122nd General Meeting of the KCS

Type Poster Presentation
Area Medicinal Chemistry
Room No. Grand Ballroom
Time 10월 18일 (목요일) 11:00~12:30
Code MEDI.P-321
Subject Synthesis and Evaluation of Novel Functionalized Amino Acid Derivatives for Treatment of Cryptococcal Meningitis
Authors Hyeon Ji Kim, Siwon Kim, Ki Duk Park1,*
Convergence Research Center for DTC of Dementia, Korea Institute of Science and Technology, Korea
1Convergence Research Center for DTC, Korea Institute of Science and Technology, Korea
Abstract Cryptococcus and Candida are the representative opportunistic fungus that causes fungal inflammation in a group of people whose immune system is impaired by aging or medical issues such as organ transplantation, chemotherapy, and AIDS. Especially, Cryptococcus neoformans, a type of the Cryptococcus, is easily found in soil, bird excrement. Its basidiospores are inhaled into the lungs through the respiratory system, and cryptococcal pathogens in the body cause inflammation in the lung and eventually leads to meningitis when penetrating the central nervous system (CNS) through the blood-brain barrier (BBB). In this study, we have synthesized a series of functionalized amino acid (FAA) derivatives for the development of antifungal agent against C. neoformans and evaluated their potency using in vitro antifungal susceptibility test (Minimal inhibitory concentration (MIC)). In a previous study, we derived the potent leading compound KDS1090 through MIC testing for representative fungal pathogens. (MIC: C. neoformans = 4 g/mL, C. albicans = 16 g/mL, C. glabrata = 16 g/mL). Herein, we optimized lead compound for both the antifungal efficacy and drug-like properties. Among the optimized compounds, KDS5098 showed the highest antifungal efficacies (MIC: C. neoformans = 2 g/mL, C. albicans = 4 g/mL). Furthermore, KDS5098 exhibited excellent ADME/Tox profiles (microsomal stability (human): 90%, (mouse) 78% remaining after 30 min; CYP inhibition (1A2, 2C9, 2C19, 2D6): IC50 > 10 μM, (3A4; 56% inhibition at 10 μM); single dose toxicity (mice): LD50 > 1,000 mg/kg; PK: F=40%).
E-mail 117523@kist.re.kr