Palladium-catalysed synthesis of arylnaphthoquinones as antiprotozoal and antimycobacterial agents.

Kalt MM; Schuehly W; Saf R; Ochensberger S; Solnier J; Bucar F; Kaiser M; Presser A

doi:10.1016/j.ejmech.2020.112837

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Journal article

Palladium-catalysed synthesis of arylnaphthoquinones as antiprotozoal and antimycobacterial agents.

Kalt MM Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, A-8010, Graz, Austria.
Schuehly W Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Universitaetsplatz 4, A-8010, Graz, Austria.
Saf R Institute for Chemistry and Technology of Materials (ICTM), University of Technology, Stremayrgasse 9, A-8010, Graz, Austria.
Ochensberger S Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Universitaetsplatz 4, A-8010, Graz, Austria.
Solnier J Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Universitaetsplatz 4, A-8010, Graz, Austria.
Bucar F Institute of Pharmaceutical Sciences, Pharmacognosy, University of Graz, Universitaetsplatz 4, A-8010, Graz, Austria.
Kaiser M Swiss Tropical and Public Health Institute, Socinstrasse 57, CH-4002, Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003, Basel, Switzerland.
Presser A Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz, Schubertstrasse 1, A-8010, Graz, Austria. Electronic address: armin.presser@uni-graz.at.

2020-10-01

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European journal of medicinal chemistry. - 2020

English Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of anti-infective agents. Herein, we report an optimised, high yield process for the preparation of various 2-arylnaphthoquinones by a palladium-catalysed Suzuki reaction. All synthesised compounds were evaluated for their in-vitro antiprotozoal and antimycobacterial activity. Antiprotozoal activity was assessed against Plasmodium falciparum (P.f.) NF54 and Trypanosoma brucei rhodesiense (T.b.r.) STIB900, and antimycobacterial activity against Mycobacterium smegmatis (M.s.) mc2 155. Substitution with pyridine and pyrimidine rings significantly increased antiplasmodial potency of our compounds. The 2-aryl-NQs exhibited trypanocidal activity in the nM range with a very favourable selectivity profile. (Pseudo)halogenated aryl-NQs were found to have a pronounced effect indicating inhibition of mycobacterial efflux pumps. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. In addition, the physicochemical parameters of the synthesised compounds were discussed.

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