Synthesis, spectroscopic, thermal characterization, and antimicrobial activity of miconazole drug and its metal complexes

Metal complexes having the general composition [MCl₂(H₂O)₂(L)₂]·yH₂O (where y?=?1?C3, M?=?Mn(II), Cu(II), Co(II), Ni(II), and Zn(II) and L?=?miconazole drug?=?MCNZ) and [MCl₂(H₂O)₂(L)₂]Cl·3H₂O (where M?=?Cr(III) and Fe(III)) have been synthesized. All the synthesized complexes were identified and confirmed by elemental analyses, IR, diffused reflectance, and thermal analyses (TG and DTA) techniques as well as molar conductivity and magnetic moment measurements. The molar conductance data reveals that bivalent metal complexes are non-electrolytes while Cr(III) and Fe(III) complexes are electrolytes and of 1:1 type. IR spectral studies reveal that MCNZ is coordinated to the metal ions in a neutral unidentate manner with N donor site of the imidazole-N. On the basis of magnetic and solid reflectance spectral studies, an octahedral geometry has been assigned for the complexes. Detailed studies of the thermal properties of the complexes were investigated by thermogravimetry (TG) and differential thermal analyses (DTA) techniques and the activation thermodynamic parameters are calculated using Coats?CRedfern method. The free MCNZ drug and its complexes were also evaluated against bacterial species (P. aeruginosa, S. aureus, B. subtilis, E. Coli) and fungi (A. fumigatus, P. italicum, and C. albicans) in vitro. The activity data show that the metal complexes have higher biological activity than the parent MCNZ drug.     

Spectrofluorimetric and Spectrophotometric Stability‐Indicating Methods for the Analysis of Veralipride in Presence of Its Degradants and in Spiked Human Plasma

Spectrofluorimetric and spectrophotometric stability‐indicating methods were developed and validated for analysis of veralipride (Ver) in presence of its hydrolytic and oxidative degradants. The spectrofluorimetric method was based on direct measurement of the intrinsic fluorescence of Ver at 366 nm after excitation at 299 nm using sodium lauryl sulfate (SLS) as micelle enhancer. The fluorescence intensity plot was linear over the concentration range 1.0–10.0 µg·mL^?1. The high sensitivity of the method allowed its successful application to the analysis of Ver in spiked human plasma. Two other methods were developed. They are based on the oxidative coupling reaction of Ver with 3‐methyl benzothiazolin‐2‐one hydrazone (MBTH) hydrochloride in presence of ceric ammonium sulphate in an acidic medium. The first method depends on spectrophotometric measurement of the stable green colored oxidative coupling product at 660 nm. The different experimental parameters affecting the reaction were optimized. Linearity range is 10.0–100.0 µg·mL^?1. The second method depends on a fluorescence quenching effect of Ver on the fluorescence of Ce³⁺. The difference in fluorescence intensity was measured at 380 nm after excitation at 300 nm. This method is applicable over the concentration ranges 0.25–2.50 µg·mL^?1. The methods were validated according to the ICH guidelines. They were successfully applied for the analysis of Ver in drug substance, drug product and in laboratory prepared mixtures containing different percentages of hydrolytic and oxidative degradants.     

Formation of dioxospiroindene[1,3]thiazine and thioxoindeno[2,1-<Emphasis Type="Italic">d</Emphasis>]imidazolone derivatives from alkenylidene-hydrazinecarbothioamides

The reaction of (substituted) alkenylidene-hydrazinecarbothioamides with 2-(1,3-dioxo-2,3-dihydro-1H-inden-2-ylidene)propanedinitrile led to the formation of 1,3-dioxospiroindene[1,3]-thiazine and thioxoindeno[2,1-d]imidazolone derivatives in modest yields. In addition, 1,3-dihydroxyindan-2-ylidenepropanedinitrile was found. Explanations of these conversions involving nucleophilic reactions and condensations are presented.     

Design of Drug Efficacy Guided by Free Energy Simulations of the β2-Adrenoceptor

G-protein-coupled receptors (GPCRs) play important roles in physiological processes and are modulated by drugs that either activate or block signaling. Rational design of the pharmacological efficacy profiles of GPCR ligands could enable the development of more efficient drugs, but is challenging even if high-resolution receptor structures are available. We performed molecular dynamics simulations of the β₂ adrenergic receptor in active and inactive conformations to assess if binding free energy calculations can predict differences in ligand efficacy for closely related compounds. Previously identified ligands were successfully classified into groups with comparable efficacy profiles based on the calculated shift in ligand affinity upon activation. A series of ligands were then predicted and synthesized, leading to the discovery of partial agonists with nanomolar potencies and novel scaffolds. Our results demonstrate that free energy simulations enable design of ligand efficacy and the same approach can be applied to other GPCR drug targets.     

Bimetallic Anionic Organic Frameworks with Solid-State Cation Conduction for Charge Storage Applications

A new phosphonate-based anionic bimetallic organic framework, with the general formula of A₄−Zn−DOBDP (wherein A is Li⁺ or Na⁺, and DOBDP⁶⁻ is the 2,5-dioxido-1,4-benzenediphosphate ligand) is prepared and characterized for energy storage applications. With four alkali cations per formula unit, the A₄−Zn−DOBDP MOF is found to be the first example of non-solvated cation conducting MOF with measured conductivities of 5.4×10⁻⁸ S cm⁻¹ and 3.4×10⁻⁸ S cm⁻¹ for Li₄- and Na₄- phases, indicating phase and composition effects of Li⁺ and Na⁺ shuttling through the channels. Three orders of magnitude increase in ionic conductivity is further attained upon solvation with propylene carbonate, placing this system among the best MOF ionic conductors at room temperature. As positive electrode material, Li₄−Zn−DOBDP delivers a specific capacity of 140 mAh g⁻¹ at a high average discharge potential of 3.2 V (vs. Li⁺/Li) with 90 % of capacity retention over 100 cycles. The significance of this research extends from the development of a new family of electroactive phosphonate-based MOFs with inherent ionic conductivity and reversible cation storage, to providing elementary insights into the development of highly sought yet still evasive MOFs with mixed-ion and electron conduction for energy storage applications.     

Supramolecular Thermotropic Liquid Crystalline Materials with Nematic Mesophase Based on Methylated Hyperbranched Polyethylenimine and Mesogenic Carboxylic Acid

Summary: Supramolecular interaction of fully methylated hyperbranched polyethylenimines (PEI) with a mesogen‐based carboxylic acid, 5‐(p‐cyanobiphenoxy)pentanoic acid, results in the formation of supramolecular complexes exhibiting thermotropic liquid crystalline (LC) mesophases. In contrast to the common smectic mesophases of most dendritic LC polymers, nematic LC phases were observed. The complexation of PEI and the mesogen units is due to electrostatic interaction between the carboxylate groups and the ammonium end groups of PEI. LC properties were investigated by a combination of differential scanning calorimetry, polarizing light optical microscopy, and X‐ray diffractometry.

Schematic illustration of the supramolecular assembly of CBPA with PEIMe backbone.