Mechanochemically-Assisted Passerini Reactions: A Practical and Convenient Method for the Synthesis of Novel α-Acyloxycarboxamide Derivatives.

A carboxylic acid, an aldehyde, and an isonitrile were combined in a single step (Passerini reaction) under mechanochemical activation to produce several α-acyloxycarboxamide derivatives in high to excellent yields within 15 min of milling. Mechanochemistry, when combined with the diversity provided by multicomponent reactions, enables the efficient synthesis of the target compounds, with great atom economy, shorter reaction times, and experimental simplicity. The method allows for the rapid production of a vast library of complex compounds from a limited number of substrates.

N-Formamide as a carbonyl precursor in the catalytic synthesis of Passerini adducts under aqua and mechanochemical conditions.

A new simple, efficient, and environmentally friendly protocol is presented for the catalytic synthesis of α-acyloxycarboxamides using N-formamides as a carbonyl precursor under aqua and mechanochemical conditions. Immobilized sulfuric acid on silica gel was employed for the synthesis of desired products, via the reaction of benzoic acid, 1-napthylisocyanide and various heterocyclic N-formamides. After a careful optimization of the reaction conditions, the desired Passerini products were obtained in high to excellent yields in short reaction times (10-30 min) at room temperature. The highly efficient and environmentally friendly method provides a facile access to a library of α-acyloxycarboxamides derivatives for future research on bioactivity screening.

Aqua/Mechanochemical Mediated Synthesis of Novel Spiro [Indole-Pyrrolidine] Derivatives.

Spirocyclic scaffolds are found in many pharmacologically active natural and synthetic compounds. From time to time, efforts have been made to develop new or better processes for the synthesis of spirocyclic compounds. Spiro [Indole-pyrrolidine] Derivatives are readily synthesized in high to excellent yields by the Michael condensation of 3-dicyanomethylene-2H-indol-2-ones (produced via the Knoevenagel condensation of indole-2,3-dione with malononitrile) with isothiocyanate derivatives under aqueous and mechanochemical conditions. The advantages of this protocol are that the reactions are solvent-free, occur at ambient temperature, require short reaction times, have experimental simplicity, and produce excellent yields. These environmentally friendly reaction media are useful alternatives to volatile organic solvents.

High Pressure In Situ Single-Crystal X-Ray Diffraction Reveals Turnstile Linker Rotation Upon Room-Temperature Stepped Uptake of Alkanes.

The rare availability of suitable single-crystal X-ray diffraction (SCXRD) structural data allows for the direct interpretation of the response of a framework to gas sorption and may lead to the development of improved functional porous materials. We report an in situ SCXRD structural investigation of a flexible MOF subjected to methane, ethane, propane, and butane gas pressures. Supporting theoretical investigations indicate weak host-guest interactions for the crystallographically modelled gaseous guests and, in addition, reveal that a turnstile mechanism facilitates the transport of alkanes through the seemingly nonporous system. Inflections present in the adsorption isotherms are furthermore rationalized as due to gate-opening, but without the expected creation of new accessible space.

Nano Co-Crystal Embedded Stimuli-Responsive Hydrogels: A Potential Approach to Treat HIV/AIDS.

Currently, the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS) can only be treated successfully, using combination antiretroviral (ARV) therapy. Lamivudine (3TC) and zidovudine (AZT), two compounds used for the treatment of HIV and prevention of disease progression to AIDS are used in such combinations. Successful therapy with 3TC and AZT requires frequent dosing that may lead to reduced adherence, resistance and consequently treatment failure. Improved toxicity profiles of 3TC and AZT were observed when combined as a nano co-crystal (NCC). The use of stimuli-responsive delivery systems provides an opportunity to overcome the challenge of frequent dosing, by controlling and/or sustaining delivery of drugs. Preliminary studies undertaken to identify a suitable composition for a stimulus-responsive in situ forming hydrogel carrier for 3TC-AZT NCC were conducted, and the gelation and erosion time were determined. A 25% w/w Pluronic® F-127 thermoresponsive hydrogel was identified as a suitable carrier as it exhibited a gelation time of 5 min and an erosion time of 7 days. NCC-loaded hydrogels were evaluated using in vitro dissolution and cytotoxicity assays. In vitro dissolution undertaken using membrane-less diffusion over 168 h revealed that 3TC and AZT release from NCC-loaded hydrogels was complete and followed zero-order kinetic processes, whereas those loaded with the micro co-crystal and physical mixture were incomplete and best described using the Korsmeyer-Peppas kinetic model. The release of AZT and 3TC from the physical mixture and MCC-loaded gel exhibited a value for n of 0.595 for AZT release from the physical mixture and 0.540 for the MCC technology, whereas the release exponent for 3TC was 0.513 for the physical mixture and 0.557 for the MCC technology indicating that diffusion and erosion controlled 3TC and AZT release. In vitro cytotoxicity assay data revealed that the addition of NCC to the thermoresponsive hydrogel resulted in an improved cell viability of 88.0% ± 5.0% when compared to the cell viability of the NCC of 76.9% ± 5.0%. The results suggest that the use of a thermoresponsive nanosuspension may have the potential to be delivered as an intramuscular injection that can subsequently increase bioavailability and permit dose reduction and/or permit use of a longer dosing frequency.

Quality by Design Optimization of Cold Sonochemical Synthesis of Zidovudine-Lamivudine Nanosuspensions.

Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium dodecyl sulphate (SDS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) to electrosterically stablize the nano co-crystals was used to develop, produce and optimize 3TC and AZT nano co-crystals. Equimolar solutions of 3TC in surfactant dissolved in de-ionised water and AZT in methanol were rapidly injected into a vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer and the particle size, polydispersity index and Zeta potential determined. Optimization of the nanosuspensions was conducted using a Central Composite Design to produce nano co-crystals with specific identified and desirable Critical Quality Attributes including particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < -30mV. Further characterization was undertaken using Fourier Transform infrared spectroscopy, energy dispersive X-ray spectroscopy, differential scanning calorimetry, powder X-ray diffraction and transmission electron microscopy. In vitro cytotoxicity studies revealed that the optimized nano co-crystals reduced the toxicity of AZT and 3TC to HeLa cells.

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives.

With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC50 values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic.

A Comparative Study of the Effect of Different Stabilizers on the Critical Quality Attributes of Self-Assembling Nano Co-Crystals.

Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol were rapidly injected into a pre-cooled vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer. The particle size, polydispersity index and Zeta potential were elucidated. Further characterization was undertaken using powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and energy dispersive X-ray spectroscopy scanning electron microscopy. Different surfactants were assessed for their ability to stabilize the nano co-crystals and for their ability to produce nano co-crystals with specific and desirable critical quality attributes (CQA) including particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < -30 mV. All surfactants produced co-crystals in the nanometer range. The PDI and PS are concentration-dependent for all nano co-crystals manufactured while only ZP was within specification when sodium dodecyl sulfate was used in the process.

Direct Determination of Enthalpies of Sorption Using Pressure-Gradient Differential Scanning Calorimetry: CO2 Sorption by Cu-HKUST.

Enthalpy of sorption (ΔH) is an important parameter for the design of separation processes using adsorptive materials. A pressure-ramped calorimetric method is described and tested for the direct determination of ΔH values. Combining a heatflow thermogram with a single sorption isotherm enables the determination of ΔH as a function of loading. The method is validated by studying CO2 sorption by the well-studied metal-organic framework Cu-HKUST over a temperature range of 288-318 K. The measured ΔH values compare well with previously reported data determined by using isosteric and calorimetric methods. The pressure-gradient differential scanning calorimetry (PGDSC) method produces reliable high-resolution results by direct measurement of the enthalpy changes during the sorption processes. Additionally, PGDSC is less labor-intensive and time-consuming than the isosteric method and offers detailed insight into how ΔH changes over a given loading range.

Correction: A combined stretching-tilting mechanism produces negative, zero and positive linear thermal expansion in a semi-flexible Cd(ii)-MOF.

Correction for 'A combined stretching-tilting mechanism produces negative, zero and positive linear thermal expansion in a semi-flexible Cd(ii)-MOF' by Prem Lama et al., Chem. Commun., 2014, 50, 6464-6467.

Reversible thermosalience of 4-aminobenzonitrile.

Crystals of 4-aminobenzonitrile grown by sublimation undergo reversible thermosalient phase changes during cooling and subsequent heating. Single-crystal diffraction studies have been carried out at 20 K intervals during cooling from 300 to 100 K in order to explain the structural change that occurs.

Hand-twistable plastically deformable crystals of a rigid small organic molecule.

4-Bromobenzonitrile was crystallised by sublimation under vacuum. The crystals show highly flexible plastic bending along two perpendicular faces when a mechanical force is applied. The rare occurrence of bending along two perpendicular faces results in twisting or helix formation.

Solvent- and Pressure-Induced Phase Changes in Two 3D Copper Glutarate-Based Metal-Organic Frameworks via Glutarate (+gauche ⇄ -gauche) Conformational Isomerism.

Two isoreticular three-dimensional copper(II) glutarate-based pillared-layered metal-organic frameworks (MOFs) with flexible pillars, [Cu2(glu)2(bpa)] and [Cu2(glu)2(bpp)] (bpa = 1,2-bis(4-pyridyl)ethane; bpp = 1,3-bis(4-pyridyl)propane), undergo spontaneous phase changes upon solvent loss at room temperature. Using single-crystal X-ray diffraction analysis (SCXRD), we show that the phase changes result in new narrow-channel forms that experience a large reduction in solvent-accessible volume. Moreover, the [Cu2(glu)2(bpa)] MOF displays a stepped sorption isotherm for the uptake of CO2 at room temperature. This is indicative of reversion of the framework to the wide-channel form under CO2 pressure. Supercritical CO2 was used to isolate the gas-included structures, and by means of SCXRD we were able to determine the positions of the CO2 molecules in the channels of the frameworks. Finally, we report the use of molecular modeling simulations to elucidate the phase-change mechanism, including the energetic changes involved. Structural limitations in both MOFs allow for only direct gauche-gauche enantiomeric interconversion of the glutarate moieties.

Creation of new guest accessible space under gas pressure in a flexible MOF: multidimensional insight through combination of in situ techniques.

Metal-organic frameworks (MOFs) are an important class of porous materials with numerous potential applications. Molecular level understanding of various processes involving MOFs is very important in order to design porous materials with improved properties. Here we describe the elucidation by means of single-crystal X-ray diffraction (SCD) of three different phases of Zn2(bdc)2(bpy) at different pressures of CO2. Moreover, this is a rare example where new space is created in the structure under gas pressure - space that was not previously occupied by guest molecules in any of the related structures. In addition to in situ SCD and sorption analysis, pressure-gradient differential scanning calorimetry (PG-DSC) provides very useful information about the system. This study represents the first instance where PG-DSC has been used to study the sorption behavior of a flexible porous framework.

Solid-State Conformational Flexibility at Work: Zipping and Unzipping within a Cyclic Peptoid Single Crystal.

A peptidomimetic compound undergoes a reversible single-crystal-to-single-crystal transformation upon guest release/uptake with the transformation involving a drastic conformational change. The extensive and reversible alteration in the solid state is connected to the formation of an unprecedented "CH-π zipper" which can reversibly open and close (through the formation of CH-π interactions), thus allowing for guest sensing.

Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents.

7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50 : 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50 : 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against ß-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 µm.

Giant Negative Area Compressibility Tunable in a Soft Porous Framework Material.

A soft porous material [Zn(L)2(OH)2]n·Guest (where L is 4-(1H-naphtho[2,3-d]imidazol-1-yl)benzoate, and Guest is water or methanol) exhibits the strongest ever observed negative area compressibility (NAC), an extremely rare property, as at hydrostatic pressure most materials shrink in all directions and few expand in one direction. This is the first NAC reported in metal-organic frameworks (MOFs), and its magnitude, clearly visible and by far the highest of all known materials, can be reversibly tuned by exchanging guests adsorbed from hydrostatic fluids. This counterintuitive strong NAC of [Zn(L)2(OH)2]n·Guest arises from the interplay of flexible [-Zn-O(H)-]n helices with layers of [-Zn-L-]4 quadrangular puckered rings comprising large channel voids. The compression of helices and flattening of puckered rings combine to give a giant piezo-mechanical response, applicable in ultrasensitive sensors and actuators. The extrinsic NAC response to different hydrostatic fluids is due to varied host-guest interactions affecting the mechanical strain within the range permitted by exceptionally high flexibility of the framework.

Extreme carbon dioxide sorption hysteresis in open-channel rigid metal-organic frameworks.

A systematic study is presented of three closely related microporous metal-organic frameworks the pore dimensions of which vary according to the choice of 4,4'-bipyridyl linker. The tunable linker allows exploration of the effect of increasing pore dimensions on the sorption behavior of the frameworks. The MOFs described capture CO2 under supercritical conditions and continue to sequester the gas under ambient conditions. Gas sorption isotherms for CO2 are compared with thermogravimetric data, and the CO2 molecules in the channels of the frameworks could be modeled using single-crystal X-ray diffraction analysis. Crystallographic data were used to construct a theoretical model based on DFT methods to calculate framework electrostatic potential maps with a view to understanding the nature of the sorbate-sorbent interactions.

Inclusion complexes of 2-methoxyestradiol with dimethylated and permethylated ß-cyclodextrins: models for cyclodextrin-steroid interaction.

The interaction between the potent anticancer agent 2-methoxyestradiol (2ME) and a series of cyclodextrins (CDs) was investigated in the solid state using thermal analysis and X-ray diffraction, while the possibility of enhancing its poor aqueous solubility with CDs was probed by means of equilibrium solubility and dissolution rate measurements. Single crystal X-ray diffraction studies of the inclusion complexes between 2ME and the derivatised cyclodextrins heptakis(2,6-di-O-methyl)-ß-CD (DIMEB) and heptakis(2,3,6-tri-O-methyl)-ß-CD (TRIMEB) revealed for the first time the nature of the encapsulation of a bioactive steroid by representative CD host molecules. Inclusion complexation invariably involves insertion of the D-ring of 2ME from the secondary side of each CD molecule, with the 17-OH group generally hydrogen bonding to a host glycosidic oxygen atom within the CD cavity, while the A-ring and part of the B-ring of 2ME protrude from the secondary side. In the case of the TRIMEB·2ME complex, there is evidence that complexation proceeds with mutual conformational adaptation of host and guest molecules. The aqueous solubility of 2ME was significantly enhanced by CDs, with DIMEB, TRIMEB, randomly methylated ß-CD and hydroxypropyl-ß-CD being the most effective hosts. The 2:1 host-guest ß-CD inclusion complex, prepared by two methods, yielded very rapid dissolution in water at 37 °C relative to untreated 2ME, attaining complete dissolution within 15 minutes (co-precipitated complex) and 45 minutes (complex from kneading).

A combined stretching-tilting mechanism produces negative, zero and positive linear thermal expansion in a semi-flexible Cd(II)-MOF.

A novel semi-flexible Cd(II)-MOF has been synthesized and characterized by variable temperature powder and single-crystal X-ray diffraction. The material displays an unusual combination of thermal expansion (TE) i.e. negative, zero and positive, which is an extremely rare finding, especially for metal-organic frameworks as a result of a combined stretching-tilting mechanism.