Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity

被引：3

作者：

Fan, Dongguang ^{[1
]}

Wang, Bin ^{[2
]}

Stelitano, Giovanni ^{[3
]}

Savkova, Karin ^{[4
]}

Riabova, Olga ^{[5
]}

Shi, Rui ^{[1
]}

Wu, Xiaomei ^{[1
]}

Chiarelli, Laurent R. ^{[3
]}

Mikusova, Katarina ^{[4
]}

Makarov, Vadim ^{[5
]}

Lu, Yu ^{[2
]}

Hong, Yuzhi ^{[6
,7
]}

Qiao, Chunhua ^{[1
,7
]}

机构：

[1] Soochow Univ, Coll Pharmaceut Sci, Suzhou 215123, Peoples R China

[2] Beijing Chest Hosp, Dept Pharmacol, Beijing Key Lab Drug Resistance TB Res, Beijing TB & Thorac Tumor Res, Beijing 101149, Peoples R China

[3] Univ Pavia, Dept Biol & Biotechnol, I-27100 Pavia, Italy

[4] Comenius Univ, Fac Nat Sci, Dept Biochem, Bratislava 84215, Slovakia

[5] Russian Acad Sci, Res Ctr Biotechnol, Moscow 119071, Russia

[6] Soochow Univ, Inst Mol Enzymol, Suzhou Med Coll, Sch Biol & Basic Med Sci, Suzhou 215123, Peoples R China

[7] Soochow Univ, Suzhou Med Coll, Suzhou Key Lab Pathogen Biosci & Antiinfect Med, Suzhou 215123, Peoples R China

来源：

BIOMEDICINES | 2023年 / 11卷 / 07期

基金：

中国国家自然科学基金;

关键词：

anti-tubercular agents; DprE1; inhibitor; structure activity relationship; in vivo activity; TUBERCULOSIS;

D O I：

10.3390/biomedicines11071975

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-& beta;-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 & mu;M. The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.

引用

页数：18

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