Discovery of Novel α-Methylene-γ-Butyrolactone Derivatives Containing Vanillin Moieties as Antiviral and Antifungal Agents

Abstract

On the basis of the structure of nicotlactone A (L1), a series of novel α-methylene-γ-butyrolactone derivatives B1–B43 were designed and synthesized by structure simplification and active fragment replacement strategies, and their antiviral and antifungal activities were evaluated. The bioassay studies indicated that many target compounds possessed good to excellent antiviral activity against tobacco mosaic virus (TMV) and some of these compounds exhibited specific antifungal activities against Valsa mali and Fusarium graminearum. Compound B32 exhibited the best anti-TMV activity (inactivation effect, 88.9%; protection effect, 65.8%; curative effect, 52.8%) in vivo at 500 mg/L, which is significantly higher than that of commercial virucides ribavirin and ningnanmycin. The inhibition effect of compound B32 was also visualized by the inoculation test using green fluorescent protein (GFP)-labeled TMV. The preliminary antiviral mechanism of compound B32 was investigated. Transmission electron microscopy (TEM) showed that compound B32 could destroy the integrity of virus particles. Then, molecular docking and isothermal titration calorimetry (ITC) analysis further demonstrated that compound B32 exhibited a strong binding affinity to the TMV coat protein with a dissociation constant (K d) of 3.06 μM, superior to ribavirin. Thus, we deduced that compound B32 may interfere with the self-assembly of TMV particles by binding TMV coat protein (CP). In addition, compound B28 showed good in vitro activity against F. graminearum with an inhibition rate of 90.9% at 50 mg/L, which was greater than that of fluxapyroxad (59.1%) but lower than that of the commercial fungicide carbendazim (96.8%). The present study provides support for the application of these α-methylene-γ-butyrolactone derivatives as novel antiviral and antifungal agents in crop protection.

Furofuran Lignans for Plant Protection: Discovery of Sesamolin and Its Derivatives as Novel Anti-Tobacco Mosaic Virus and Antibacterial Agents

“…The results showed that compound A24 had an optimum binding affinity of −43.065 kcal/mol, and it could be inlayed in the TMV CP active pockets formed by the key amino acid residues such as Asn73, Trp217, Val75, Lys253, Gln257, Val260, and Lys268 via hydrogen bonding and some key noncovalent interactions (Figure ). Most of these related amino acid residues are known to be essential for the self-assembly of TMV particles. , As shown in Figure C, for compound A24 there are two hydrogen bonding interactions between the O atom and Asn73 (2.74 Å) or Gln257 (2.14 Å), one halogen with Trp217 (2.93 Å), one alkyl interaction with Lys253 (4.12 Å), two π-alkyl interactions with Val75 (5.34 Å) and Val260 (3.78 Å), and one π-cation with Lys268. Nevertheless, the optimum binding affinity of ribavirin is −40.045 kcal/mol, and it forms six hydrogen bonding interactions with four amino acid residues including Arg134 (2.40 Å, and 3.66 Å), Asn73 (2.27 Å), Lys268 (2.04 Å, and 2.92 Å), and Pro254 (2.13 Å) and one alkyl−π interaction with Val260 (5.28 Å) (Figure F).…”

“…The interaction of compound A24 and positive control ribavirin with TMV CP was investigated through ITC. The TMV CP was prepared according to the reported method, 20 and the different samples were monitored by SDS-PAGE (12.5%) (Figure 5). With freshly purified TMV CP in hand, we determined the binding capacity of compound A24 or ribavirin (positive control) with TMV CP (Figure 6).…”

“…The target TMV CP was prepared according to a previous work. 20 The binding affinity of compound A24 or positive control ribavirin to TMV CP was recorded by ITC (Nano-ITC, Waters).…”

“…In recent years, large amounts of effective antiviral agents have been discovered through modification of natural products, such as dufulin, NK-007, methiadinil, 3-acetonyl-3-hydroxyoxindole (AHO), and xiangcaoliusuobingmi . In addition, many other natural product derivatives, including alkaloids, coumarins, , lignans, lactones, − sesquiterpenes, and polyphenolic compounds, , have also been reported to have good antiviral activities.…”

Heterocycle-Substituted α-Methylene-γ-Butyrolactones Derivatives Synthesis, Antifungal Activity, and 3D-QSAR

“…Natural products can be a good arsenal for discovering agriculturally active agents due to their distinct structures, potent biological activities, and environmental friendliness. − The α-methylene-γ-butyrolactone (MBL) is a significant structural scaffold in pharmaceutics and agriculture. , Up to now, more than 5000 MBL-containing natural products have been confirmed, the majority of which exhibit vital pharmacologically potential and attractive biological characteristics, , such as anti-inflammatory, anticancer, antioxidant, insecticidal, bacteriostatic, antiviral, and antifungal activities. − In addition, MBL has been used as a key pharmacophore in a variety of pharmaceutical preparations and chemical probes. − Compounds containing MBL fragments have been reported to exert their biological effects by acting as Michael receptors in the sulfhydryl reactions with biophilic reagents . The remarkable biological activities of MBL containing compounds have been widely used in the pharmaceutical sector; in contrast, little research has been done in the pesticide field.…”