TY - JOUR
T1 - Palladium-catalysed synthesis of arylnaphthoquinones as antiprotozoal and antimycobacterial agents
AU - Kalt, Marc-Manuel
AU - Schuehly, Wolfgang
AU - Saf, Robert
AU - Ochensberger, Sandra
AU - Solnier, Julia
AU - Bucar, Franz
AU - Kaiser, Marcel
AU - Presser, Armin
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.) mc
2 155. 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.
AB - 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.) mc
2 155. 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.
KW - Antiprotozoal
KW - Tuberculosis
KW - Suzuki cross-coupling
KW - Naphthoquinone
UR - http://www.scopus.com/inward/record.url?scp=85091749944&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2020.112837
DO - 10.1016/j.ejmech.2020.112837
M3 - Article
SN - 0223-5234
VL - 207
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 112837
ER -