Synthesis and structure-activity relationship (SAR) studies of novel side chain analogues of Q203 as antitubercular agents
결핵 후보물질 개발을 위한 새로운 Q203 유도체 합성 및 구조-활성 상관관계 연구
- 약학대학 약학과
- Issue Date
- 서울대학교 대학원
- extensively drug resistance (XDR); Q203; imidazo[1; 2-a]pyridine-3-carboxamide (IPA); structure-activity relationship (SAR); Tuberculosis; multi-drug resistance (MDR)
- 학위논문 (박사)-- 서울대학교 대학원 약학대학 약학과, 2017. 8. 김상희.
- A clinical unmet need to respond to spread of multi-drug resistance (MDR) and extensively drug resistance (XDR) is rapidly increasing and novel drug which has novel mode of action (MOA) is urgently needed. Q203 is new TB drug candidate in clinical trials having imidazo[1,2-a]pyridine-3-carboxamide (IPA) scaffold. In this study, a set of new analogues of Q203 which were varied side chain region was synthesized and evaluated their anti-tubercular activities. According to our structure-activity relationship studies, many analogues showed potent anti-tubercular activities against H37Rv-GFP replicating liquid broth culture medium as well as within the macrophage in spite of conformational changes. On the other hand, reduced lipophilicity of the side chain region led to decreased anti-tubercular activity. The small set of compounds, 8, 16, 21 and 42 exibited excellent in vivo pharmacokinetic values with high drug exposure level after oral administration. The representative compounds, 21 and 42 reduce significant bacterial burden in the lung and spleen in the infected mouse model, which suggests that they are promising clinical candidates as new anti-tubercular agent.