121st General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Event Hall
Time 4월 19일 (목요일) 11:00~12:30
Code MEDI.P-608
Subject Synthesis and Development of Novel anti-inflammatory compounds for Treatment of Meningitis
Authors Seul Ki Yeon, Ki Duk Park*
Convergence Research Center for DTC, Korea Institute of Science and Technology, Korea
Abstract Cryptococcus and Candida are the most representative opportunistic fungal pathogens which cause fungal inflammation in a group of people that are impaired immunity by aging or medical issues such as organ transplant operation, chemotherapy, and AIDS. Particularly, Cryptococcus neoformans, a type of fungal pathogen that is belonging to a Cryptococcus, is easily found in soil. Its basidiospores are inhaled into the lungs through respiratory system, then, cryptococcal pathogens that were existing in the body cause lung inflammation and eventually leads to meningitis when it invades central nervous system (CNS) by passing through blood-brain barrier (BBB). In this study, we synthesized a series of chemical library for potent antifungal compounds and evaluated their potency using in vitro antifungal susceptibility test (Minimal inhibitory concentration (MIC)). Among the synthesized compounds, we derived KDS1090 as a potent lead compound by MIC test against representative fungal pathogens (MIC: C. neoformans = 4 g/mL, C. albicans = 16 g/mL, C. glabrata = 16 g/mL). KDS1090 exhibited excellent ADME/Tox profiles (microsomal stability (human): 92% remaining after 30 min; CYP inhibition (1A2, 2C9, 2C19, 2D6, 3A4): IC50 > 10 μM; single dose toxicity (mice): LD50 > 1,000 mg/kg). In addition, we have investigated the mechanism of action and found that KDS1090 may down-regulate cell wall chitin levels. Now, we are working on the identification of the target molecule and the optimization of the lead compound to improve efficacy and drug-like properties.
E-mail 214507@kist.re.kr