Synthesis and antitubercular activity of 1- and 3-substituted benzo[g]isoquinoline-5,10-diones

Organic & Biomolecular Chemistry
Robert J SmetsKourosch Abbaspour Tehrani

Abstract

In this study, a small library of twenty benzo[g]isoquinoline-5,10-diones were synthesized in a novel straightforward approach, starting from 2-methyl-1,4-naphthoquinone (vitamin K). An intramolecular Heck reaction of a N-vinylacetamide was a crucial step in the synthetic route, at which the combination of cesium carbonate and a bulky, electron rich trialkylphosphine (tBuCy2P.HBF4) provided high 6-endo-trig selectivity. The anti-tubercular activity against Mycobacterium tuberculosis H37Ra and acute cytotoxicity against J774 A.1 macrophages were studied. From the structure activity relationship, it could be derived that in general the substitution of position 3 yielded analogs with a higher antitubercular potency. Among these, two analogs, 27a and 27b, showed remarkable activity with minimal inhibition concentrations of respectively 28.92 μM and 1.05 μM, and acute cytotoxic concentrations of >128 μM and 34.85 μM. In addition, the analogs and their possible metabolites were evaluated using a Vitotox™ assay to study the possibility of genotoxicity. Results indicated that none of the evaluated analogs and their possible metabolites showed early signs of genotoxicity.

References

Feb 1, 1995·Planta medica·P N SolisJ D Phillipson
Jul 27, 1999·Planta medica·A L OkunadeB O Oguntimein
Aug 24, 1999·Infection and Immunity·V A SnewinD B Young
Feb 3, 2005·Bioorganic & Medicinal Chemistry Letters·Junko KoyamaMakoto Taniguchi
Oct 5, 2006·Current Medicinal Chemistry·Manar M Salem, Karl A Werbovetz
Mar 13, 2014·Journal of Medicinal Chemistry·Davie CappoenNorbert De Kimpe
Mar 19, 2014·European Journal of Medicinal Chemistry·Davie CappoenJanez Košmrlj
Jan 15, 2016·Organic & Biomolecular Chemistry·G RotthierK Abbaspour Tehrani
Mar 24, 2017·The European Respiratory Journal·Dennis FalzonKarin Weyer

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Citations

Jan 19, 2021·World Journal of Microbiology & Biotechnology·Natalia I Di MarcoCarlos R Pungitore

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Methods Mentioned

BETA
column chromatography
NMR
scraping

Software Mentioned

JohnPhos
Biotage

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