Activity-based protein profiling in drug/pesticide discovery: Recent advances in target identification of antibacterial compounds.

Given the escalating incidence of bacterial diseases and the challenge posed by pathogenic bacterial resistance, it is imperative to identify appropriate methodologies for conducting proteomic investigations on bacteria, and thereby promoting the target-based drug/pesticide discovery. Interestingly, a novel technology termed "activity-based protein profiling" (ABPP) has been developed to identify the target proteins of active molecules. However, few studies have summarized advancements in ABPP for identifying the target proteins in antibacterial-active compounds. In order to accelerate the discovery and development of new drug/agrochemical discovery, we provide a concise overview of ABPP and its recent applications in antibacterial agent discovery. Diversiform cases were cited to demonstrate the potential of ABPP for target identification though highlighting the design strategies and summarizing the reported target protein of antibacterial compounds. Overall, this review is an excellent reference for probe design towards antibacterial compounds, and offers a new perspective of ABPP in bactericide development.

Identification of Novel Bisamide-Decorated Benzotriazole Derivatives as Anti-Phytopathogenic Virus Agents: Bioactivity Evaluation and Computational Simulation.

As a notorious phytopathogenic virus, the tobacco mosaic virus (TMV) severely reduced the quality of crops worldwide and caused critical constraints on agricultural production. The development of novel virucides is a persuasive strategy to address this predicament. Herein, a series of novel bisamide-decorated benzotriazole derivatives were elaborately prepared and screened. Biological tests implied that the optimized compound 7d possessed the most brilliant antiviral inactive profile (EC50 = 157.6 µg/mL) and apparently surpassed that of commercial ribavirin (EC50 = 442.1 µg/mL) 2.8-fold. The preliminary antiviral mechanism was elaborately investigated via transmission electron microscopy, microscale thermophoresis (MST) determination, RT-qPCR, and Western blot analysis. The results showed that compound 7d blocked the assembly of TMV by binding with coat protein (Kd = 0.7 µM) and suppressed TMV coat protein gene expression and biosynthesis process. Computational simulations indicated that 7d displayed strong H-bonds and pi interactions with TMV coat protein, affording a lower binding energy (ΔGbind = -17.8 kcal/mol) compared with Ribavirin (ΔGbind = -10.7 kcal/mol). Overall, current results present a valuable perception of bisamide decorated benzotriazole derivatives with appreciably virustatic competence and should be profoundly developed as virucidal candidates in agrochemical.

Identification of natural Rutaecarpine as a potent tobacco mosaic virus (TMV) helicase candidate for managing intractable plant viral diseases.

BACKGROUND: Naturally occurring alkaloids are particularly suitable for use as pesticide precursors and further modifications due to their cost-effectiveness, unique mechanism of action, tolerable degradation, and environmental friendliness. The famous tobacco mosaic virus (TMV) is a persistent plant pathogenic virus that can parasitize many plants and severely reduce crop production. To treat TMV disease, TMV helicase acts as a crucial target by hydrolyzing adenosine triphosphate (ATP) to provide energy for double-stranded RNA unwinding. RESULTS: To seek novel framework alkaloid leads targeting TMV helicase, this work successfully established an efficient screening platform for TMV helicase inhibitors based on natural alkaloids. In vivo activity screening, enzyme activity detection, and binding assays showed that Rutaecarpine from Evodia rutaecarpa (Juss.) Benth exhibited excellent TMV helicase inhibitory properties [dissociation constant (Kd ) = 1.1 µm, half maximal inhibitory concentration (IC50 ) = 227.24 µm] and excellent anti-TMV ability. Molecular docking and dynamic simulations depicted that Rutaecarpine could stably bind in active pockets of helicase with low binding energy (ΔGbind = -17.8 kcal/mol) driven by hydrogen bonding and hydrophobic interactions. CONCLUSION: Given Rutaecarpine's laudable bioactivity and structural modifiability, it can serve as a privileged building block for further pesticide discovery.

Engineering Phenothiazine-Based Functional Mimics of Host Defense Peptides as New Agrochemical Candidates: Design, Synthesis, and Antibacterial Evaluation.

In the protracted "arms race" between host and plant pathogenic bacteria, host organisms have evolved powerful weapons known as host defense peptides (HDPs). However, natural HDPs are not suitable for large-scale applications; therefore, researchers have chosen to develop bespoke small-molecule functional mimics. Phenothiazine derivatives were developed as functional HDPs mimics, owing to their broad biological activity and high lipophilicity. The phenothiazine analogues designed in this study exhibited excellent in vitro bioactivity against the three Gram-negative bacteria Xanthomonas oryzae pv oryzae, Xanthomonas axonopodis pv citri, and Pseudomonas syringae pv actinidiae, with optimal EC50 values of 0.80, 0.31, and 1.91 µg/mL, respectively. Preliminary evidence suggests that compound C2 may act on bacterial cell membranes and interact with bacterial Deoxyribonucleic acid in the groove binding mode. In vivo trials showed that compound C2 was highly effective against rice leaf blight (51.97-56.69%), with activity superior to those of bismerthiazol (40.7-43.4%) and thiodiazole copper (30.2-37.1%). Our study provides strong evidence to support the development of phenothiazine derivatives into pesticide candidates.

Discovery of novel phenothiazine derivatives as new agrochemical alternatives for treating plant viral diseases.

BACKGROUND: Plant viral diseases, namely 'plant cancer', are extremely difficult to control. Even worse, few antiviral agents can effectively control and totally block viral infection. There is an urgent need to explore and discover novel agrochemicals with high activity and a unique mode of action to manage these refractory diseases. RESULTS: Forty-one new phenothiazine derivatives were prepared and their inhibitory activity against tobacco mosaic virus (TMV) was assessed. Compound A8 had the highest protective activity against TMV, with a half-maximal effective concentration (EC50 ) of 115.67 µg/mL, which was significantly better than that of the positive controls ningnanmycin (271.28 µg/mL) and ribavirin (557.47 µg/mL). Biochemical assays demonstrated that compound A8 could inhibit TMV replication by disrupting TMV self-assembly, but also enabled the tobacco plant to enhance its defense potency by increasing the activities of various defense enzymes. CONCLUSION: In this study, novel phenothiazine derivatives were elaborately fabricated and showed remarkable anti-TMV behavior that possessed the dual-action mechanisms of inhibiting TMV assembly and invoking the defense responses of tobacco plants. Moreover, new agrochemical alternatives based on phenothiazine were assessed for their antiviral activities and showed extended agricultural application. © 2023 Society of Chemical Industry.

Design, synthesis, and biological evaluation of novel triazoloquinazolinone derivatives as SHP2 protein inhibitors.

A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their in vitro biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds 12f, 12l, 12j, 17e, and 17f have strong antiproliferative activity on A375 cells. The compound 12l showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with SHP244. The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound 12l displayed improved physicochemical properties as well as metabolic stability compared to SHP244. Our efforts identified 12l as a promising SHP2 protein inhibitor, warranting its further investigation.