Four phthalazinones (CIDs 22334057, 22333974, 22334032, 22334012) and one isoquinolone (CID 5224943) were previously shown to be potent enhancers of antifungal activity of fluconazole against Candida albicans. Several even more potent analogues of these compounds were identified, some with EC 50 as low as 1 nM, against C. albicans. The compounds exhibited pharmacological synergy (FIC < 0.5) with fluconazole. The compounds were also shown to enhance the antifungal activity of isavuconazole, a recently FDA approved azole antifungal. Isoquinolone 15 and phthalazinone 24 were shown to be active against several resistant clinical isolates of C. albicans. KEYWORDS: Candida albicans, antifungal agents, fluconazole, synergy, phthalazinone, isoquinolone A zoles continue to be the drug of choice for many types of invasive fungal infections, acting on a key enzyme, sterol 14α-demethylase, in the ergosterol biosynthesis pathway. The azole family of antifungals has evolved continuously since the initial introduction of ketoconazole in the 1980s 1 with the goal of achieving high affinity toward the fungal P450 14α-demethylase, low affinity toward human CYP enzymes, 2,3 and, more recently, evasion of fungal resistance mechanisms. 4 Fluconazole, introduced in 1990, proved well-tolerated in patients and has been used ubiquitously to treat invasive candidiasis. 1 The emergence of fluconazole resistance has led to the increasing use of echinocandins and the development of third-generation azoles (voriconazole, posoconazole, isavuconazole) with higher affinity. 5 Of the third-generation drugs, posoconazole and voriconazole work against a broader range of fungal pathogens but are more expensive and have other disadvantages: posoconazole has a less flexible dosing and absorption profile than fluconazole; voriconazole may be ineffective against strains that have already developed resistance toward fluconazole. 6 Newer azole drugs like albaconazole and fosravuconazole are still in development.The development of improved azoles has been paralleled by the search for small molecules that enhance the antifungal effect of existing azoles, 7−10 but the efforts have been met with limited success. 11,12 A wide range of azole enhancers have been shown to exhibit antifungal synergy; 13 two approved drugs, flucytosine 14 and calcineurin inhibitors, 15−19 have been shown to synergize with fluconazole against at low concentrations (<10 μg/mL) against strains of C. albicans but have limitations for general use. Against other species, 20 flucytosine instead antagonizes the effect of fluconazole, so the benefits of flucytosine-azole combinations are not clear. 21 Calcineurin inhibitors such as sirolimus and tacrolimus depend on human CYP enzymes for metabolic clearance; azole drugs like fluconazole exert off-target effects on these human CYP enzymes. Buildup of these calcineurin inhibitors in plasma increases risk of nephrotoxicity and, as immunosuppressants, may increase rates of infection from other pathogenic fungal species. 22−24 Giv...

We report a technique to coat polymers onto 3D surfaces distinct from traditional spray, spin, or dip coating. In our technique, the surface of a template structure composed of poly(lactic acid) swells and entraps a soluble polymer precursor. Once entrapped, the precursor is cured, resulting in a thin, conformal membrane. The thickness of each coating depends on the coating solution composition, residence time, and template size. Thicknesses ranged from 400 nm to 4 μm within the experimental conditions we explored. The coating method was compatible with a range of polymers. Complicated 3D structures and microstructures of 10 μm thickness and separation were coated using this technique. The templates can also be selectively removed, leaving behind a hollow membrane structure in the shape of the original printed, extruded, or microporous template structures. This technique may be useful in applications that benefit from three-dimensional membrane topologies, including catalysis, separations, and potentially tissue engineering.

Designing new liquids for CO2 absorption is a challenge in CO2 removal. Here, achieving low regeneration energies while keeping high selectivity and large capacity are current challenges. Recent cooperative metal–organic frameworks have shown the potential to address many of these challenges. However, many absorbent systems and designs rely on liquid capture agents. We present herein a liquid absorption system which exhibits cooperative CO2 absorption isotherms. Upon introduction, CO2 uptake is initially suppressed, followed by an abrupt increase in absorption. The liquid consists of a bifunctional guanidine and bifunctional alcohol, which, when dissolved in bis(2-methoxyethyl) ether, forms a secondary viscous phase within seconds in response to increases in CO2. The precipitation of this second viscous phase drives CO2 absorption from the gas phase. The isotherm of the bifunctional system differs starkly from the analogous monofunctional system, which exhibits limited CO2 uptake across the same pressure range. In our system, CO2 absorption is strongly solvent dependent. In DMSO, both systems exhibit hyperbolic isotherms and no precipitation occurs. Subsequent 1H NMR experiments confirmed the formation of distinct alkylcarbonate species having either one or two molecules of CO2 bound. The solvent and structure relationships derived from these results can be used to tailor new liquid absorption systems to the conditions of a given CO2 separation process.

C3‐substituted indoles and carbazoles react with α‐aryl‐α‐diazoesters under palladium catalysis to form α‐(N‐indolyl)‐α‐arylesters and α‐(N‐carbazolyl)‐α‐arylesters. The products result from insertion of a palladium‐carbene ligand into the N−H bond of the aromatic N‐heterocycles. Enantioselection was achieved using a chiral bis(oxazoline) ligand, in many cases with high enantioselectivity (up to 99 % ee). The method was applied to synthesize the core of a bioactive carbazole derivative in a concise manner.

We use optical transient-grating spectroscopy to measure spin diffusion of optically oriented electrons in bulk, semi-insulating GaAs(100). Trapping and recombination do not quickly deplete the photoexcited population. The spin diffusion coefficient of 88 ± 12 cm 2 /s is roughly constant at temperatures from 15 K to 150 K, and the spin diffusion length is at least 450 nm. We show that it is possible to use spin diffusion to estimate the electron diffusion coefficient. Due to electron-electron interactions, the electron diffusion is 1.4 times larger than the spin diffusion. The burgeoning field of semiconductor spintronics relies on moving spin-polarized electrons through distances comparable to the dimensions of an electronic device. The importance of spin transport has led to several studies of spin diffusion in GaAs quantum wells. Spin transport in quantum wells can differ markedly from the bulk material, due to to different scattering rates and especially to the different spin-orbit coupling 1 . Nonetheless, there have been relatively few measurements 2-4 of spin diffusion in bulk GaAs. In n-doped samples with n = 1 × 10 16 and 2 × 10 16 cm −3 , the spin diffusion coefficient D s ranged from 10 to 200 cm 2 /s. Spin diffusion in semi-insulating GaAs (SI-GaAs) has not been reported. SI-GaAs has been proposed as a platform for nuclear spintronics 5 due to its low carrier density. Moreover, Kikkawa et al. showed that electrons could be optically oriented in SI-GaAs and would subsequently diffuse into an adjacent ZnSe film, maintaining their spin polarization 6 . Since SI-GaAs is a ubiquitous substrate material for thin film growth and for spintronic devices, such spin diffusion is of practical consequence, whether intentional or not. In this work, we find that SI-GaAs has a large, temperature-independent spin diffusion coefficient.We measured spin diffusion with an ultrafast transient spin grating 7 , which measures the decay rate γ s of a spin-density wave (the "grating") with wavelength Λ and wavevector q = 2π/Λ. The grating amplitude decays-through spin relaxation, electron-hole recombination, and diffusion-at a rate of Here, D s is the spin diffusion coefficient, and τ 0 is the lifetime for trapping, recombination, and spin relaxation. Measurement at several q determines D s . We measure in a reflection geometry, and improve the detection efficiency by heterodyne detection 8 . Noise is further suppressed by 95 Hz modulation of the grating phase and lock-in detection 9 . The SI-GaAs sample was grown by Wafer Technology. It was undoped, oriented (100), had room temperature resistivity ρ ≥ 107 Ω-cm and Hall mobility µ H ≥ 5000 cm 2 /V-s. The pump and probe pulses came from a mode-locked Ti:Sapphire laser with wavelength near 800 nm and repetition rate of 80 MHz. The two pump pulses were focused to a spot of 65 µm diameter with total fluence 3.0 µJ/cm 2 except as indicated; probe pulses were always a factor of 2.5 weaker. Assuming one photoexcited electron per absorbed photon in a 1 µm absorption length 10 , we p...