Abstract
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-14C]methionine into the C-24 of ergosterol in whole cells of C. albicans (IC50 20 μM). However, HWY-289 (100 μM) had no effect on mammalian cholesterol biosynthesis in rat microsomes while miconazole (100 μM) 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 IC50 values of 22 μM for each enzyme. The effect was highly specific in that HWY-289 had no significant effect on C. albicans CaCHS3 (IC50 > 200 μM). 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.
Original language | English |
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Pages (from-to) | 513-519 |
Number of pages | 7 |
Journal | Journal of Antimicrobial Chemotherapy |
Volume | 47 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2001 |
All Science Journal Classification (ASJC) codes
- Pharmacology
- Microbiology (medical)
- Infectious Diseases
- Pharmacology (medical)