New 2-aryl-7,8-dimethoxy-3,4-dihydroisoquinolin-2-ium salts as potential antifungal agents: synthesis, bioactivity and structure-activity relationships

Abstract

The title compounds can be considered as simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs). In order to develop potent QBA-like antifungal agents, as our continuing study, a series of new title compounds were synthesized and evaluated for bioactivity against five plant pathogenic fungi by the mycelium growth rate method in this study. The SAR were also derived. The majority of the compounds showed good to excellent inhibition activity with average EC50 values of 7.87–20.0 μM for the fungi, superior to sanguinarine and cherythrine (two QBAs) and the commercial fungicide azoxystrobin. Part of the compounds were more active than commercial fungicides thiabendazole or carbendazim against F. solani, F. graminearum and C. gloeosporioides. Six compounds with average EC50 of 3.5–5.1 μg/mL possessed very great potential for development of new antifungal agents. SAR found that substitution patterns of the two aryl-rings significantly affect the activity. There exists a complex interaction effect between substituents of the two aryl-rings on the activity. Generally, the presence of electron-withdrawing groups on the C-ring can significantly increase the activity. These findings will be of great importance for the design of more potent antifungal isoquinoline agents.

New 2-aryl-6-methyl-3,4-dihydro-β-carbolin-2-iums as potential antifungal agents: Synthesis, bioactivity and structure-activity relationship

“…1) with the aim of developing QBAs-like drugs. Compared with SA or CH, these analogues generally showed the higher anti-phytopathogenic 9–13 , anti-cancer 8,14 and acaricidal activities 15,16 . Additionally, the analogues also showed high safety to plant growth 17,18 .…”

Simple Analogues of Quaternary Benzo[c]phenanthridine Alkaloids: Discovery of a Novel Antifungal 2-Phenylphthalazin-2-ium Scaffold with Excellent Potency against Phytopathogenic Fungi

“…It was worth mentioning that compared with the analogues A ,− and B , , compound C had more potent activity and a broader antifungal spectrum.…”

“…Our previous studies showed that the analogue A possesses a variety of excellent pharmacological activities of QBAs such as antimicrobial, ,− anticancer, − acaricidal, , and anti-acetylcholinesterase activities . Therefore, the analogue A can be used as the secondary lead of QBAs to develop novel QBA -like antifungal agents. − …”

“…All final compounds exhibited purities greater than 95%. 1 H NMR and 13 C NMR spectra were recorded on an Avance III 500 MHz instrument (Bruker, Karlsruhe, Germany). Chemical shifts were measured relative to the residual solvent peaks of dimethyl sulfoxide-d 6 (DMSO-d 6 ) ( 1 H, δ 2.50 ppm; 13 C, δ 39.52 ppm).…”

“…Based on the understanding of the structure–activity relationships (SARs) of QBAs and with the aim of seeking more potent QBA -like antifungal agents, we previously deigned two classes of structurally simple analogues of QBAs , that is, isoquinoline analogues ( A ) and β-carboline analogues ( B ) (Figure ) by structural simulation. These analogues generally showed similar or even more potent antifungal activity than SA and CH. ,− Besides, the analogues also showed high safety for plant growth . Encouraged by the findings above, herein we further designed a class of novel phthalazine analogues ( C ) (Figure ).…”