Modular Synthesis and Antimicrobial Investigation of Mycoleptodiscin A and Simplified Indolosesquiterpenoids.

The structure-activity relationship of the unusual indolosesquiterpenoid mycoleptodiscin A is unknown due to natural scarcity and inefficient synthesis. A modular approach leveraging Larock indole synthesis has been established to access mycoleptodiscin A and a divergent collection of drimenyl indoles. It features the utilization of an inexpensive (+)-sclareolide, modularity, purification-economy, and scalability, which facilitates the first biological evaluation of mycoleptodiscin A and related precursors.

Degradation-Risk-Inspired Optimization of the Antifungal Oxazolinyl Aniline Lead by a Fusion of Triazole with Nicotinamide.

The discovery of readily available and easily modifiable new models is a crucial and practical solution for agrochemical innovation. Antifungal function-oriented fusion of triazole with the prevalidated lead (R)-LE001 affords a novel framework with a broad and enhanced antifungal spectrum. Characterized by the easy accessibility and adjustability of [1,2,4]triazolo[4,3-a]pyridine, modular fine-tuning provided a set of unprecedented leads (e.g., Z23, Z25, Z26, etc.) with superior antifungal potentials than the positive control boscalid. Candidate Z23 exhibited a more promising antifungal activity against Sclerotinia sclerotiorum, Botrytis cinerea, and Phytophthora capsici with EC50 values of 0.7, 0.6, and 0.5 µM, respectively. This candidate could effectively control boscalid-resistant B. cinerea strains and also exhibit good vivo efficacy in controlling gray mold. Noteworthily, both the SDH-inhibition and the efficiency against Oomycete P. capsici are quite distinct from that of the positive control boscalid. A molecular docking simulation also differentiates Z23 from boscalid. These findings highlight the potential of [1,2,4]triazolo[4,3-a]pyridine amide as a novel antifungal model.

Multidimensional Optimization of R-LE001 for New Leads with Enhanced Antifungal Profiles.

Scaffold hopping and structural fine-tuning are important strategies for agrochemical innovation. Multidimensional optimization of the prevalidated antifungal lead R-LE001 was conducted via the design, synthesis, and bioevaluation of 53 new compounds differing in either scaffold or substituent. The antifungal structure-activity relationship (SAR) revealed that a number of amides containing 2-(2-oxazolinyl) aniline (NHPhOx) or 2-(2-thiazolinyl) aniline (NHPhthiOx) demonstrated a more promising antifungal effect than both R-LE001 and the positive control boscalid. Specifically, compound 10 (encoded LEX-K01) shows an excellent antifungal effect against Botrytis cinerea with an EC50 value lower than 0.11 µM. This small change leads to a significant improvement (over 1 order of magnitude) in bioactivity compared to that of either R-LE001 (EC50 = 1.41 µM) or boscalid (EC50 = 2.01 µM) and fluxapyroxad (EC50 = 4.35 µM). With much lower resistance factors, LEX-K01 (10) was more efficacious against the two boscalid-resistant strains of B. cinerea TZ01 and NJBH2017. A combination of LEX-K01 (10) and boscalid in a ratio of 1:3 showed synergistic effects against resistant B. cinerea TZ01 and NJBH2017, with SR values of 3.01 and 2.55, respectively. LEX-K01 (10) has a curative efficacy (70.3%) more prominent than that of boscalid (51.2%) in controlling disease caused by B. cinerea. The molecular docking simulation of LEX-K01 (10) with the SDH protein of B. cinerea displayed four hydrogen bonds with amino acid residues TYR144, ARG88, TRP81, and SER84, rationalizing a stronger affinity than boscalid. The scanning electron microscopy (SEM) characteristic revealed that it could cause an obvious collapse of B. cinerea mycelium. This work indicates that LEX-K01 (10) has the potential to be further explored as a new antifungal agent.

Eudistomins Y-Inspired Design and Divergent Optimization of Heteroaryl Ketones for New Antifungal Leads.

The discovery of structurally distinct leads is imperative in modern agrochemical science. Inspired by eudistomins Y and the framework-related pharmaceuticals, aryl heteroaryl ketone was drawn as a common model intriguing the design and divergent synthesis of 14 kinds of heteroaryl ketones aligned with their oxime derivatives. Antifungal function-oriented phenotypical screen protruded benzothiazolyl-phenyl oxime 5a as a promising model, and the concomitant modification led to benzothiazolyl oxime 5am (EC50 = 5.17 µM) as a superior lead than fluoxastrobin (EC50 = 7.54 µM) against Sclerotinia sclerotiorum. Scaffold hopping of the phenyl subunit identified benzothiazolyl-pyridyl oxime as a novel antifungal scaffold accompanied by acquiring oxime 5bm with remarkable activity (EC50 = 3.57 µM) against Pyricularia oryzae. Molecular docking showed that candidate 5am could form more hydrogen bonds with the amino acid residues of actin than metrafenone. This compound also demonstrated better curative efficacy than that of fluoxastrobin and metrafenone in controlling the plant disease caused by S. sclerotiorum. These results rationalize the discovery of antifungal candidates based on aryl heteroaryl ketone.

Facile Synthesis and First Antifungal Exploration of Tetracyclic Meroterpenoids: (+)-Aureol, (-)-Pelorol, and Its Analogs.

As an important bioactive molecular backbone, drimane meroterpenoids have drawn a great deal of attention from both pharmacologists and chemists. Inspired by the prevalidated success of conformational restriction in the discovery of novel pharmaceutical leads, two distinct tetracyclic drimane meroterpenoids, (-)-pelorol and (+)-aureol, were synthesized from the inexpensive starting material (-)-sclareol through 10 and 8 steps with 5.6% and 5.4% overall yield, respectively. The mild conditions, operational facility, and scalability enabled the expedient synthesis and biological exploration of not only natural products themselves but also their mimics. The first agrochemical exploration showed (-)-pelorol and (+)-aureol possessed good antifungal activity against Rhizoctonia solani, with EC50 values of 7.7 and 6.9 µM, respectively. This revealed that tetracyclic drimane meroterpenoids are valuable models for antifungal lead discovery.

Design and Discovery of α-Oximido-arylacetamides as Novel Antifungal Leads.

The discovery of novel and easily accessible antifungal compounds is an imperative issue in agrochemical innovation. Our continuing research with the o-aminophenyloxazoline (NHPhOx) scaffold demonstrated the viability of introducing phenylacetamides for identifying novel antifungal leads. An antifungal function-oriented molecular evaluation was conducted for the previously identified lead R-LE008. Fine-tuning of the α-position and scaffold hopping of acid segment and NHPhOx enables α-oximido-arylacetamide as a novel antifungal model. The concomitant function-oriented diversification produces a panel of antifungal leads CN19, CN21b, CN28, and CN31 against Sclerotinia sclerotiorum and Botrytis cinerea. The crucial and multidimensional effect of the configuration of the acquired amides on the antifungal performance is demonstrated specifically by the separable CN21 isomers. The Z-isomer (CN21b), with an EC50 value of 0.97 µM against B. cinerea, is significantly more potent than its E-isomer (CN21a) and the positive control boscalid. More importantly, compound CN21b can efficiently inhibit resistant B. cinerea strains. CN21b demonstrates a better in vivo preventative effect (82.1%) than those of CN21a (48.1%) and boscalid (55.1%) at 100 µM. CN21b showed a distinct binding model from those of the boscalid and CN21a in the molecular docking simulation. A further morphological investigation by scanning electron microscopy revealed the different mycelia shrinkage of B. cinerea treated by CN21 isomers. The easy accessibility and cost-effectiveness demonstrated the practical potential of α-oximido-phenylacetamide containing NHPhOx as a new model for agrochemical innovation.

Antifungal Function Oriented Scaffold Hopping for the Discovery of Oxazolyl-oxazoline as a Novel Model against Fusarium graminearum.

Discovery of novel structural models is extremely important in agrochemical innovation. Scaffold hopping was conducted, and 16 kinds of novel models were synthesized and biologically evaluated. Oxazolyl-oxazoline 25 showed a promising in vitro potential against Fusarium graminearum with EC50 value of 18.25 µM, which was 2.4 times more potent than that of carbendazim (EC50 = 43.06 µM). The antifungal structure-activity relationship (SAR) revealed that compound 25am had the most promising antifungal activity against F. graminearum, with an EC50 value of 13.46 µM, which was 3.2 more potent than that of carbendazim. Different from carbendazim, the candidate 25am could form five hydrogen bonds with the amino acid residues in ß-tubulin in the molecular docking and could effectively inhibit the carbendazim-resistant F. graminearum strain. Scanning electron microscopy (SEM) revealed that compound 25am induced the mycelia of F. graminearum slight collapse. This work suggests that compound 25am should be prioritized for further evaluation for new antifungal agents.

Bioactivity-Guided Subtraction of MIQOX for Easily Available Isoquinoline Hydrazides as Novel Antifungal Candidates.

The discovery of novel and easily available leads provides a convincing solution to agrochemical innovation. A bioassay-guided scaffold subtraction of the previous "Chem-Bio Model" isoquinoline-3-oxazoline MIQOX was conducted for identifying the easily available isoquinoline-3-hydrazide as a novel antifungal scaffold. The special and practical potential of this model was demonstrated by a phenotypic antifungal bioassay, molecular docking, and cross-resistance evaluation. A panel of antifungal leads (LW2, LW3, and LW11) was acquired, showing much better antifungal performance than the positive controls. Specifically, compound LW3 exhibited a broad antifungal spectrum holding EC50 values as low as 0.54, 0.09, 1.52, and 2.65 mg/L against B. cinerea, R. solani, S. sclerotiorum , and F. graminearum, respectively. It demonstrated a curative efficacy better than that of boscalid in controlling the plant disease caused by B. cinerea. The candidate LW3 did not show cross-resistance to the extensively used succinate dehydrogenase inhibitor (SDHI) fungicides and can efficiently inhibit resistant B. cinerea strains. The molecular docking of compound LW3 is quite different from that of the positive controls boscalid and fluopyram. This progress highlights the practicality of isoquinoline hydrazide as a novel model in fungicide innovation.

Practical Synthesis and Antifungal Investigation of Drimane Meroterpenoids Enabled by Nickel-Catalyzed Decarboxylative Coupling.

Drimane meroterpenoids have drawn increasing attention in the discovery of novel pharmaceutical leads owing to their structural diversity and bioactivity variation, but further development is significantly impeded by the lack of an efficient modular route of preparation. A nickel-catalyzed decarboxylative cross-coupling paradigm has been established to expeditiously access a constellation of drimane meroterpenoids. The redox-active drimane precursor is a bench-stable coupling partner and is easily available from the inexpensive feedstock sclareol. This transformation features the tolerance of challenging functional groups (phenol, aldehyde, ester, etc.) and mild conditions with a low-cost nickel catalytic system. The synthetic utility is further highlighted by the direct scalable synthesis of challenging drimane meroterpenoids as diversifiable advanced intermediates for late-stage functionalizations. This method facilitated antifungal investigations and culminated in the discovery of compounds C8 and C3 as new antifungal leads against Rhizoctonia solani, with EC50 values of 4.9 and 7.2 µM, respectively.

Autonomous Planning of Discontinuous Terrain-Dependent Crawling for Space Dobby Robots.

Complex space missions require more space robotic extravehicular operations required to crawl on spacecraft surfaces with discontinuous features at the graspable point, greatly increasing the difficulty of space robot motion manipulation. Therefore, this paper proposes an autonomous planning method for space dobby robots based on dynamic potential fields. This method can realize the autonomous crawling of space dobby robots in discontinuous environments while considering the task objectives and the self-collision problem of robotic arms when crawling. In this method, a hybrid event-time trigger with event triggering as the main trigger is proposed by combining the working characteristics of space dobby robots and improving the gait timing trigger; the dynamic potential field function is designed to adjust the space robot robotic arm grasping point adaptively according to the space robot state. Simulation results verify the effectiveness of the proposed autonomous planning method.

An LEO Constellation Early Warning System Decision-Making Method Based on Hierarchical Reinforcement Learning.

The cooperative positioning problem of hypersonic vehicles regarding LEO constellations is the focus of this research study on space-based early warning systems. A hypersonic vehicle is highly maneuverable, and its trajectory is uncertain. New challenges are posed for the cooperative positioning capability of the constellation. In recent years, breakthroughs in artificial intelligence technology have provided new avenues for collaborative multi-satellite intelligent autonomous decision-making technology. This paper addresses the problem of multi-satellite cooperative geometric positioning for hypersonic glide vehicles (HGVs) by the LEO-constellation-tracking system. To exploit the inherent advantages of hierarchical reinforcement learning in intelligent decision making while satisfying the constraints of cooperative observations, an autonomous intelligent decision-making algorithm for satellites that incorporates a hierarchical proximal policy optimization with random hill climbing (MAPPO-RHC) is designed. On the one hand, hierarchical decision making is used to reduce the solution space; on the other hand, it is used to maximize the global reward and to uniformly distribute satellite resources. The single-satellite local search method improves the capability of the decision-making algorithm to search the solution space based on the decision-making results of the hierarchical proximal policy-optimization algorithm, combining both random hill climbing and heuristic methods. Finally, the MAPPO-RHC algorithm's coverage and positioning accuracy performance is simulated and analyzed in two different scenarios and compared with four intelligent satellite decision-making algorithms that have been studied in recent years. From the simulation results, the decision-making results of the MAPPO-RHC algorithm can obtain more balanced resource allocations and higher geometric positioning accuracy. Thus, it is concluded that the MAPPO-RHC algorithm provides a feasible solution for the real-time decision-making problem of the LEO constellation early warning system.

Novel (Z)/(E)-1,2,4-triazole derivatives containing oxime ether moiety as potential ergosterol biosynthesis inhibitors: design, preparation, antifungal evaluation, and molecular docking.

Inspired by the highly effective and broad-spectrum antifungal activity of ergosterol biosynthesis inhibitions, a series of novel 1,2,4-triazole derivatives containing oxime ether moiety were constructed for screening the bioactivity against phytopathogenic fungi. The (Z)- and (E)-isomers of target compounds were successfully separated and identified by the spectroscopy and single crystal X-ray diffraction analyses. The bioassay results showed that the (Z)-isomers of target compounds possessed higher antifungal activity than the (E)-isomers. Strikingly, the compound (Z)-5o exhibited excellent antifungal activity against Rhizoctonia solani with the EC50 value of 0.41 µg/mL in vitro and preventive effect of 94.58% in vivo at 200 µg/mL, which was comparable to the positive control tebuconazole. The scanning electron microscopy observation indicated that the compound (Z)-5o caused the mycelial morphology to become wizened and wrinkled. The molecular docking modes of (Z)-5o and (E)-5o with the potential target protein RsCYP51 were especially compared. And the main interactions between ligands and amino acid residues were carefully analyzed to preliminarily explain the mechanism leading to the difference of activity between two isomers. The study provided a new lead molecular skeleton for developing novel triazole fungicides targeting ergosterol biosynthesis.