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Identification of novel benzothiopyranone compounds against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones.

Abstract：

:In this study, three novel series of benzoxazinone, benzothiopyranone and benzopyranone derivatives were designed through scaffold morphing from benzothiazinones to target DprE1. All compounds were evaluated for their in vitro activities against Mycobacterium tuberculosis and cytotoxicity against Vero cell line. Among these three series, the benzothiopyranone series displayed excellent antimycobacterial activity and low cytotoxicity. In particular, compound 6b exhibited potent in vitro activity against both drug-susceptible and drug-resistant tuberculosis clinical strains with MICs <0.016 μg/mL. In addition, compound 6b demonstrated excellent ADME/T and PK properties and potent in vivo efficacy with bactericidal activity in an acute mouse model of tuberculosis. The antituberculosis effect of compound 6b is most likely attributed to its excellent anti-DprE1 activity. As such, compound 6b is under evaluation as a potential clinical candidate for treatment of tuberculosis. The current study provided new insight into the structural and pharmacological requirements for DprE1 inhibitors as potent antitubercular agents.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Li P,Wang B,Zhang X,Batt SM,Besra GS,Zhang T,Ma C,Zhang D,Lin Z,Li G,Huang H,Lu Y

doi

10.1016/j.ejmech.2018.09.042

subject

Has Abstract

pub_date

2018-12-05 00:00:00

pages

157-170

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30814-6

journal_volume

160

pub_type

杂志文章

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