Thesis Of DMF As Carbon Source To Synthesize Benzothiadiazine 1,1-Dioxide Derivatives And The Design,Synthesis And Anti-Tubercular Activity Of DprE1 Inhibitors

The first part is DMF as carbon source to synthesize benzothiadiazine 1,1-dioxide derivatives.Benzothiadiazine 1,1-dioxide scaffold exist in a number of drugs,and their biological activities are revealed as antihypertensive,antibacterial,and antiviral.Synthesis of the benzothiadiazine 1,1-dioxide scaffold was explored in this thesis.I report here using DMF and its analogues as reactant and solvent,imidazolium chloride as catalyst to construct the ring.By comparison,my method is atom economical,applicable to a wide substrate scope,and the reaction yield is as high as 70%to 98%.The second part is design,synthesis and anti-tubercular activity of DprE1 inhibitors.Tuberculosis(TB)is an infectious disease caused by Mycobacterium tuberculosis(Mtb).With the widespread use of first-and second-line anti-TB drugs such as isoniazid,rifampicin,pyrazinamide,ethambutol,the occurrence of TB has been effectively controlled.However,emergence of multidrug-resistant tuberculosis(MDR-TB)and extensively drug-resistant tuberculosis(XDR-TB)add extra challenge for TB treatment.Consequently,there is an urgent need to develop new anti-TB drugs.Decenyl phosphoryl-β-D-ribose oxidase(DprE1)is a flavin containing enzyme,with flavin adenine dinucleotide(FAD)as the prosthetic group.DprE1,along with the downstream decaprenyl phosphoryl-keto-β-D-erythro-pentose 2’reductase(DprE2),catalyze the biosynthesis of decaprenyl-phospho-arabinose(DPA).While DPA is the only precursor for the biosynthesis of arabinogalactan,an essential component of the TB cell wall.Therefore,DprE1 has become a promising drug target for the development of new anti-TB drugs.As a reported covalent DprE1 inhibitor,The MIC value of PBTZ-169 against Mtb H37Rv is less than 0.0003 μg/mL,and its currently undergoing phase II clinical trial.Unfortunately,the single oral dose(1280 mg/d)of PBTZ-169 in the phase Ⅱ clinical trial was clearly inconsistent with its extremely low MIC value.Therefore,the clinical evaluation was repeated after the dosage form was changed in 2018.At the same time,PBTZ-169 exhibits poor water solubility(clogP:5.10).Therefore,in the early stage of the laboratory,we first started to improve the water solubility of PBTZ169.We replaced the 6-position trifluoromethyl group with a more hydrophilic methanesulfonyl group to give MsPBTZ169,and we found the water solubility of MsPBTZ 169 has been significantly improved(clogP:3.04),and the MIC value of Mtb H37Rv is 0.007 μg/mL.However,the metabolic half-life(T1/2)of MsPBTZ169 in human liver microsomal enzymes is less than 30 min.In order to improve the metabolic stability of the compound,we further investigated the side chain position by opening the piperazine ring.Using thiazole,oxazole and thiadiazole as a linker,we prepared three series of compounds:A,B,and C.In subsequent in vitro antibacterial experiments on Mtb H37Rv,compound A4(MIC:0.010 μg/mL),B1(MIC:0.007μg/mL),C4(MIC:0.002μg/mL),C5(MIC:0.008 μg/mL),C6(MIC:0.009 μg/mL)and C7(MIC:0.006 μg/mL)all showed similar antibacterial activity to MsPBTZ169(MIC:0.007 μg/mL).Among them,the antibacterial activity of compound C4 is slightly better than that of MsPBTZ169,which is 25 times that of Isoniazid.At the same time,the clogP value of compound C4 is 2.17,which is more water-soluble than MsPBTZ 169,which is very important to improve the bioavailability of the compound.Currently,the metabolic stability of these compounds are under investigation.