4-Nitropyrazolin-5-ones as Readily Available Fungicides of the Novel Structural Type for Crop Protection: Atom-Efficient Scalable Synthesis and Key Structural Features Responsible for Activity

Abstract

The development of new types of fungicides for agriculture and medicine is highly desirable due to the uprising fungal resistance against commonly used compounds. Herein, 4-substituted-4-nitropyrazolin-5-ones (nitropyrazolones) were proposed as highly active fungicides of the novel structural type. The first scalable and practical method for the nitropyrazolone synthesis was proposed, which is atom-efficient, is applicable for the multigram scale synthesis, and allows for production of a wide variety of nitropyrazolones with high yields and purity. The synthesized compounds demonstrated high fungicidal activity against the broad spectrum of phytopathogenic fungi (Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum). Their mycelium growth inhibiting activity was comparable or superior to that of kresoximmethyl. In vitro activity against Staphyloccocus aureus, Candida albicans, and Aspergillus niger revealed that nitropyrazolones are promising candidates against human pathogens. The key factors for the manifestation of high fungicidal activity were established to be an aromatic substituent on the N1 atom and small substituents, such as methyl, at the C3 and C4 positions of the pyrazolone ring.

4-Disubstituted Pyrazolin-3-Ones—Novel Class of Fungicides against Phytopathogenic Fungi

“…We have synthesized and tested a series of pyrazolones with variable substituent at position 4 instead of the NO2 group to reveal the role of this substituent. The structure of one of the most active nitropyrazolones, 4,5-dimethyl-4-nitro-2-phenyl-2,4-dihydro-3Hpyrazol-3-one (1a, Scheme 1), was used as the reference [51,52]. Synthetic approaches to the target compounds 1b-1j and 2d-g are shown in Scheme 1.…”

“…Synthetic approaches to the target compounds 1b-1j and 2d-g are shown in Scheme 1. A previously developed synthetic procedure using N 2 O 4 as a nitrating agent [51] was used for the synthesis of 1a. The advantages of this method are the absence of metal-containing reagents in contrast to the metal salt/NaNO 2 system [52], high selectivity, and scalability up to multigram quantities without the yield drop and without the need for chromatographic purification of the target product.…”

“…Our previous study [51] of the structure-activity relationship revealed the importance of the aromatic substituent at N2, a small alkyl substituents at the C4 and C5 atoms of the pyrazolone ring, and the C(sp 3 )-hybridized C4 atom for high fungicidal activity [51]. Since the In our previous reports, 4-nitropyrazoline-3-ones were discovered as the novel class of highly potent broad spectrum fungicides [51,52]. However, the understanding of the underlying modes of action was lacking.…”

“…However, their potential as effective fungicides has not been expected. In our previous reports, 4-nitropyrazoline-3-ones were discovered as the novel class of highly potent broad spectrum fungicides [51,52]. However, the understanding of the underlying modes of action was lacking.…”

“…To shed light on this issue, it is desirable to know how the structure of pyrazolone derivatives affects their fungicidal activity. Our previous study [51] of the structure-activity relationship revealed the importance of the aromatic substituent at N2, a small alkyl substituents at the C4 and C5 atoms of the pyrazolone ring, and the C(sp 3 )-hybridized C4 atom for high fungicidal activity [51]. Since the In our previous reports, 4-nitropyrazoline-3-ones were discovered as the novel class of highly potent broad spectrum fungicides [51,52].…”