Design,Synthesis And SAR Studies Of Novel Pks13 Inhibitors Against Mycobacterium Tuberculosis Based On Benzofuran Derivatives

According to the 2018 World Health Organization assessment report,there are about 10 million tuberculosis patients worldwide in 2017.China is one of the 8countries with high global tuberculosis.In addition,the prevalence of AIDS and the increasing number of drug-resistant tuberculosis have made TB Treatment is even more tricky.Tuberculosis is caused by M.tuberculosis infection.Related literature reports indicate that the polyketide synthase Pks13 in Mycobacterium tuberculosis is targeted to destroy the bacterial cell wall structure,and to find a new anti-tuberculosis drug with a new mechanism,which has a good development prospect.In the previous work,our group used the benzofuran anti-tuberculosis small molecule TAM1(MIC=1.0 μg/m L)targeting Pks13 as a hit compound,and obtained a kind of natural product coumestan skeleton with excellent antibacterial activity and pharmacological properties.A structure-based drug design method was used to design and synthesize a class of benzofuro[3,2-c]quinolin-6(5H)-one derivatives with high anti-tuberculosis activity TM11(MIC=0.0313-0.0625 μg/m L)and showed good results in both cytotoxicity and microbial selectivity tests.A new class of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized by molecular dynamics simulation technology,and the anti-tuberculosis activity was studied.Based on the preliminary work of our own group and the research results of the Sacchettini group,a class of benzofuran small molecules was designed and synthesized,and a preliminary structure-activity relationship study was carried out.