) and polydispersity indices of the polymers were determined using gel permeation chromatography (GPC). Thermal behaviors of copolymers with various compositions were investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Also, the apparent thermal decomposition activation energies (ΔE_d) were calculated by Ozawa method using the SETARAM Labsys TGA thermobalance. The antibacterial and antifungal effects of polymers were also tested on various bacteria, fungi and yeast.     

Identification of potential HIV-1 integrase strand transfer inhibitors: In silico virtual screening and QM/MM docking studies

HIV-1 integrase (IN) is a retroviral enzyme that catalyses integration of the reverse-transcribed viral DNA into the host genome, which is necessary for efficient viral replication. In this study, we have performed an in silico virtual screening for the identification of potential HIV-1 IN strand transfer (ST) inhibitors. Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to 3-Hydroxypyrimidine-2,4-diones. Based on the ligand-based pharmacophore model, we obtained a five-point pharmacophore with two hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic group (H) and one aromatic ring (R) as pharmacophoric features. The pharmacophore hypothesis AADHR was used as a 3D query in a sequential virtual screening study to filter small molecule databases Maybridge, ChemBridge and Asinex. Hits matching with pharmacophore hypothesis AADHR were retrieved and passed progressively through Lipinski’s rule of five filtering, molecular docking and hierarchical clustering. The five compounds with best hits with novel and diverse chemotypes were subjected to QM/MM docking, which showed improved docking accuracy. We further performed molecular dynamics simulation and found three compounds that form stable interactions with key residues. These compounds could be used as a leads for further drug development and rational design of HIV-1 IN inhibitors.     

Theory of docking scores and its application to a customizable scoring function

In general, the docking scoring tends to have a size dependence related to the ranking of compounds. In this paper, we describe a novel method of parameter optimization for docking scores which reduce the size dependence and can efficiently discriminate active compounds from chemical databases. This method is based on a simplified theoretical model of docking scores which enables us to utilize large amounts of data of known active and inactive compounds for a particular target without requiring large computational resources or a complicated procedure. This method is useful for making scoring functions for the identification of novel scaffolds using the knowledge of active compounds for a particular target or a customized scoring function for an interesting family of drug targets.     

Pharmacophore modelling,molecular docking and virtual screening for EGFR (HER 1) tyrosine kinase inhibitors

A pharmacophore model has been developed using diverse classes of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitors useful in the treatment of human tumours. Among the top 10 generated hypotheses, the second hypothesis, with one hydrogen bond acceptor, one ring aromatic and three hydrophobic features, was found to be the best on the basis of Cat Scramble validation as well as test set prediction (r _training?=?0.89, r _test?=?0.82). The model also maps well to the external test set molecules as well as clinically active molecules and corroborates the docking studies. Finally, 10 hits were identified as potential leads after virtual screening of ZINC database for EGFR TK inhibition. The study may facilitate the designing and discovery of novel EGFR TK inhibitors.     

Synthesis,characterization and antimicrobial activities of copper complexes derived from 4-aminoantipyrine derivatives

Cu(II) complexes have been synthesized from the Schiff base ligands derived from furfurlyidene-4-aminoantipyrine and aniline (L¹)/p-nitroaniline (L²)/p-hydroxyaniline (L³). They were characterized using analytical and spectral techniques. All the Cu(II) complexes exhibit square planar geometry. The X-band ESR spectra of the copper complexes in DMSO solution at 300 and 77 K were recorded and their salient features are reported. The in vitro biological screening effects of the investigated compounds were tested against the bacterial species, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris and Pseudomonas aeruginosa and fungal species, Aspergillus niger, Rhizopus stolonifer, Aspergillus flavus, Rhizoctonia bataicola and Candida albicans by serial dilution method. A comparative study of inhibition values of the Schiff base ligands and their complexes indicate that the complexes exhibit higher antimicrobial activity than the Schiff base ligands. Superoxide dismutase and reducing power activities of the copper complexes have also been studied. Depending on the molecular structure, the [CuL²(OAc)₂] complex possess promising SOD mimetic activities.     

Palladium-catalyzed hydrodehalogenation of aryl halides using paraformaldehyde as the hydride source: high-throughput screening by paper-based colorimetric iodide sensor

Paraformaldehyde was employed as a hydride source in the palladium-catalyzed hydrodehalogenation of aryl iodides and bromides. High throughput screening using a paper-based colorimetric iodide sensor (PBCIS) showed that Pd(OAc)₂ and Cs₂CO₃ were the best catalyst and base, respectively. Aryl iodides and bromides were hydrodehalogenated to produce the reduced arenes using Pd(OAc)₂ and Pd(PPh₃)₄ catalyst. This catalytic system showed good functional group tolerance. In addition, it was found that paraformaldehyde is the hydride source and the reducing agent for the formation of palladium nanoparticles.     

Bismuth Tri‐ and Tetraarylcarboxylates: Crystal Structures,In Situ X‐ray Diffraction,Intermediates and Luminescence

A systematic investigation of the systems Bi³⁺/carboxylic acid/HNO₃ for the tri‐ and tetracarboxylic acids pyromellitic acid (H₄Pyr), trimellitic acid (H₃Tri) and trimesic acid (H₃BTC) acid led to the discovery of five new bismuth carboxylates. Structural characterisation allowed the influence of the linker geometry and the Bi³⁺:linker molar ratio in the starting solution on the crystal structure to be determined. The crystallisation of three selected compounds was investigated by in situ energy‐dispersive X‐ray diffraction. Three new crystalline intermediates were observed within minutes, and two of them could be isolated by quenching of the reaction mixture. Their crystal structures were determined from laboratory and synchrotron X‐ray powder diffraction data and allowed a possible reaction pathway to be established. In depth characterisation of the luminescence properties of the three bismuth pyromellate compounds was carried out. Fluorescence and phosphorescence could be assigned to (mainly) ligand‐ and metal‐based transitions. The polymorphs of Bi(HPyr) exhibit different luminescence properties, although their structures are very similar. Surprisingly, doping of the three host structures with Eu³⁺ and Tb³⁺ ions was only successful for one of the polymorphs.     

Rapid determination of enantiomeric excess of α-chiral aldehydes using circular dichroism spectroscopy

A method for enantiodiscrimination of α-chiral aldehydes is reported. The method utilizes circular dichroism (CD) spectroscopy and a sensing ensemble composed of 2-(1-methylhydrazinyl) pyridine (1) and Fe(II)(TfO)₂. Aldehydes react rapidly with hydrazine (1) to form chiral imines, which form complexes with Fe(II). By monitoring the CD bands above 320 nm, one can determine the enantiomeric excess (ee) values of α-chiral aldehydes with an average absolute error of ±5%. The analysis was fast, and thus can have potential applications in high-throughput screening (HTS) of catalytic asymmetric induction.     

Conductor‐like screening model for relaxed excited states: Implementation in the semiempirical method MSINDO

Two approaches to treat solvent polarization and reorientation effects for excited states of molecules and surfaces have been implemented in the recently developed MSINDO‐sCIS method (Gadaczek, Krause, Hintze, Bredow, J. Chem. Theory Comput. 2011, 7, 3675). They allow for an efficient calculation of analytical energy gradients and hence open the opportunity to investigate fluorescence effects or photochemical reactions in solution for large molecules that are difficult to treat with high‐level methods. Both approaches are based on the conductor‐like screening model (COSMO) (Klamt and Schüürmann, J. Chem. Soc., Perkin Trans. 1993, 2, 799) in combination with the configuration interaction singles (CIS) method (Foresman, Head‐Gordon, Pople, and Frisch, J. Phys. Chem. 1992, 96, 135). The paper gives a brief outline of the theoretical background. As a first application, solvent shifts of three well‐studied, environment‐sensitive fluorescent dyes (Kucherak, Didier, Mély, and Klymchenko, J. Phys. Chem. Lett. 2010, 1, 616) have been calculated and compared with experimental results and standard time‐dependent density functional theory. A statistical evaluation of MSINDO‐COSMO‐sCIS is provided for a set of 39 molecules suggested recently by Jacquemin et al. (Jacquemin, Planchat, Adamo, and Mennucci, J. Chem. Theory Comput. 2012, 8, 2359). Calculated vertical and adiabatic excitation energies and fluorescence energies are compared to experimental data. © 2014 Wiley Periodicals, Inc.