Cyclic Amines Coupled to Indole Derivatives With Improved Efflux Pump Inhibiting Activity in Bacteria and Cancer Cells

Hegedűs, Dóra and Szemerédi, Nikoletta and Gábor, Maja and Sas, Judit and Belasri, Khadija and Szatmári, István and Spengler, Gabriella (2024) Cyclic Amines Coupled to Indole Derivatives With Improved Efflux Pump Inhibiting Activity in Bacteria and Cancer Cells. ANTICANCER RESEARCH, 44 (3). pp. 1149-1160. ISSN 0250-7005

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Abstract

Background/Aim: Indole skeleton has become a significant tool in the field of anticancer and antibacterial therapeutic strategies. The modified aza-Friedel–Crafts reaction by direct coupling of different cyclic imines and indole derivatives has been explored. To investigate the scope and limitations of the reaction and observe the effect of structural modifications, our aim was to resynthesize selected compounds as well as prepare new derivatives starting from 6,7-dimethoxy-3,4-dihydroisoquinoline, (4aR,8aR)-4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one and 7-azaindole. Our further aim was the systematic biological evaluation of selected C-3-coupled indole and azaindole derivatives in favour of having a preliminary overview about the structure–activity relationships. Materials and Methods: The synthesis and resynthesis of selected compounds were accomplished by extension of aza-Friedel–Crafts reaction. The products have been tested on bacteria and cancer cells. Results: The most significant efflux pump inhibiting (EPI) activity was observed in the case of 6,7-dihydrothieno[3,2- c]pyridine coupled indole derivative. The reaction of 6,7- dimethoxy-3,4-dihydroisoquinoline with 7-azaindole resulted in the most potent biofilm inhibitor product. Applying indole and 4,9-dihydro-3H-β-carboline, 6,7-dihydrothieno[3,2- c]pyridine led to the formation of a product with the highest anticancer activity. 6,7-Dimethoxy-3,4-dihydroisoquinoline.

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