Application of photopharmacology in agrochemicals

The pursuit of new succinate dehydrogenase (SDH) inhibitors is a leading edge in fungicide research and development. The use of 3D quantitative structure−activity relationship (3D-QSAR) models significantly enhances the development of compounds with potent antifungal properties. In this study, we leveraged the natural product coumarin as a molecular scaffold to synthesize 74 novel 3-coumarin hydrazide derivatives. Notably, compounds 4ap (0.28 μg/mL), 6ae (0.32 μg/mL), and 6ah (0.48 μg/mL) exhibited exceptional in vitro effectiveness against Rhizoctonia solani, outperforming the commonly used fungicide boscalid (0.52 μg/mL). Furthermore, compounds 4ak (0.88 μg/mL), 6ae (0.61 μg/mL), 6ah (0.65 μg/mL), and 6ak (1.11 μg/mL) showed significant activity against Colletotrichum orbiculare, surpassing both the SDHI fungicide boscalid (43.45 μg/mL) and the broadspectrum fungicide carbendazim (2.15 μg/mL). Molecular docking studies and SDH enzyme assays indicate that compound 4ah may serve as a promising SDHI fungicide. Our ongoing research aims to refine this 3D-QSAR model further, enhance molecular design, and conduct additional bioactivity assays.

Section: Introductionmentioning

confidence: 99%

3D-QSAR-Directed Synthesis of Halogenated Coumarin-3-Hydrazide Derivatives: Unveiling Their Potential as SDHI Antifungal Agents

Dai,

Ma,

et al. 2024

“…Photopharmacology , is an emerging approach for novel drug discovery. This technology can be achieved by one way of incorporating photoswitches into existing pharmaceuticals and agrochemicals . The new photosensitive molecules undergo configurational variations if exposed to light, leading to pharmacodynamical modifications, consequently resulting in the emergence of distinct biological activities .…”

Section: Introductionmentioning

confidence: 99%

Optical Control of Insect Behavior and Receptors with Azobenzene-Bridged Fipronil and Imidacloprid

Fu,

Sheng,

Qiao

et al. 2024

Self Cite

Photopharmacology can be implemented in a way of regulating drug activities by light-controlling the molecular configuations. Three photochromic ligands (PCLs) that bind on one or two sites of GABARs and nAChRs were reported here. These multiphoton PCLs, including FIP-AB-FIP, IMI-AB-FIP, and IMI-AB-IMI, are constructed with an azobenzene (AB) bridge that covalently connects two fipronil (FIP) and imidacloprid (IMI) molecules. Interestingly, the three PCLs as well as FIP and IMI showed great insecticidal activities against Aedes albopictus larvae and Aphis craccivora. IMI-AB-FIP in both trans/cis isomers can be reversibly interconverted depending on light, accompanied by insecticidal activity decrease or increase by 1.5–2.3 folds. In addition, IMI-AB-FIP displayed synergistic effects against A. craccivora (LC50, IMI‑AB‑FIP = 14.84–22.10 μM, LC50, IMI‑AB‑IMI = 210.52–266.63 μM, LC50, and FIP‑AB‑FIP = 36.25–51.04 μM), mainly resulting from a conceivable reason for simultaneous targeting on both GABARs and nAChRs. Furthermore, modulations of wiggler-swimming behaviors and cockroach neuron function were conducted and the results indirectly demonstrated the ligand–receptor interactions. In other words, real-time regulations of receptors and insect behaviors can be spatiotemporally achieved by our two-photon PCLs using light.

“…Succinate dehydrogenase inhibitor (SDHI) fungicides are well-known for their ability to inhibit the function of SDH, which blocks the tricarboxylic acid cycle (TCA) and electron transfer (ETC) in the mitochondrial respiratory chain, resulting in fungi death due to energy deprivation. − Until now, there are several SDHI fungicides which could be used to control PM, such as boscalid, fluxapyroxad, penthiopyrad, benzovindiflupyr, fluopyram, isofetamid, and pydiflumetofen (Figure ). As we all know, the chemical structure of classical SDHI fungicides mainly contained three moieties: a heterocyclic acid core, an amide linker, and a hydrophobic fragment. − As shown in Figure , fluopyram, isofetamid, and pydiflumetofen stood out from the classical SDHIs because of their unique stretched amide bond, which is enlarged by flexible alkyl chains.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of New Succinate Dehydrogenase Inhibitors via Scaffold Hopping Strategy

Huang,

Wei,

Wang

et al. 2023

Scaffold hopping strategy has become one of the most successful methods in the process of molecular design. Seeking to develop novel succinate dehydrogenase inhibitors (SDHIs), we employed a scaffold hopping strategy to design compounds featuring geminate dichloralkenes (gem-dichloralkenes) fragment. After stepwise modifications, a series of N-cyclopropyl-dichloralkenes-pyrazole-carboxamide derivatives was synthesized. Among them, compounds G28 (IC50 = 26.00 nM) and G40 (IC50 = 27.00 nM) were identified as the best inhibitory activity against porcine SDH, with IC50 values reaching the nanomolar range, outperforming the lead compound pydiflumetofen. Additionally, the greenhouse assay indicated that compounds G37 (EC90 = 0.031 mg/L) and G34 (EC90 = 1.67 mg/L) displayed extremely high activities against wheat powdery mildew (WPM) and cucumber powdery mildew (CPM), respectively. Computational results further revealed that the gem-dichloralkene fragment and fluorine substituted pyrazole form an extra hydrophobic interaction and dipolar–dipolar interaction with SDH. In summary, our study provides a novel gem-dichloralkene scaffold with outstanding fungicidal properties, obtained through scaffold hopping, that holds great potential for future research on PM control.