Design,Synthesis,Activity Study Of 3,4-Dihyro-2(1H)-Quinolone Anti-TB Compunds And QSAR Of Quinolone Anti-TB Compunds

Tuberculosis epidemic is a major public health and social problem of global concern,andtuberculosis is still a serious threat to human life and health.Due to the current emergence of multi-drug-resistant and extensively drug-resistant tuberculosis,HIV-positive tuberculosis and new coronary pneumonia,there is an urgent need for anti-tuberculosis drugs with new structures,mechanisms of action,strong therapeutic effects,and less toxic side effects.In this paper,based on the reported structure and activity data of quinolones with anti-tuberculosis activity,and using Discovery studio software to conduct three-dimensional quantitative structure-activity relationship studies on the collected compounds,the quinolones with anti-tuberculosis activity were established.3D-QSAR model,the five-fold cross-validation coefficient q²of this model is 0.521,the non-cross-validation coefficient r² is 1.000,the adjusted determination coefficient r²（adjusted）is 1.000,and the RMS residual is 0.002891.The model has good application ability,and the establishment of the model can provide new ideas for the design and screening of quinolone anti-tuberculosis drugs.At present,compounds targeting Dpr E1 with a new mechanism of action have received extensive attention in the industry in recent years.In this paper,OPC-167832（the drug is a Dpr E1 inhibitor）,which has entered phase II clinical trials by Japan’s Otsuka Pharmaceutical Company,is used as the template.Fifty-four 3,4-dihydro-2（1H）-quinolone target compounds were designed and synthesized,the structures of 29 new 3,4-dihydro-2（1H）-quinolones were elucidated and identified by spectroscopic methods such as MS,¹H NMR,¹³C NMR,and preliminarily evaluated the in vitro anti-tuberculosis activity of some target compounds,among which 21 target compounds have achieved anti-tuberculosis activity in vitro In the test,it was found that 4 have anti-tuberculosis activity,among which IIb1 has better anti-tuberculosis activity,reaching the nanomolar level,which is worthy of further study.In this paper,according to the anti-tuberculosis activity data obtained after the core and sidechains of 3,4-dihydro-2（1H）-quinolones were modified,the structure-activity relationship of these compounds was preliminarily explored:only the 5-position hydroxyl substituent has better activity.The activity of the hydroxy-substituted derivatives at positions 6 and 7 is basically inactive.It points out the direction for further structural modification of 3,4-dihydro-2（1H）-quinolone anti-tuberculosis drugs,and also opens up a way for the discovery of such drugs with better activity.