Study On The Relationship Between The Design, Synthesis And Anti - Tuberculosis - Structure Of Imidazole [1,2 - A] Pyridine - 3 - Amide Compounds

The rising incidence of tuberculosis (TB), especially for multidrug resistant TB (MDR-TB), has caused a major public health and social problem. The combination of HIV/AIDS and TB is contributing to the worsening impact of this disease. Therefore, it is urgent to discover and develop new anti-TB drugs, and particular for anti-MDR-TB drugs.After more than 40 years endurance exploration, the research of new anti-TB drugs recently obtained some significant breakthrough. For example, Bedaquiline and Delamanid with new scaffolds and mechanisms, have been approved by FDA and EMA for the treatment of MDR-TB in clinic. Inspired by this remarkable achievement, the research of anti-TB drugs has been intensified by Pharmaceutical industry and research groups in recent years. Some anti-TB candidates are currently under clinical or pre-clinical research.N-(2-phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamides possessing good activity against Mycobacterium tuberculosis (MTB), were discovered in our lab with independent intellectual property rights. Among them, compounds 1MB-1302/3 showed potent activity against MTB H37Rv ATCC 27294 and MDR-MTBs, low oral toxicity (LD50>2000 mg/kg) and fast absorption. However, both of them have a short half-life in vivo which restricted their further development. Accordingly,1MB-1302/3 were selected as our lead compounds in this study. All the 3 structural segments (Linker, L ring and R ring) of 1MB-1302/3 were modified sequentially. Based on their activity MTB and metabolic stability in vitro, the simple structure-activity relationship (SAR) and structure-pharmacokinetics relationship (SPR) were also explored. Besides,5-10 compounds were selected for further research including acute toxicity, in vivo pharmacokinetics, in vivo activity and also the further modification.This dissertation is composed by the following 4 parts:Firstly, a series of different linkers (8 linkers) were designed and introduced to the 37 target compounds. Based on the preliminary anti-MTB, SAR were explored, and the ethane 1,2-diamine-yl and 2-aminoethanol-yl were confirmed to be the best linkers. Compounds 21e and 21f (MICs:0.015 p.g/ml) were found to be more active against MTB than rifampin and isoniazid, and comparable to 1MB-1302/3.Secondly, a series of L-rings were designed and introduced to the 37 target compounds with the best linkers. SAR were explored based on the preliminary anti-MTB. Compounds 24j,24p,24t,25t,26n and 261 (MICs:0.023-0.029 μg/ml) were found to be more active against MTB than lead compounds and control drugs. Half-lifes in vitro of compounds 24j,241,24p and 24t are longer than the lead compounds. Thereby, the L-Rings of the four compounds were selected as the best ones.In this part, a fast and efficient way for synthesis a series of key intermediate imidazo[1,2-a]pyridine-3-carboxylic esters (IPCEs) was also established. These results have already been published on Heterocycles (2015,11,91,2087-2096).Thirdly, a series of R rings were designed and introduced to the 37 target compounds which maintain the best linkers and L rings. Some of them were evaluated for their activity and metabolic stability in vitro. Compound 38a (MIC:0.030μg/ml) was found to be almost 3 times better against MTB than the lead compounds. Half-life in vitro of 36c (t1/2,168.6 min) was longer than the lead compounds. The other compounds are still under testing, and their activity are expected to be attractive.Fourthly, a series of novel imidazo[1,2-a]pyridineamide-cinnamamide hybrids were designed, synthesized and evaluated for their anti-MTB activity. Compounds 43e and 43k (MIC:4 μg/mL) were found to be have considerable activity against MTB. These results have already been published on Molecules (2016,21,49).In this dissertation, totally 280 compounds have been synthesized, and 210 of them are structurally novel (including 149 target compounds). All the target compounds were characterized by1H NMR、 MS and 13C NMR, some of them were further confirmed by HRMS.