The antifungal properties of 515 synthetic and semi-synthetic protoberberines were investigated. HWY-289 was chosen for further study because it exhibited the most significant anti-Candida activity (MICs were 1.56 mg/L for Candida albicans and Candida krusei; 6.25 mg/L for Candida guilliermondii) but did not demonstrate toxicity in rats. HWY-289 inhibited the incorporation of L-[methyl-(14)C]methionine into the C-24 of ergosterol in whole cells of C. albicans (IC(50) 20 microM). However, HWY-289 (100 microM) had no effect on mammalian cholesterol biosynthesis in rat microsomes while miconazole (100 microM) was a potent inhibitor of cholesterol biosynthesis under identical assay conditions. A second major target site for HWY-289 was identified that involves cell wall biosynthesis in C. albicans. HWY-289 was a potent inhibitor of the chitin synthase isozymes CaCHS1 and CaCHS2, with IC(50) values of 22 microM for each enzyme. The effect was highly specific in that HWY-289 had no significant effect on C. albicans CaCHS3 (IC(50) > 200 microM). Thus, HWY-289 compared favourably with well-established antifungal agents as an inhibitor of the growth of Candida species in vitro, and may have considerable potential as a new class of antifungal agent that lacks toxic side effects in the human host.
Simulation of detecting photoelectrons using multi-level multi-electron (MLME) finite-difference time-domain (FDTD) method with an application to near-field subwavelength imaging based on semiconductor nanophotodetector (NPD) array is reported. The photocurrents from the photodiode pixels are obtained to explore the resolution of this novel NPD device for subwavelength imaging. One limiting factor of the NPD device is the optical power coupling between adjacent detector pixels. We investigate such power coupling in the presence of absorbing media as well as the spatial distributions of the electric field and photoelectron density using the MLME FDTD simulation. Our results show that the detection resolution is about one tenth of the operating wavelength, which is comparable to that of a near-field scanning optical microscope based on metal clad tapered fiber.
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