Synthesis and biological evaluation of new 2­substituted­4­amino-quinolines and -quinazoline as potential antifungal agents.

Aiming to discover novel antifungal agents, a series of 2­substituted­4­amino-quinolines and -quinazoline were prepared and characterized using IR, 1H NMR, 13C NMR, and HRMS spectroscopic techniques. Their antifungal activities against four invasive fungi were evaluated, and the results revealed that some of the target compounds exhibited moderate to excellent inhibitory potencies. The most promising compounds III11, III14, III15, and III23 exhibited potent and broad-spectrum antifungal activities with MIC values of 4-32 µg/mL. The mechanism studies showed that compound III11 (N,2-di-p-tolylquinolin-4-amine hydrochloride) did not play antifungal potency by disrupting fungal membrane, which was quite different from many traditional membrane-active antifungal drugs. Meanwhile, III11 also demonstrated a low likelihood of inducing resistance, and excellent stability in mouse plasma. In addition, some interesting structure-activity relationships (SARs) were also discussed. These results suggest that some 4­aminoquinolines may serve as new and promising candidates for further antifungal drug discovery.

4-Aminoquinolines Bearing a 1,3-Benzodioxole Moiety: Synthesis and Biological Evaluation as Potential Antifungal Agents.

In search of new environmentally friendly and effective antifungal agents, a series of 4-aminoquinolines bearing a 1,3-benzodioxole moiety were prepared and their structures were fully elucidated by spectroscopic analyses. The antifungal activities of all the target compounds against five phytopathogenic fungi were evaluated in vitro. The results revealed that most of the newly synthesized compounds exhibited obvious inhibitory activities at the concentration of 50 µg/mL. Among them, 6-(furan-2-yl)-N-(4-methylphenyl)-2H-[1,3]dioxolo[4,5-g]quinolin-8-amine hydrochloride (7m) displayed more promising antifungal potency with EC50 values of 10.3 and 14.0 µg/mL against C. lunata and A. alternate, respectively. Particularly, the EC50 value of 7m against C. lunata was 7.3-fold as potent as the standard azoxystrobin. There were some significant morphological alterations in the mycelia of C. lunata when treated with 7m at 50 µg/mL. Additionally, the preliminary structure-activity relationships (SARs) were also discussed. Thus, this study suggests that 4-aminoquinolines bearing a 1,3-benzodioxole moiety are interesting scaffolds for the development of novel antifungal agents.

Synthesis and biological evaluation of 2-phenyl-4-aminoquinolines as potential antifungal agents.

A series of 2-phenyl-4-aminoquinolines were designed, synthesized and evaluated for their antifungal activities against three phytopathogenic fungi in vitro. All of the target compounds were fully elucidated by 1H NMR, 13C NMR and HRMS spectra. The results indicated that most of the target compounds demonstrated significant activities against the tested fungi. Among them, compound 6e exhibited more promising inhibitory activities against C. lunata (EC50 = 13.3 µg/mL), P. grisea (EC50 = 14.4 µg/mL) and A. alternate (EC50 = 15.6 µg/mL), superior to azoxystrobin, a commercial agricultural fungicide. The structure-activity relationship (SAR) revealed that the aniline moiety at position 4 of the quinoline scaffold played a key role in the potency of a compound. And the substitution positions of the aniline moiety significantly influenced the activities. These encouraging results yielded a variety of 2-phenylquinolines bearing an aniline moiety acting as promising antifungal agents.