Abstract of the work The need to develop new fungicides remains a major driving force, as fungal plant pathogens continue to develop resistance against existing fungicides at great speed, and also because new disease situations continually arise. The science of natural products has advanced significantly in recent times, and many compounds derived from nature have found a use in crop protection. Natural products, with their tremendous structural diversity, are an important source of new toxophores. If their properties allow and if sufficient quantities can be obtained from natural sources or by synthesis, such compounds may be used directly as agricultural chemicals. Alternatively, they may constitute useful starting points for the synthesis of analogues with improved biological and physical properties. The aim of this PhD work was to synthesize naturally occurring antifungal compounds and to test their biological activity. Three compounds were chosen in the literature: Farinomalein, Epicoccamide and Harzianic acid, as their biological activity and novel chemical structure made them attractive targets for chemical synthesis. Thus, during the PhD work, efforts were made to synthesize the natural compounds and their analogues. First, a practical and convenient synthesis of the fungicidal natural compound Farinomalein was carried out starting from readily available ethyl 3-methyl-2-oxobutyrate and triethyl phosphonoacetate, employing a Horner-Wadsworth-Emmons condensation as the key step. The antifungal activity of a series of analogues of farinomalein was evaluated against Cladosporium cladosporioides. Changing the linear side chain into a branched one seemed not to be crucial for the activity, whereas increasing the number of side chain carbons significantly affected the antifungal activity. Efforts towards the first total synthesis of Epicoccamide D were also made. Epicoccamide D exhibits antifungal activity; moreover, it shows weak to moderate cytotoxicity towards HeLa a cell lines (CC50 17.0µM) and good antiproliferative effects on mouse fibroblast (L-929) and human leukaemia cell lines (K-562) with inhibition of growth (GI50) of 50.5 and 33.3µM, respectively. Finally, a synthetic strategy of Harzianic acid was developed. Harzianic acid has significant antifungal and plant growth promotion effect, which makes it a potential lead for the design of new antifungals. The evaluation of the biological activity of this intermediates and completion of total synthesis of harzianic acid is in progress. During the PhD an expedient synthesis of 3,7-diaryl-1,4-dihydro[1,2,4]triazolo[5,1-c][1,2,4]triazines was also developed. It was carried out in three steps from 3,5-dibromo-1H-1,2,4-triazole.The reactions were conducted under easy-to-perform, mild conditions with moderate to good yields. The synthesis affords easy entry to previously unreported heterocyclic compounds of potential pharmacological and agrochemical interest.

SYNTHESIS AND BIOLOGICAL ACTIVITY EVALUATION OF NATURALANTIFUNGALS AND THEIR ANALOGUES / S. Aiwale ; tutore: Sabrina Dallavalle ; coordinatore: D. Daffonchio. UNIVERSITA' DEGLI STUDI DI MILANO, 2013 Jan 21. 25. ciclo, Anno Accademico 2012. [10.13130/aiwale-sachin_phd2013-01-21].

SYNTHESIS AND BIOLOGICAL ACTIVITY EVALUATION OF NATURALANTIFUNGALS AND THEIR ANALOGUES

S. Aiwale
2013

Abstract

Abstract of the work The need to develop new fungicides remains a major driving force, as fungal plant pathogens continue to develop resistance against existing fungicides at great speed, and also because new disease situations continually arise. The science of natural products has advanced significantly in recent times, and many compounds derived from nature have found a use in crop protection. Natural products, with their tremendous structural diversity, are an important source of new toxophores. If their properties allow and if sufficient quantities can be obtained from natural sources or by synthesis, such compounds may be used directly as agricultural chemicals. Alternatively, they may constitute useful starting points for the synthesis of analogues with improved biological and physical properties. The aim of this PhD work was to synthesize naturally occurring antifungal compounds and to test their biological activity. Three compounds were chosen in the literature: Farinomalein, Epicoccamide and Harzianic acid, as their biological activity and novel chemical structure made them attractive targets for chemical synthesis. Thus, during the PhD work, efforts were made to synthesize the natural compounds and their analogues. First, a practical and convenient synthesis of the fungicidal natural compound Farinomalein was carried out starting from readily available ethyl 3-methyl-2-oxobutyrate and triethyl phosphonoacetate, employing a Horner-Wadsworth-Emmons condensation as the key step. The antifungal activity of a series of analogues of farinomalein was evaluated against Cladosporium cladosporioides. Changing the linear side chain into a branched one seemed not to be crucial for the activity, whereas increasing the number of side chain carbons significantly affected the antifungal activity. Efforts towards the first total synthesis of Epicoccamide D were also made. Epicoccamide D exhibits antifungal activity; moreover, it shows weak to moderate cytotoxicity towards HeLa a cell lines (CC50 17.0µM) and good antiproliferative effects on mouse fibroblast (L-929) and human leukaemia cell lines (K-562) with inhibition of growth (GI50) of 50.5 and 33.3µM, respectively. Finally, a synthetic strategy of Harzianic acid was developed. Harzianic acid has significant antifungal and plant growth promotion effect, which makes it a potential lead for the design of new antifungals. The evaluation of the biological activity of this intermediates and completion of total synthesis of harzianic acid is in progress. During the PhD an expedient synthesis of 3,7-diaryl-1,4-dihydro[1,2,4]triazolo[5,1-c][1,2,4]triazines was also developed. It was carried out in three steps from 3,5-dibromo-1H-1,2,4-triazole.The reactions were conducted under easy-to-perform, mild conditions with moderate to good yields. The synthesis affords easy entry to previously unreported heterocyclic compounds of potential pharmacological and agrochemical interest.
21-gen-2013
Settore CHIM/06 - Chimica Organica
DALLAVALLE, SABRINA
DAFFONCHIO, DANIELE GIUSEPPE
Doctoral Thesis
SYNTHESIS AND BIOLOGICAL ACTIVITY EVALUATION OF NATURALANTIFUNGALS AND THEIR ANALOGUES / S. Aiwale ; tutore: Sabrina Dallavalle ; coordinatore: D. Daffonchio. UNIVERSITA' DEGLI STUDI DI MILANO, 2013 Jan 21. 25. ciclo, Anno Accademico 2012. [10.13130/aiwale-sachin_phd2013-01-21].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/215697
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