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[Display omitted] • The design and synthesis of new indolinone-tethered benzothiophene hybrids were reported. • First, MICs were determined against the sensitive M. tuberculosis strain ATCC 25177. • The most potent compounds were furtherly assessed versus resistant MDR-TB and XDR-TB. • Validated in vivo pharmacokinetic study was performed for the most potent derivative 6 h. • Molecular docking was carried out in DprE1 active site. Joining the global effort to eradicate tuberculosis, one of the deadliest infectious killers in the world, we disclose in this paper the design and synthesis of new indolinone-tethered benzothiophene hybrids 6a-i and 7a-i as potential anti-tubercular agents. The MICs were determined in vitro for the synthesized compounds against the sensitive M. tuberculosis strain ATCC 25177. Potent compounds 6b , 6d , 6f , 6h , 7a , 7b, 7d , 7f , 7h and 7i were furtherly assessed versus resistant MDR-TB and XDR-TB. Structure activity relationship investigation of the synthesized compounds was illustrated, accordingly. Superlative potency was unveiled for compound 6h (MIC = 0.48, 1.95 and 7.81 µg/mL for ATCC 25177 sensitive TB strain, resistant MDR-TB and XDR-TB, respectively). Moreover, validated in vivo pharmacokinetic study was performed for the most potent derivative 6h revealing superior pharmacokinetic profile over the reference drug. For further exploration of the anti-tubercular mechanism of action, molecular docking was carried out for the former compound in DprE1 active site as one of the important biological targets of TB. The binding mode and the docking score uncovered exceptional binding when compared to the co-crystallized ligand suggesting that it maybe the underlying target for its outstanding anti-tubercular potency. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Compound 50 was cherry-picked from ~6.2 million compounds by virtual screening. • The anti-TB effects of compound 50 were evaluated in vivo and in vitro. • The compound 50 was confirmed no toxicity in vivo and in vitro. Abstract Despite the increasing need of new antituberculosis drugs, the number of agents approved for the market has fallen to an all-time low. In response to the emerging drug resistance followed, structurally unique chemical entities will be highlighted. decaprenylphosphoryl- β - d -ribose oxidase (DprE1) participating in the biosynthesis of mycobacterium cell wall is a highly vulnerable and validated antituberculosis target. On the basis of it, a systematic strategy was applied to identify a high-quality lead compound (compound 50) that inhibits the essential enzyme DprE1, thus blocking the synthesis of the mycobacterial cell wall to kill M. tuberculosis in vitro and in vivo. Correspondingly, the rational design and synthetic strategy for compound 50 was reported. Notably, the compound 50 has been confirmed to be no toxicity. Altogether, our data suggest the compound 50 targeting DprE1 is a promising candidate for the tuberculosis (TB) therapy. [ABSTRACT FROM AUTHOR]