Benzofuran-isatin hybrids tethered via different length alkyl linkers and their in vitro anti-mycobacterial activities.

ID: ALA4390694

Journal: Bioorg Med Chem

Title: Benzofuran-isatin hybrids tethered via different length alkyl linkers and their in vitro anti-mycobacterial activities.

Authors: Gao F, Chen Z, Ma L, Qiu L, Lin J, Lu G.

Abstract: A series of novel benzofuran-isatin hybrids 6a-m tethered through different length alkyl linkers propylene, butylene, pentylene and hexylene were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against both drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis (MTB) and cytotoxicity towards VERO cells. All hybrids with acceptable cytotoxicity in VERO cells (CC₅₀: 64 to >1024 μg/mL) also exhibited considerable anti-mycobacterial activities against both drug-susceptible and MDR-MTB strains with MIC in a range of 0.125-4 μg/mL. The SAR indicated that the length of the linker played a pivotal role on the activity, and the longer linker could enhance the activity. The most active hybrid 6d (MIC: 0.125 and 0.125 μg/mL) was comparable to or better than rifampicin (MIC: 0.5 μg/mL) and isoniazid (MIC: 0.06 μg/mL) against MTB H₃₇Rv, and was ≥256 folds more potent than rifampicin (MIC: 64 μg/mL) and isoniazid (MIC: >128 μg/mL) against MDR-MTB strain, but was less active than TAM16 (MIC: <0.06 μg/mL against the tested two strains). The hybrid 6d also showed low cytotoxicity towards VERO cell (CC₅₀: 128 μg/mL), but it was inferior to TAM16 in metabolic stability and in vivo pharmacokinetic profiles.

CiteXplore: 30992202

DOI: 10.1016/j.bmc.2019.04.017

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