Design,Synthesis And Anti-Tuberculosis Activity Of Imidazopyridine And Benzofuran Compounds Targeting Pks13

Tuberculosis has threatened human health for thousands of years.Mycobacterium tuberculosis(Mtb)was discovered as a pathogen in 1882 for the first time by Dr.Robert Koch,and caused approximately 10 million patients in 2019.China is one of the countries with a high burden of tuberculosis and drug-resistant tuberculosis.The emergence of drug-resistant Mtb has brought a crisis to global public health security,and there is an urgent need to develop anti-tuberculosis drugs with novel mechanisms.Mycolic acid,the main lipid component of the Mtb`s cell wall,is essential for the survival of Mtb and its biosynthesis process has found to be rich in anti-tuberculosis drug targets.Pks13 is the key enzyme in the final step of mycolic acid synthesis,and has been proven to be an effective anti-tuberculosis drug target.There are two main types of Pks13 inhibitors reported so far,thiophene compounds targeting the Pks13 N-ACP domain and benzofuran compounds targeting the Pks13-TE domain.A natural product-inspired cyclization strategy has been successfully used to improve the metabolic stability of the benzofuran inhibitors in our previous study.In this dissertation,a scaffold hopping strategy was implied and those groups favorable for activity was retained,including hydroxyl group on the2-phenyl,3-carboxylic acid ester or amide,4-methylene piperidine and 5-phenolic hydroxyl.While the benzofuran skeleton was replaced by imidazopyridine to afford a class of imidazo[1,2-a]pyridine compounds.The molecular docking results showed that these new compounds has a good binding with Pks13,in which the previous hydrogen bond and the π-π stacking were basically maintained.In order to improve the chemical stability of this structure,an oxazine ring were introduced to take place of the 4-Mannich base and 5-hydroxyl group.A Nano-DSF test of the imidazo[1,2-a]pyridine compounds was also conducted using the purified protein Pks13-TE.The thermal shift of Pks13-TE has proven the interaction between our compounds and Pks13-TE,but no inhibitory activity against the H37 Rv strain was shown in the following MIC test.The hydroxyl substituent on the 2-phenyl group and the 5-hydroxyl substituent in the structure of benzofuran Pks13 inhibitors have been proven critical to the activity.However,these two substituents may contribute to the Phase Ⅱ metabolism,by combination with glutathione,sulfuric acid and glucuronic acid et al.Here,a prodrug design strategy was used to improve the metabolic stability as well as the water solubility of the benzofuran Pks13 inhibitors.Some hydrophilic groups,such as phosphoric acid and succinic acid,have been introduced to the phenolic hydroxyl substituents,and this work makes preparations for the improvement of the pharmacokinetic properties of benzofuran Pks13 inhibitors.