Design, synthesis and anti-mycobacterial activity evaluation of benzofuran-isatin hybrids

• Published in: European journal of medicinal chemistry Vol. 159; pp. 277 - 281
• Main Authors: Gao, Feng, Yang, Hua, Lu, Tianyu, Chen, Zijian, Ma, Long, Xu, Zhi, Schaffer, Paul, Lu, Guangming
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.11.2018; Elsevier
• Subjects: Anti-mycobacterial; Anti-tubercular; Benzofuran-isatin hybrids; Chemistry, Medicinal; Life Sciences & Biomedicine; Multi-drug resistant; Pharmacology & Pharmacy; Science & Technology; Structure-activity relationship; Multi-drug resistant; Anti-tubercular; Anti-mycobacterial; Structure-activity relationship; Benzofuran-isatin hybrids; CYCLOADDITION; CONTAINING DERIVATIVES; ANTIMICROBIAL EVALUATION; INHIBITORS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.09.049

Herein we report the design and synthesis of a series of novel benzofuran-isatin hybrids, and in vitro evaluation of their anti-mycobacterial activity against both drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis (MTB) strains. In parallel, cytotoxicity of these hybrids was also tested in VERO cells. Preliminary results indicated that all hybrids with acceptable cytotoxicity in VERO cells (CC50: 128->1024 μg/mL) exhibited considerable anti-mycobacterial activities against MTB H37Rv and MDR-TB with MIC ranging from 0.25 to 8 μg/mL. It is worth noting that hybrid 8f with no cytotoxicity towards VERO cells (CC50: >1024 μg/mL) was found to be the most active compound (MIC: 0.25 and 0.5 μg/mL) against MTB H37Rv and MDR-TB strains. Comparing to the first-line anti-tuberculosis agents rifampicin and isoniazid, hybrid 8f has shown over two magnitude more active against MDR-TB. The hybrid 8f was further evaluated for its metabolic stability and in vivo pharmacokinetic profiles, with the results showing that hybrid 8f exhibited lower metabolic stability compared to inhibitor TAM16. Further modification based on hybrid 8f is needed to improve the metabolic stability and pharmacokinetic profiles. A series of novel benzofuran-isatin hybrids were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities as well as cytotoxicity. Preliminary results indicated that all hybrids with acceptable cytotoxicity in VERO cells exhibited considerable anti-mycobacterial activities against MTB H37Rv and MDR-TB strains. It is worth noting that hybrid 8f with no cytotoxicity towards VERO cells, was found to be the most active compound against MTB H37Rv and MDR-TB. Comparing to the first-line anti-TB agents (rifampicin and isoniazid), hybrid 8f was more active against MDR-TB. However, both the metabolic stability and in vivo pharmacokinetic profiles of 8f were inferior to inhibitor TAM16. Further modification based on hybrid 8f is needed to improve metabolic stability and pharmacokinetic profiles. [Display omitted] •Hybrid 8f with no cytotoxicity towards VERO cells, was found to be the most active compound against MTB H37Rv and MDR-TB.•Comparing to the first-line anti-TB agents (rifampicin and isoniazid), hybrid 8f was more active against MDR-TB.•The metabolic stability and pharmacokinetic profiles of hybrid 8f still need to be improved.