Soriano, Gabriele (2024) Natural compounds as potential new bioherbicides. [Tesi di dottorato]

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Abstract

Among all pests, holoparasitic weeds represent a tremendous threat to agriculture, having a huge economic impact all over the world. Despite many attempts to contain them, through the use of various traditional management approach, such as fumigation, solarization, intercropping and development of resistant varieties, parasitic weeds persistently adapt and spread, posing growing challenges in effectively minimizing their impact on crops. The holoparasitic weed species broomrapes (Orobanche, Phelipanche) and the dodder Cuscuta campestris are particularly problematic, because they compete with a large number of important cultivated crops, such as tomato, eggplant, potato and sunflower, by penetrating their roots for nutrient and water absorption. They are also known as obligate parasite, in fact they cannot complete their life-cycle without exploiting a suitable host. If an obligate parasite cannot identify and therefore exploit a host, it will fail to complete its life-cycle. In the last years an alternative approach, for the management of these noxious plants, consists in targeting the early stage of parasitic plants seeds development, with the final goal of a progressive reduction of parasitic plant seedbank in the cultivated soil. In this regard, nature comes to the rescue, as source of specialized metabolites that can be used as inhibitors or stimulators, in absence of the host plant, of parasitic plants seed germination and development. The aim of this PhD project has been the investigation of several weed plants, donor of allelopathic activity, in order to identify natural compounds to be used as bioherbicides. Many different specialized metabolites were isolated, such as glycosylated fatty acids, iridoid glycosides, gamma-lactone compounds, sesquiterpene lactones, flavonoids and isoflavonoids. In particular, ephedroidin from Retama raetam, melampyroside from Bellardia trixago and arvenic acids from Convolvulus arvensis, were identified as species and concentration dependent inhibitors of Orobanche crenata, Orobanche cumana, Orobanche minor, Phelipanche ramosa and Cuscuta campestris seedling growth. Furthermore, the acetylenic furanone (4Z)-lachnophyllum lactone isolated from the plant Conyza bonariensis exhibited high percentage of inhibition activity, up to 0.3 mM, against all the plant studied. Specifically, an IC50 value of 24.8 μg/mL was observed against 3 Cuscuta campestris seedling growth. Thus, considering its activity and the low amount isolated from natural sources, that pose limitation for its deeper and wider investigation, it was selected and total synthesized on gram scale. The developed methodology towards (4Z)-lachnophyllum lactone (84) synthesis is reported for the first time. Starting from a retrosynthetic analysis, the key step was identified in a Pd-Cu bimetallic cascade cross-coupling cyclization. The five-step methodology allow to obtain the (4Z)-lachnophyllum lactone on gram scale, besides being easy modulable, whereby changing the intermediate of the synthetic pathway many different analogues can be obtained. Furthermore, two natural analogues were synthesized, namely the (4E)-lachnophyllum lactone and the (4Z,8Z)-matricaria lactone, that showed, in most cases, the same inhibitory trend with slight differences, highlighting the importance of the stereochemistry and unsaturation of the side chain. The design and implementation of this scalable and modulable total synthesis of acetylenic furanones on gram scale, allow the production of large amount of these natural products, overcoming the limit imposed by isolation from natural sources and simplifying the exploration and refinement of bio-formulations. In this regard, first attempts for the development of a novel and easy-to-use tool for the agrochemical industry were already performed. Indeed, preliminary results showed that (4Z)-lachnophyllum lactone can be included into cyclodextrins or readily water solubilized by the use of the natural surfactants rhamnolipids, encouraging and paving the way for its final application in field. Additionally, the last step of the developed synthetic strategy towards (4Z)-lachnophyllum lactone, was exploited to obtain several analogues, aiming to gain further understanding into the structural features that impact and define its mode of action. A panel of synthetic analogues deprived of the side chain triple bond were prepared. Specifically, the reactions allow to obtain the delta-lactone, E and Z-gamma-lactone to investigate how side chain unsaturation, length and dimension of the lactone framework can affect the activity. In conclusion, the results obtained contribute to enlarge the pool of natural products to be used as bio-inspired herbicides and provide a practical, ecofriendly and ready-to-use herbicide, the (4Z)-lachnophyllum lactone, with potential application in the agrochemical industry.

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