Design,Synthesis And Antitubercular Study Of DprE1 Inhibitors

With an auxiliary group flavin adenine dinucleotide(FAD),DprEl catalyzes the oxidation of decenyl phosphate dinucleose(DPR)to decaprenylphosphoryl-2-ketoribose(DPX),and DPX is further reduced to Decaprenylphosporyl arabinose(DPA)by the downstream enzyme DprE2.While DPA is the only donor of mycobacterial cell wall component arabinogalactan.Consenquently,the proper function of DprEl is critical to the mycobacteria growth,It has been reported that DprEl inhibition led to the abnormal synthesis of mycobacterial cell wall and resulted in death of mycobacteria.Benzothiazinone(BTZs)is reported as a new class of anti-tuberculosis compounds with excellent inhibitory activity against DprE1.Among these BTZ derivatives,PBTZ169 exhibits the highest antibacterial activity with MIC value less than 1 nM;However,its poor water solubility(less than 0.01 μg/mL)and high clogP(5.09)value implied the undesired drug like property.At phase Ⅱ clinical stage,a single oral dose of 1280 mg/day was implemented,clearly not correlate with its reported low MIC value.Therefore,reevaluation was performed after change of formulation in 2018.To improve the water solubility of BTZ compounds,we sought to replace the hydrophobic trifluoromethyl group at the 6 position in PBTZ169 by introducing more hydrophilic sulfonyl group.R group optimization on sulfonyl led to the discovery of A1 with methanesulfonyl at 6 position,showing MIC 14 nM,and water solubility of 0.74 μg/mL,that is more than 80 folds of PBTZ169.Unfortunately,A1 displays t1/2 less than 30 min in human liver microsomal.To improve the metabolic stability,we then set to optimize the side chain,by opening the piperazine ring and introducing five-member aromatic heterocycles as linker.Two series of compounds B and C were designed and prepared,and we are delighted to observe several compounds activity outperformed the first-line drug isoniazid or rifampicin.Specifically,compound B7 displayed MIC 10 nM.Moreover,the compounds water solubility was significantly improved compared to PBTZ169.In addition,three series of compounds D,E and F with 6-CF3 on the phenyl ring and and the same side chain as type B and C were synthesized.The anti-mycobacterial activity revealed all three series had compounds with MIC less than 10 nM,such as D2(MIC:8 nM),D10(MIC:8 nM),E3(MIC:6 nM),F1(MIC:6 nM),F2(MIC:6 nM),F3(MIC:6 nM)and F4(MIC:6 nM).Taken together,several compounds from the above 5 series demonstrated superior activity compared to the current first line drug INH or RIF,solubility,metabolic stability and toxcicity properties are being evaluated for some selected compounds.