Design, Synthesis, and Antifungal Evaluation of Neocryptolepine Derivatives against Phytopathogenic Fungi

Abstract

Neocryptolepine is an alkaloid isolated from traditional African herbal medicine <i>Cryptolepis sanguinolenta</i>, and its broad spectrum of biological activities has been illuminated in past decades. In this study, neocryptolepine and its derivatives (<b>1</b>-<b>49</b>) were designed and synthesized from economical and readily available starting materials. Their structures were confirmed by proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and mass spectrometry. The synthesized compounds were screened for their antifungal profile against six agriculturally important fungi <i>Rhizoctonia solani</i>, <i>Botrytis cinerea</i> (<i>B. cinerea</i>), <i>Fusarium graminearum</i>, <i>Mycosphaerella melonis</i>, <i>Sclerotinia sclerotiorum</i>, and <i>Magnaporthe oryzae</i>. The results of in vitro assay revealed that compounds <b>5</b>, <b>21</b>, <b>24</b>, <b>35</b>, <b>40</b>, <b>45</b>, and <b>47</b> presented remarkable antifungal activity against the fungi tested with EC₅₀ values lower than 1 μg/mL. Significantly, compound <b>24</b> displayed the most effective inhibitory potency against <i>B. cinerea</i> (EC₅₀ = 0.07 μg/mL), and the data from in vivo experiments revealed that compound <b>24</b> demonstrated comparable protective activity with the positive control boscalid. Preliminary mechanism studies indicated that compound <b>24</b> showed impressive spore germination inhibitory effectiveness and lower cytotoxicity than azoxystrobin, imparted on normal function of the cell membrane and cell wall, and arrested the normal function of the nucleus. Besides the excellent inhibitory activity against agriculturally important phytopathogenic fungi tested, the designed assemblage possesses several benefits with a high profile of variation in synthesized molecules, the ease of synthesis, and good cost-effectiveness of commercially available synthetic reagents, all of these have highlighted the potential worth of compound <b>24</b> as a new and highly efficient agricultural fungicide.