Functional Analogues of Salicylic Acid and Their Use in Crop Protection

agronomy

Review Functional Analogues of Salicylic Acid and Their Use in Crop Protection

Lydia Faize 1 and Mohamed Faize 2,* 1 Group of Fruit Tree Biotechnology, Department of Plant Breeding, CEBAS-CSIC, 30100 Murcia, Spain; [email protected] 2 Laboratory of Plant Biotechnology and Ecosystem Valorisation, Faculty of Sciences, University Chouaib Doukkali, El Jadida 24000, Morocco * Correspondence: [email protected]; Tel.: +212-671-276-6617

Received: 9 December 2017; Accepted: 4 January 2018; Published: 9 January 2018

Abstract: Functional analogues of salicylic acid are able to activate plant defense responses and provide attractive alternatives to conventional biocidal agrochemicals. However, there are many problems that growers must consider during their use in crop protection, including incomplete disease reduction and the ﬁtness cost for plants. High-throughput screening methods of chemical libraries allowed the identiﬁcation of new compounds that do not affect plant growth, and whose mechanisms of action are based on priming of plant defenses, rather than on their direct activation. Some of these new compounds may also contribute to the discovery of unknown components of the plant immune system.

Keywords: salicylic acid; functional analogues; priming; crop protection

1. Introduction Increasing demand for environmentally-friendly alternatives to traditional pesticides is an impetus for designing new biological strategies for crop protection. Stimulating the natural plant immunity through induced resistance is among those strategies [1]. Upon infection, the plants are able to fight against pathogen attacks by activating their immune mechanisms that are initiated after the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors. This activated immunity is called PAMP-triggered immunity (PTI) [2]. However, some pathogens are able to suppress PTI via effector proteins. In this case, plants are able to defend themselves via effector triggered immunity (ETI) involving resistance genes products (R) and is usually associated with hypersensitive responses (HR) that are characterized by rapid programmed cell death at the penetration site [3]. Both responses involve accumulation of reactive oxygen species (ROS) in infected tissues, followed by the activation of mitogen activated protein kinases (MAPKs) and increase in the expression of defense-related genes, including pathogenesis that are related (PR) genes and salicylic acid (SA) accumulation [4,5]. Subsequently an immune response, called systemic acquired resistance (SAR) is induced in distal non-inoculated parts of the plant against broad spectrum of pathogen [6]. Other phytohormones including jasmonic acid (JA), ethylene (ET), and abscisic acid (ABA) are also involved in regulation of induced plant immunity. While SA induces defenses by and against biotrophic pathogens JA mediate defenses by and against necrotrophic pathogens and herbivorous insects. The cross-talk among these different signaling pathways leads to the fine-tune of the plant defense responses against specific aggressors [7,8]. SAR is considered as the most agronomically relevant type of plant immunity [6] and can also be triggered by signal molecules that are involved in plant resistance to pathogens, including SA and a wide range of synthetic compounds. Among these compounds functional analogues of SA are able to activate plant defense responses and provide attractive alternatives to conventional biocidal

Agronomy 2018, 8, 5; doi:10.3390/agronomy8010005 www.mdpi.com/journal/agronomy Agronomy 2018, 8, 5 2 of 20 agrochemicals. They are able to mimic a subset of known SA functions by directly interfering with its receptors or by triggering transcriptional and physiological responses that are related to those induced by SA without directly interfering with SA targets [9]. Although they generally do not possess antimicrobial activity in vitro and can activate resistance against broad spectra of pathogens by inducing SAR genes that are triggered by biological or SA inducers they are many problems that growers must consider during their use in crop protection, including incomplete disease reduction and the fitness cost for plants [10]. High-throughput screening methods of chemical libraries allowed the identification of new compounds that do not affect plant growth, and whose mechanisms of action are based on priming of plant defenses upon pathogen infection rather on their direct activation [11–13]. After a brief description of the mode of action of SA in plant defense we will review the most important groups of functional analogues of SA with their use as plant protective agents. Particular attention will also be given to the methods used for screening of chemical libraries to obtain new compounds. These new agrochemicals will not only provide resistance against a broader spectrum of plant pathogens, but may also contribute to the identification of novel pathway components of SAR.

2. Mode of Action of SA in Plant Defense SA is one of several plant hormones acting as an endogenous signal to trigger plant immunity responses and to allow the establishment of disease resistance. The SA pathway is primarily induced by and against biotrophic pathogens and is often hindered by various feedback loops and cross-talk with other phytohormones that modulate the SA signal, including jasmonic acid (JA) and ethylene (ET) [7,8]. Exogenous application of SA can induce ROS production, PR genes expression, and disease resistance against a wide range of biotrophic and hemibiotrophic fungal, bacterial, viral, as well as phloem-feeding insects. For instance, exogenous application of SA confers resistance against tobacco mosaic virus (TMV) [7], cauliflower mosaic virus [14] and turnip crinkle virus in Arabidopsis thaliana [15]. Treatment of Nicotiana benthamiana with SA results in reduced grown gall symptoms caused by Agrobacterium tumefaciens [16]. It is also effective in controlling fire blight disease that is caused by the bacterium Erwinia amylovora in pear [17]. Regarding phytopathogenic fungi SA induces resistance in A. thaliana against the powdery mildew pathogen Erysiphe orontii [18] and the downy mildew pathogen Hyaloperonospora parasitica [19]. Its efficacy was also probed in tobacco against the powdery mildew pathogen Oidium sp. [20], in tomato against leaf blight caused by Alternaria solani [21], and in cherry fruits against fruit rot caused by Monilia fructicola [22]. SA is synthesized via two distinct and compartmentalized pathways [23]. It is produced through the phenylalanine pathway by decarboxylation of trans-cinnamic acid to benzoic acid, followed by hydroxylation to SA. Alternatively, cinnamic acid may be hydroxylated to o-coumaric acid and then decarboxylated to SA [24]. In the isochorismate pathway, SA synthesis involves isochorismate synthase (ICS), which converts chorismate to isochorismate [25]. The expression of ICS1 is positively regulated by several transcription factors (TFs), including calmodulin-binding protein 60 g (CBP60g). PAMP recognition generates calcium influx in the cytosol which is transduced to calmodulin-binding protein CBP60g and WRKY28 triggering activation of isochorismate synthase and SA biosynthesis [26]. Recently, a third pathway involving cyanogenic glycosides, such as prunasin and mandelonitrile have been also recognized to be involved in SA synthesis in peach [27]. In Arabidopsis, the regulation of SA involves two lipase-like proteins acting upstream of SA: EDS1 (for enhanced disease susceptibility) and PAD4 (for phytoalexin deficient) [28]. EDS1 represents an important node that controls SA production to amplify defense signals. It forms a heterodimer with PAD4 that transduces ROS-derived signals leading to enhanced SA production through the accumulation of benzoic acid (BA) and its conversion to SA by benzoic acid 2-hydroxylase (BA2H) [29,30]. SID2 (for SA induction deficient) encodes for an ICS that is involved in the biosynthesis of SA, because a mutation sid2 reduces SA synthesis in A. thaliana and the expression of the PR1 gene [25]. EDS5, also named SID1, is involved in the regulation of SA. It belongs to the multidrug and toxin extrusion (MATE) transporter proteins and is located downstream of PAD4. It is involved in the transport of SA Agronomy 2018, 8, 5 3 of 20 precursors and its expression requires PAD4 [31]. EDS4 is another component that plays a role in SA signaling and in SA-induced SAR [32]. EDS1, PAD4, and EDS4 activate SID2, which produce SA [33]. Upon its synthesis in the chloroplast, SA is transported to the cytosol via EDS5 protein where it will be inactivated via glycosylation or methylation [7,34]. Glycosylation of SA generates SA 2-O-β-D-glucoside (SAG), which is transported to the vacuole and will be hydrolyzed to release free SA after pathogen attack [35]. Methylation of SA generates methyl SA (MeSA), which is supposed to be the mobile SAR signal that travels from the infected to the systemic tissues, where it activates resistance following its reconversion to SA. Following pathogen infection, SA levels increase dramatically in the inoculated leaves, however it is converted to biologically inactive MeSA by SA methyl transferase (SAMT). Once SA concentration becomes sufficiently high, it binds in the active site of salicylic acid binding protein 2 (SABP2) and prevents its ability to convert MeSA back into SA [35]. Methylation of SA causes a change in the potential redox of the chloroplast cell wall facilitating its translocation to cytoplasm of the distal, uninfected tissue. Since SA levels in the distal tissue are too low to inhibit SABP2, the transported MeSA is converted to active SA, which then induces systemic defense responses [35]. Other mobile signaling molecules includes a non-proteinaceous amino acid pipecolic acid (Pip) [36] and azelaic acid; a 9-carbon dicarobxylic acid, which has been reported to be limited to vascular sap in A. thaliana inoculated with P. syringae [37]. The diterpenoid Dehydroabietinal (DA) was also shown to be translocated far from treated tissues in Arabidopsis, tobacco, and tomato, where it enhances the accumulation of SA and the expression of PR1 gene [38]. Other mechanisms that are preventing over-accumulation of SA and generation of the mobile signal of SAR involve its conversion to 2,3-dihydroxybenzoic acid (2,3-DHBA) by SA 3-hydroxylase (S3H; also termed DLOL1) and the formation of SA-amino acid conjugates such as salicyloyl-aspartate (SA-Asp) synthesized by a member of the GH3 acyl adenylase family of early auxin-responsive genes named GH3.5 [39]. Defense signaling downstream of SA is regulated via NPR1 and NPR3/4 homeostasis in a concentration dependent manner. This determines the levels and selective activation of defense responses, which should be switched on during pathogen infection [40]. NPR1 is a considered as master regulator of the SA-mediated defense genes. It binds to SA through two Cysteine residues 521 and 529 [41]. NPR1 is located in the cytoplasm, but pathogen induced SA accumulation activates its expression, and stimulates its translocation into the nucleus where it interacts with TGA transcription factors binding to the so called as-1 (activation sequence-1) like element of the PR1 promoter [42]. In the absence of infection NPR1 is continuously cleared from the nucleus via proteasome-mediated degradation, a process mediated by NPR3 and NPR4, which are adaptors for Cullin 3 ubiquitin E3 ligase [40]. NPR4 maintains low NPR1 levels, however after infection, at higher concentration SA binds to NPR4 and disrupts the NPR1–NPR4 interaction, allowing for NPR1 to accumulate and defense signaling to occur. In cells containing sufficiently high SA levels, NPR3 binds NPR1; this promotes NPR1 turnover, which optimizes defense activation and resets NPR1 levels [43].

3. Functional Analogues of SA Although SA is a potent inducer of plant resistance its rapid glycosylation often leads to its reduced efficacy. In addition, its phytotoxicity has prevented its development as plant protection compounds [44]. For this reason, several functional analogues of SA with stable and effective activities have been explored so far. Most of the synthetic compounds targeting SA pathways demonstrated their effectiveness as plant defense activators in the field of crop protection, while others constitute valuable tools for dissecting components of the plant immune system. Apart from β-aminobutyric acid (BABA), we have classified these compounds according to their structures: (I) salicylate and benzoate compounds; (II) nicotinic acid derivatives; (III) pyrazole, thiazole, and thiadiazole heterocycles; (IV) pyrimidin derivatives; and, (V) neonicotinoid compounds. Agronomy 2018, 8, 5 4 of 20

3.1. β-Aminobutyric Acid Agronomy 2018, 8, 5 4 of 21 BABA is a non-protein amino acid that is known to induce resistance against many plant pathogens3.1. β-Aminobutyric in various Acid systems, by inducing both SA-dependent and SA-independent plant defense mechanisms [45] (Table1). BABA has been shown to protect Arabidopsis against H. parasitica and BABA is a non-protein amino acid that is known to induce resistance against many plant Botrytispathogens cinerea in various[46]. Insystems, lettuce, by application inducing both of SA BABA-dependent prior toand inoculation SA-independent with theplant fungal defense pathogen Bremiamechanisms lactucae [45]prevented (Table 1). pathogenBABA has developmentbeen shown to withoutprotect Arabidopsis the involvement against H. of parasitica SA [47]. and BABA also providedBotrytis cinerea significant [46]. In control lettuce, of application the late blight of BABA pathogen prior toPhytophthora inoculation with infestans the fungalon tomato pathogen [48 ]. BABA protectedBremia lactucaeBrassica prevented napus against pathogen the development fungal pathogen withoutLeptosphaeria the involvement maculans of SAby [47] activating. BABA SAalso synthesis andprovided the expression significant of controlPR1, of but the was late also blight found pathogen to act Phytophthora as an antifungal infestans agent on tomato [49]. [48] Field. BABA experiments revealedprotected that Brassica BABA napus was against able the to reduce fungal pathogen severity Leptosphaeria of Plasmopara maculans viticola byon activating grapevine SA synthesis [50]. BABA also providedand the expression significant of control PR1, but of was potato also late found blight to act in as the an field antifungal when usedagent alone[49]. Field or in experiments combination of the standardrevealed fungicidethat BABA [was51]. able In potato, to reduce it wasseverity able of to Plasmopara induce HR-like viticola on lesions grapevine surrounded [50]. BABA by also callose and provided significant control of potato late blight in the field when used alone or in combination of the production of H O , as well as the enhancement of phenolic content and activation of PR1 [52]. the standard fungicide2 [51]2 . In potato, it was able to induce HR-like lesions surrounded by callose To elucidate in depth molecular mechanisms of BABA-induced resistance against potato late blight, and the production of H2O2, as well as the enhancement of phenolic content and activation of PR1 Bengtsson[52]. To elucidate et al., developed in depth molecular an original mechanisms approach of based BABA on-induced a transcript resistance analysis against in potato combination late with quantitativeblight, Bengtsson proteomic et al., developed analysis ofan theoriginal apoplast approach secretome. based on Theya transcript showed analysis that severalin combination processes that werewith relatedquantitative to plant proteomic hormones analysis and of the amino-acid apoplast secretome. metabolisms They wereshowed affected, that several in addition processesto genes thatthat are were involved related to in plant sterol hormones biosynthesis and amino that were-acid metabolisms down regulated were affected, and those in involvedaddition to in genes phytoalexin biosynthesisthat are involved that werein sterol up-regulated biosynthesis [that53]. were down regulated and those involved in phytoalexin biosynthesis that were up-regulated [53]. Table 1. β-Aminobutyric acid and used pathosystems. Table 1. β-Aminobutyric acid and used pathosystems.

ChemicalChemical ChemicalChemical Name Name Plant/PathogenPlant/Pathogen Interaction Laboratory/Field Laboratory/Field Experiments) Experiments) Reference Reference StructureStructure ArabidopsisArabidopsis/hyalo/hyaloperonosporaperonospora parasitica, parasitica, Botrytis Botrytis cinerea cinerea [46] [46] (Laboratory)(Laboratory) BrassicaBrassica napus napus/Leptosphaeria/Leptosphaeria maculans maculans (Laboratory)(Laboratory) [49] [49] β--AminobutyricAminobutyric acid acid Lettuce/Lettuce/BremiaBremia lactucae lactucae (Laboratory)(Laboratory) [47] [47] TomatoTomato//PhytophthoraPhytophthora infestans infestans (Laboratory)(Laboratory) [48] [48] Potato/Potato/PhytophthoraPhytophthora infestans infestans (Laboratory/Field)(Laboratory/Field) [51,52] [ 51,52] Grapevine/Grapevine/PlasmoparaPlasmopara viticola viticola [50] [50]

3.2.3.2 Salicylate. Salicylate and Benzoate Derivatives Derivatives SeveralSeveral derivatives of ofSA SA were were tested tested as SAR as activators SAR activators in the greenhouse in the greenhouse [54] (Table 2 [)54. 3,5] (Table- 2). 3,5-dichlorosalicylicdichlorosalicylic acid, acid, 4-chlorosalicylic 4-chlorosalicylic acid, acid,and 5 and-chlorosalicylic 5-chlorosalicylic acid, induced acid, induced PR1 genePR1 expressiongene expression and enhanced disease resistance to TMV infection in tobacco [55]. Screening experiments revealed and enhanced disease resistance to TMV infection in tobacco [55]. Screening experiments revealed that that the monosubstituted salicylates; 3‐chlorosalicylic acid, 3‐fluorosalicylic acid and the monosubstituted salicylates; 3-chlorosalicylic acid, 3-fluorosalicylic acid and 5-fluorosalicylic acid 5‐fluorosalicylic acid caused increased PR1 induction than SA and that substitution on position 3‐ or caused5 enhanced increased further PR1 PR1 induction activity than[56]. Recently, SA and that Cui substitution et al., [57] synthetized on position a 3-series or 5 of enhanced salicylic further PR1glycoconjugate activity [56 containing]. Recently, hydrazine Cui et al. and [57 hydrazone] synthetized moieties a series and found of salicylic that the glycoconjugatesalicylate hydrazine containing hydrazinederivative andwas able hydrazone to enhance moieties cucumber and resistance found thatagainst the several salicylate phytopathogenic hydrazine derivativefungi including was able to enhanceColletotrichum cucumber orbicular resistancee, Fusarium against oxysporum several, Ralstonia phytopathogenic solani and Phyt fungiophthora including capsiciColletotrichum. Although it is orbiculare , Fusariumstructurally oxysporum related ,toRalstonia SA it did solani not mimicand Phytophthorathe mode of action capsici of. AlthoughSA as it activated it is structurally the JA rather related than to SA it didSA not pathway mimic [57] the. mode of action of SA as it activated the JA rather than SA pathway [57]. AminobenzoicAminobenzoic derivatives derivatives were were also alsoreported reported to induce to induceSAR (Table SAR 2). (Table For instance,2). For Para instance,- aminobenzoic acid (PABA), which is a cyclic amino acid that belongs to the vitamin B group, was Para-aminobenzoic acid (PABA), which is a cyclic amino acid that belongs to the vitamin B group, able to induce SAR in pepper against cucumber mosaic virus (CMV) and Xanthomonas axonopodis pv. was able to induce SAR in pepper against cucumber mosaic virus (CMV) and Xanthomonas axonopodis vesicatoria through SA pathway [58]. The substituted benzoates, 3-chlorobenzoic acid and 3,5- pv.dichlorobenzoicvesicatoria through acid induced SA pathwaybasal defense [58 ].against The H. substituted parasitica in benzoates, A. thaliana [54] 3-chlorobenzoic. The compound acid and 3,5-dichlorobenzoic3,5-dichlorobenzoic acid, inducedknown as basal 3,5-dichloroanthranilic defense against H. acid parasitica (DCA), inwasA. reported thaliana [to54 efficie]. Thently compound 3,5-dichlorobenzoictrigger resistance of A. acid, thaliana known against as H. 3,5-dichloroanthranilic parasitica and P. syringae acid. It up (DCA),-regulates was transcript reported levels to of efficiently triggervarious resistance known SA of-responsiveA. thaliana defenseagainst-relatedH. parasitica genes, suchand as P.PR1 syringae, WRKY70. It, up-regulatesand CaBP22. DCA transcript does levels ofnot various require known accumulation SA-responsive of SA and defense-relatedtriggered immune genes, responses such that as arePR1 largely, WRKY70 independent, and CaBP22 from . DCA does not require accumulation of SA and triggered immune responses that are largely independent Agronomy 2018, 8, 5 5 of 21 AgronomyAgronomy 201 201201888, ,8 8, ,,5 58 , 5 55 of of 21 21 5 of 20 Agronomy 2018, 8, 5 5 of 21 AgronomyNPR1. However, 2018, 8, 5 it partially targets a WRKY70-dependent branch of the defense signaling pathway5 of 21 NPR1NPR1.. However,However, itit partiallypartially targetstargets aa WRKY70WRKY70--dependentdependent branchbranch ofof thethe defensedefense signalingsignaling pathwaypathway [54]. Microarray analyses revealed that DCA triggers the expression of 202 genes that are commonly [54]fromNPR1[54].. MicroarrayMicroarray. NPR1However,. However, analyses analysesit partially revealedrevealed ittargets partially thatthat a WRKY70 DCADCA targets triggerstriggers-dependent a ttWRKY70hehe expressionexpression branch-dependent of of ofthe 202202 defense genesgenes branch thatsignalingthat areare of commonlycommonly pathway the defense signaling [54]regulated. Microarray by other analyses functional revealed analogues that DCA such triggers as INA, the and expression BTH, but of also 202 genesthe expression that are commonly of unique regulatedpathway[54]regulated. Microarray byby [54 otherother]. analyses Microarray functionalfunctional revealed analoguesanalogues analyses that DCA suchsuch revealed triggers asas INA,INA, thatthe andand expression DCA BTHBTH,, triggers butbut of alsoalso 202 thegenesthe expressionexpression expression that are commonly ofof unique ofunique 202 genes that are regulatedgenes [59] .by other functional analogues such as INA, and BTH, but also the expression of unique genescommonlyregulated [59] .by regulatedother functional by other analogues functional such as analogues INA, and BTH such, but as INA,also the and expression BTH, but of alsounique the expression of genes [59]. Table 2. Salicylate and benzoate derivatives and used pathosystems. unique genes [59TableTable]. 22.. SalicylateSalicylate andand benzoatebenzoate derivativesderivatives andand usedused pathosystemspathosystems.. Table 2. Salicylate and benzoate derivatives and used pathosystemsPlant/Pathogen. Table 2. Salicylate and benzoate derivatives and used pathosystemsPlant/Pathogen. Plant/PathogenInteraction Chemical/TradeTable Name 2. Salicylate and benzoateChemical Structure derivatives andPlant/Pathogen usedInteraction pathosystems. Reference Chemical/Trade Name Chemical Structure Laboratory/FieldPlant/PathogenInteraction Reference Chemical/Trade Name Chemical Structure Laboratory/FieldInteraction Reference Laboratory/FieldExperimentsInteraction ) Chemical/Trade Name Chemical Structure Experiments) Reference Laboratory/FieldExperimentsPlant/Pathogen) Interaction Chemical/Trade Name Chemical Structure Reference ExperimentsLaboratory/Field) Experiments) 3-chlorosalicylic acid, 33--chlorosalicylicchlorosalicylic acid, acid, 4-chlorosalicylic acid, Tobacco/TMV 434---chlorosalicylicchlorosalicylicchlorosalicylic acid, acid,acid, Tobacco/TMVTobacco/TMV [55] 3-chlorosalicylic35--chlorosalicylicchlorosalicylic acid, acid, (Laboratory) [55][55] 545---chlorosalicylicchlorosalicylicchlorosalicylic acid, acid,acid, Tobacco/TMV(Laboratory)(Laboratory) 4-chlorosalicylic3,54-chlorosalicylic-dichlorsalicylic acid, acid Tobacco/TMV [55] 3,55-chlorosalicylic-dichlorsalicylic acid, acid (Laboratory)Tobacco/TMV (Laboratory)[55] [55] 5-chlorosalicylic3,55--chlorosalicylicdichlorsalicylic acid, acid (Laboratory) 3,5-dichlorsalicylic acid 3,5-dichlorsalicylic3,5-dichlorsalicylic acid

3-fluorosalicylic acid, Tobacco/TMV 3-fluorosalicylic acid, Tobacco/TMV [56] 35-fluorosalicylic-fluorosalicylic acid, acid Tobacco/TMV(Laboratory) [56] 3-ﬂuorosalicylic35--fluorosalicylicfluorosalicylic acid,acid Tobacco/TMV(Laboratory) [56] 35-fluorosalicylic acid,acid Tobacco/TMV(Laboratory)Tobacco/TMV (Laboratory)[56] [56] 5-ﬂuorosalicylic acid [56] 5-fluorosalicylic acid (Laboratory)

Cucumber/Colletotri 2-(3,4-dihydroxy-6-(hydroxymethyl)-5-(3,4,5- Cucumber/Colletotri 2-(3,4-dihydroxy-6-(hydroxymethyl)-5-(3,4,5- Cucumber/chum orbiculareColletotri, 2-(3,4-dihydroxy-6-(hydroxymethyl)-5-(3,4,5-2trihydroxy-(3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-6-(hydroxymethyl)-5-(3,4,5-2H-- Cucumber/chum orbiculareColletotri, 2trihydroxy-(3,4-dihydroxy-6-(hydroxymethyl)tetrahydro-6-(hydroxymethyl)-5-(3,4,5-2H-- Cucumber/FusariumchumCucumber/ orbiculare oxysporumColletotri, ,Colletotrichum trihydroxy-6-(hydroxymethyl)tetrahydro-trihydroxy2-(3,4pyran-dihydroxy-2-6-yl)oxy)tetrahydro-(hydroxymethyl)tetrahydro-6-(hydroxymethyl)-2H-pyran-5-(3,4,5--22H- -2H- Fusariumchum orbiculare oxysporum, , [57] trihydroxypyran-2--6yl)oxy)tetrahydro-(hydroxymethyl)tetrahydro-2H-pyran-2-2H- - FusariumchumRalstoniaorbiculare orbiculare oxysporum solani, Fusarium,, , oxysporum[57] , pyran-2-yl)oxy)tetrahydro-trihydroxypyran-2-yl)thio)benzohydrazideyl)oxy)tetrahydro6-(hydroxymethyl)tetrahydro2H-2H-pyran-2-yl)-pyran : -2--2H- FusariumRalstonia oxysporum solani, , [57] [57] pyran-2yl)thio)benzohydrazide-yl)oxy)tetrahydro-2H-pyran : -2- FusariumPhytophthoraRalstoniaRalstonia oxysporum solani capsici solani, , , Phytophthora[57] pyranthio)benzohydrazide:SA-2yl)thio)benzohydrazideyl)oxy)tetrahydroglucoconjugate hydrazine-2H SA- pyran: -2- PhytophthoraRalstonia solani capsici, [57] SAyl)thio)benzohydrazide glucoconjugate hydrazine : PhytophthoraRalstonia(Laboratory)capsici solani capsici , (Laboratory) glucoconjugateSAyl)thio)benzohydrazide glucoconjugate hydrazine hydrazine : Phytophthora(Laboratory) capsici SA glucoconjugate hydrazine Phytophthora(Laboratory) capsici SA glucoconjugate hydrazine Arabidopsis/Hyaloper Arabidopsis(Laboratory)/Hyaloper Arabidopsisonospora parasitica/Hyaloper, 3-chlorobenzoic acid, ArabidopsisonosporaonosporaArabidopsis parasitica parasitica/Hyaloper/,Hyaloperonospora , 3-chlorobenzoic33--chlorobenzoicchlorobenzoic acid, acid, ArabidopsisPseudomonas/Hyaloper [54] 3,5-dichlorobenzoic acid onosporaPseudomonasparasiticaPseudomonas parasitica, Pseudomonas , [54][54] syringae [54] 3,5-dichlorobenzoic3,53,53---dichlorobenzoicchlorobenzoicdichlorobenzoic acid, acid acid onosporasyringae parasitica , 3-chlorobenzoic acid, Pseudomonassyringaesyringae (Laboratory) [54] 3,5-dichlorobenzoic acid Pseudomonas(Laboratory) [54] 3,5-dichlorobenzoic acid (Laboratory)(Laboratory)syringae Pepper/CMV,syringae Pepper/CMV,(Laboratory) Pepper/CMV,(Laboratory)XanthomonasPepper/CMV, Xanthomonas Pepper/CMV,Xanthomonas ParaPara amino amino benzoic benzoic acid Pepper/CMV,axonopodisXanthomonasaxonopodis pv. pv. Vesicatoria[58] [58] Para amino benzoic acid axonopodisXanthomonas pv. [58] Para amino benzoic acid axonopodisXanthomonasVesicatoria pv.(Laboratory) [58] Para amino benzoic acid axonopodisVesicatoria pv. [58] Para amino benzoic acid axonopodis(Laboratory)Vesicatoria pv. [58] (Laboratory) (Laboratory)Vesicatoria

(Laboratory) 3.3.3.2. Nicotinic Nicotinic Acid Acid Derivatives Derivatives:: 2,6-dichloro 2,6-dichloro-isonicotinic-isonicotinic Acid (INA) Acid and (INA) N-cyanomethyl and N-cyanomethyl-2-chloro-2-chloro isonicotinic 3.2.3.2. NicotinicNicotinic AcidAcid DerivativesDerivatives:: 2,62,6--dichlorodichloro--isonicotinicisonicotinic AcidAcid (INA)(INA) andand NN--cyanomethylcyanomethyl--22--chlorochloro Acidisonicotinic (NCI) Acid (NCI) isonicotinic3.2.isonicotinic Nicotinic AcidAcid Acid (NCI)(NCI) Derivatives : 2,6-dichloro-isonicotinic Acid (INA) and N-cyanomethyl-2-chloro isonicotinicINA is Acid very (NCI) effective in protecting various crops against a wide range of pathogens (Table 3). INAINAINA isis very isvery very effectiveeffective effective inin protectingprotecting in protecting variousvarious cropscrops various againstagainst aa crops widewide rangerange against ofof pathogepathoge a widensns (Table(Table range 33).). of pathogens This includes tobacco against TMV and cucumber against Colletotrichum lagenariunm [60] Cercospora (TableThisThis includesINAincludes3). is This very tobaccotobacco includeseffective againstagainst in tobacco protecting TMVTMV andand against cucumbervariouscucumber TMV crops againstagainst and against Colletotrichum cucumberColletotrichum a wide range against lagenariunmlagenariunm of pathogeColletotrichum [60][60]ns Cercospora Cercospora(Table 3 lagenariunm). [60] nicotianae, Peronospora tabacina, Phytophthora parasitica var nicotianae, and against P. syringae pv. tabaci nicotianaeThisnicotianae includes,, PeronosporaPeronospora tobacco tabacinaagainsttabacina ,TMV, PhytophthoraPhytophthora and cucumber parasiticaparasitica against varvar nicotianaenicotianae Colletotrichum,, andand againstagainst lagenariunm P.P. syringaesyringae [60] Cercospora pv.pv. tabacitabaci Cercospora[61]. Although, nicotianae INA has, Peronospora not been commercialized tabacina, Phytophthora because of its parasitica high phytotoxicityvar nicotianae it is considered, and against P. syringae [61]nicotianae[61].. Although,Although,, Peronospora INAINA hashas tabacina notnot beenbeen, Phytophthora commercializedcommercialized parasitica becausebecause var nicotianae ofof itsits highhigh, and phytotoxicityphytotoxicity against P. syringae itit isis consideredconsidered pv. tabaci pv.as usefultabaci tools[61 ]. to Although,study mechanisms INA has of induced not been resistance. commercialized INA is considered because as of a functional its high phytotoxicity SA it is as[61]as useful useful. Although, tools tools toINA to studystudy has mechanismsnot mechanisms been commercialized of of induced induced resistance. resistance.because of INA INAits high isis considered considered phytotoxicity aass a ait functional functionalis considered SA SA consideredanalogue that as acts useful downstream tools to studyof SA because mechanisms it does ofnot induced trigger any resistance. changes of INA SA iscontent considered and it as a functional analogueasanalogue useful that toolsthat actsacts to study downstreamdownstream mechanisms ofof SASA ofbecausebecause induced itit does does resistance. notnot triggertrigger INA anyanyis considered changeschanges ofof a SAsSA a contentfunctionalcontent andand SA itit induces SAR in salicylate hydroxylase (NahG) transgenic plants [62,63]. Like SA, INA is able to inhibit inducesSAanalogueinduces analogue SARSAR that inin acts thatsalicylatesalicylate downstream acts hydroxylase hydroxylase downstream of SA ((NbecauseNahGahG of SA)) transgenictransgenic it because does not plantsplants it trigger does [62,63] [62,63] notany.. Like changes triggerLike SA, SA, INAanyofINA SA is changesis contentable able to to inhibit inhibitand of SA it content and it catalase and ascorbate peroxidase (APX) activity and to induce ROS accumulation [64]. INA mediates catalaseinducesinducescatalase and SARand SAR ascorbate ascorbatein insalicylate salicylate peroxidaseperoxidase hydroxylase hydroxylase ( (APXAPX (N)) activity ahGactivity) ( NahG)transgenic andand tototransgenic induceinduce plants ROS ROS[62,63] plants accumulation accumulation. Like [62 SA,,63 INA]. [64][64] Like is.. INAINAable SA, mediatestomediates INAinhibit is able to inhibit its defense-related effects upon interaction with NPR1-related proteins, which control several TGA itscatalaseits defensedefense and--relatedrelated ascorbate effectseffects peroxidase uponupon interactioninteraction (APX) activity withwith and NPR1NPR1 to- -inducerelatedrelated ROS proteins,proteins, accumulation whichwhich controlcontrol [64]. INA severalseveral mediates TGATGA catalasetranscription and factors. ascorbate INA peroxidase seems to be (APX) a true activity SA agonist. and to It induce is able ROS to promote accumulation NPR1–NPR3 [64]. INA mediates transcriptionitstranscription defense-related factors. factors. effects INA INA upon seems seems interaction to to be be a a with true true NPR1 SA SA agonist. agonist.-related Itproteins, It is is able able which to to promote promote control NPR1 NPR1several––NPR3NPR3 TGA itsinteractions defense-related, and to reduce effects the uponbinding interaction affinity of SA with to NPR3 NPR1-related and NPR4 by proteins, competing which with SA control [40]. several TGA interactionstranscriptioninteractions,, and and factors. toto reducereduce INA the the seems bindingbinding to beaffinityaffinity a true ofof SA SA to to agonist. NPR3NPR3 and and It isNPR4NPR4 able by by to competing competing promote with NPR1with SASA–NPR3 [40][40].. transcription factors. INA seems to be a true SA agonist. It is able to promote NPR1–NPR3 interactions, interactions , and to reduce the binding affinity of SA to NPR3 and NPR4 by competing with SA [40]. and to reduce the binding afﬁnity of SA to NPR3 and NPR4 by competing with SA [40].

Agronomy 2018, 8, 5 6 of 20 Agronomy 2018, 8, 5 6 of 21 Agronomy 2018, 8, 5 6 of 21

TableTable 3. 3Nicotinic. Nicotinic acidacid derivatives and and used used pathosystems pathosystems.. Table 3. Nicotinic acid derivatives and used pathosystems. Chemical/Common or Trade Chemical Plant/Pathogen Interaction (Laboratory/Field Chemical/CommonChemical/Common or or Trade Chemical Plant/PathogenPlant/Pathogen Interaction Interaction(Laboratory/Field Reference Name ChemicalStructure Structure Experiments) ReferenceReference Trade NameName Structure (Laboratory/FieldExperiments Experiments))

Tobacco/TMV,Tobacco/TMV, CercosporaCercospora nicotiana, nicotiana,Peronospora Tobacco/TMV, Cercospora nicotiana, Peronospora 2,6-dichloro-isonicotinic acid Peronosporatabacinatabacina (Laboratory)(Laboratory) 2,6-dichloro-isonicotinic2,6-dichloro-isonicotinic acid tabacina (Laboratory) (INA)(CGA41396), Cucumber/Cucumber/ColletotrichumColletotrichum lagenarium lagenarium Sphaerotheca [60,61] acid (INA)(CGA41396),(INA)(CGA41396), Cucumber/Colletotrichum lagenarium Sphaerotheca [60,61][60,61 ] CGA41397 Sphaerothecafuliginea fuliginea (Laboratory)(Laboratory) CGA41397CGA41397 fuliginea (Laboratory) Bean/UromycesBean/Uromyces appendiculatus appendiculatus (Laboratory) Bean/Uromyces appendiculatus (Laboratory) (Laboratory)

Tobacco/Tobacco mosaic virus, Oidium Tobacco/Tobacco mosaic virus, Oidium lycopersici, lycopersici, Pseudomans syringae pv. tabaci N-cyanomethyl-2-chloroN-cyanomethyl-2-chloro Tobacco/TobaccoPseudomans syringae mosaic pv. virus, tabaci Oidium (Laboratory) lycopersici, (Laboratory) [65][65 ] isonicotinicNisonicotinic-cyanomethyl acid acid (NCI)-2 -(NCI)chloro Rice/PseudomansXanthomonas syringae oryzae pv. pv. tabaci oryzae, (Laboratory) Magnatoporthe Rice/Xanthomonas oryzae pv. oryzae, [65] isonicotinic acid (NCI) Rice/Xanthomonas oryzaegrisea (Field)pv. oryzae, Magnatoporthe Magnatoporthegrisea (Field) grisea (Field)

A second isonicotinic acid derivative, named N-cyanomethyl-2-chloro isonicotinic acid (NCI), A secondA second isonicotinic isonicotinic acid acid derivative, derivative, named NN-cyanomethyl-cyanomethyl-2-chloro-2-chloro isonicotinic isonicotinic acid (NCI) acid, (NCI), was identified by Nihon Nohyaku Co., Ltd. (Tokyo, Japan) as a potent defense inducer against rice waswas identified identified by by Nihon Nihon Nohyaku Nohyaku Co., Co., Ltd.Ltd. ( (Tokyo,Tokyo, Japan) Japan) as as a potent a potent defense defense inducer inducer against against rice rice blight under field conditions [65] (Table 3). It does not show any antifungal activity in vitro against blight under field conditions [65] (Table 3). It does not show any antifungal activity in vitro against blightMagnatoporthe under field oryzae conditions, and its [65 activity] (Table is3). long It does-lastin notg. In show tobacco, any antifungal NCI induces activity resistancein vitro againstagainst Magnatoporthe oryzae, and its activity is long-lasting. In tobacco, NCI induces resistance against Magnatoportheseveral pathogens oryzae, and including its activity TMV, isOidium long-lasting. lycopersici In and tobacco, P. syringae NCI induces pv. tabaci resistance, and enhances against the several several pathogens including TMV, Oidium lycopersici and P. syringae pv. tabaci, and enhances the pathogensexpression including of several TMV, PR genesOidium. NCI lycopersici-inducedand resistanceP. syringae does notpv. requiretabaci, andSA accumulation enhances the, but expression NPR1 of expression of several PR genes. NCI-induced resistance does not require SA accumulation, but NPR1 severalis involved.PR genes. Therefore, NCI-induced NCI seems resistance to interfere does with not defense require signaling SA accumulation, steps operating but between NPR1 SA is involved.and is involved. Therefore, NCI seems to interfere with defense signaling steps operating between SA and Therefore,NPR1 [66] NCI. seems to interfere with defense signaling steps operating between SA and NPR1 [66]. NPR1 [66]. 3.4. Pyrazole,3.3. Pyrazole, Thiazole Thiazole and and Thiadiazole Thiadiazole Derivatives Derivatives 3.3. Pyrazole, Thiazole and Thiadiazole Derivatives The heterocycles pyrazole, thiazole, and thiadiazole nucleus are prevalent five-membered ring TheThe heterocycles heterocycles pyrazole, pyrazole, thiazole, thiazole, and thiadiazole thiadiazole nucleus nucleus are are prevalent prevalent five- five-memberedmembered ring ring system harboring heteroatom nitrogen, or sulfur. They are considered as the most important systemsystem harboring harboring heteroatom heteroatom nitrogen, nitrogen, or sulfur. They They are are considered considered as the as themost most important important components of a wide variety of natural products and medicinal agents. Their derivatives are known componentscomponents of aof wide a wide variety variety of of natural natural productsproducts and and medicinal medicinal agents. agents. Their Their derivatives derivatives are known are known for their pharmacological activities, such as antimicrobial, anti-inflammatory, analgesic, antiepileptic, for theirfor their pharmacological pharmacological activities, activities, suchsuch as antimicrobial, antimicrobial, anti anti-inflammatory,-inflammatory, analgesic, analgesic, antiepileptic, antiepileptic, antiviral, antineoplastic, and antitubercular [67–69]. Some of them are extensively used as plant antiviral, antineoplastic, and antitubercular [67–69]. Some of them are extensively used as plant antiviral,defense antineoplastic, inducers [70,71] and. antitubercular [67–69]. Some of them are extensively used as plant defense inducers [70,71]. defense inducersThe pyrazole [70,71 carboxylic]. acid derivative, 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid The pyrazole carboxylic acid derivative, 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (CMPA)The pyrazole, is a very carboxylic potent inducer acid derivative, of rice defense 3-chloro-1-methyl-1 against bacterial Hblast-pyrazole-5-carboxylic that is caused by X. oryzae acid pv. (CMPA), (CMPA), is a very potent inducer of rice defense against bacterial blast that is caused by X. oryzae pv. is a veryoryzae potent and rice inducer blight ofwithout rice defense exhibiting against any antimicrobial bacterial blast activity that in is vitrocaused [72,73] by X. (Table oryzae 4).pv. Theoryzae oryzae and rice blight without exhibiting any antimicrobial activity in vitro [72,73] (Table 4). The carboxyl group at 5-position plays an important role in the observed activity, but the halogen atom andcarboxyl rice blight group without at 5-position exhibiting plays any an important antimicrobial role in activity the observedin vitro activity[72,73, but] (Table the halogen4). The atom carboxyl at 3-position enhanced further this activity. In rice, CMPA acts downstream of SA and upstream of groupat at3-position 5-position enhanced plays anfurther important this activity. role in In the rice, observed CMPA acts activity, downstream but the of halogen SA and atom upstream at 3-position of NPR1 [66]. In tobacco, it enhances resistance against P. syringae pv. tabaci and Oidium sp [74]. CMPA enhancedNPR1 [66] further. In tobacco, this activity. it enhances In rice, resistance CMPA against acts downstreamP. syringae pv. tabaci of SA and and Oidium upstream sp [74] of. CMPA NPR1 [66]. also induces the expression of several PR encoding genes. However, SA accumulation is not required In tobacco,also induces it enhances the expression resistance of several against PR P.encoding syringae genespv. tabaci. However,and OidiumSA accumulation sp [74]. CMPA is not required also induces and may interfere with defense signaling downstream from SA. In A. thaliana CMPA induced and may interfere withPR defense signaling downstream from SA. In A. thaliana CMPA induced the expressionresistance through of several NPR1 [66,74]encoding. genes. However, SA accumulation is not required and may resistance through NPR1 [66,74]. interfere with defense signaling downstream from SA. In A. thaliana CMPA induced resistance through NPR1 [66,74].

Agronomy 2018, 8, 5 7 of 21

Agronomy 2018, 8, 5 7 of 21 Agronomy 2018, 8, Table5 4. Pyrazole, thiazole, and thiadiazole derivatives and used pathosystems. 7 of 21 Agronomy 2018, 8, 5 7 of 20 Plant/Pathogen Interaction AgronomyChemical/Trade 2018, 8, Table5 Name 4. Pyrazole, thiazole,Chemical and Structure thiadiazole derivatives and used pathosystems. Reference7 of 21 (Laboratory/Field Experiments) Agronomy 2018, 8, 5 Tobacco/Plant/PathogenPseudomonas syringaeInteraction pv. tabaci, 7 of 21 Chemical/TradeTable Name 4. Pyrazole, thiazole,Chemical and Structure thiadiazole derivatives and used pathosystems. Reference Table 4. Pyrazole, thiazole, and thiadiazole derivatives(Laboratory/FieldOidium and Experimentssp used. pathosystems.) [72,74] 3-chloro-1-methyl-1TableH-pyrazole 4. Pyrazole,- thiazole, and thiadiazole derivativesTobacco/Plant/Pathogen andPseudomonas used(Laboratory) pathosystems syringaeInteraction pv.. tabaci, Chemical/Trade Name Chemical Structure Reference 5-carboxylic acid (CMPA) (Laboratory/FieldOidium spExperiments. ) [72,74] 3-chloro-1-methyl-1H-pyrazole- Rice/Plant/PathogenXanthomonasPlant/Pathogen Interaction oryzae Interaction pv. Oryzae Chemical/Trade3-chloro-Chemical/Trade1-methyl- Name1H-pyrazole Name - ChemicalChemical Structure Tobacco/Pseudomonas(Laboratory) syringae pv. tabaciReference, [73] Reference 5-carboxylic acid (CMPA) (Laboratory/Field(Laboratory/Field(Field) Experiments Experiments)) 5-carboxylic acid (CMPA) Rice/XanthomonasOidium oryzae sp. pv. Oryzae [72,74] Tobacco/Rice/PseudomonasXanthomonas syringae oryzae pv. pv. tabaci Oryzae, [73] 3-chloro-1-methyl-1H-pyrazole- Tobacco/Pseudomonas(Laboratory)(Field) syringae pv. tabaci, [73] Oidium(Field) sp. [72,74] [72,74] 3-chloro-1-methyl-15-carboxylic3-chloro-1-methyl acidH-pyrazole- (CMPA)-1H-pyrazole - Oidium sp. (Laboratory) 3-allyloxy-1,2-benzithiazole1-1- Rice/Xanthomonas(Laboratory) oryzae pv. Oryzae 5-carboxylic5-carboxylic acid (CMPA) acid (CMPA) Rice/Magnaporthe oryzae [73] dioxide (Probenazole, Rice/Xanthomonas (Field)oryzae pv. Oryzae [70] Rice/Xanthomonas(Field) oryzae pv. Oryzae (Field)[73] [73] 3-allyloxyPBZ/Oryzemate®-1,2-benzithiazole1 ) -1- (Field) Rice/Magnaporthe oryzae dioxide (Probenazole, [70] (Field) 3-allyloxyPBZ/Oryzemate®-1,2-benzithiazole1 ) -1- 3-allyloxy-1,2-benzithiazole1-1-dioxide3-allyloxy-1,2-benzithiazole1-1- Rice/MagnaportheTobacco/TMV oryzae dioxide (Probenazole, Rice/MagnaportheMagnaporthe oryzae oryzae (Field)[70] [70] (Probenazole,dioxide PBZ/Oryzemate®) (Probenazole, (Laboratory)(Field) [70] PBZ/Oryzemate® ) (Field) PBZ/Oryzemate® ) Rice/MagnaportheTobacco/TMV grisea, Xanthomonas

oryzae(Laboratory) pv. Oryzae Rice/Magnaporthe grisea, Xanthomonas Rice/MagnaportheTobacco/TMVTobacco/TMVTobacco/TMV(Field) grisea , (Laboratory) Xanthomonas 1,2-benzisothiazolin-3-one-1,1- Barley/Blumeriaoryzae pv.graminis Oryzae f. sp. Hordei Rice/Magnaporthe(Laboratory)oryzae(Laboratory) pv. Oryzae grisea , Xanthomonas [75–78] dioxide (BIT, Saccharin) Rice/Rice/MagnaportheMagnaportheoryzae(Laboratory) grisea(Field)pv. grisea, OryzaeXanthomonas , Xanthomonas (Field) 1,2-benzisothiazolin-3-one-1,1- Barley/Blumeria graminis f. sp. Hordei 1,2-benzisothiazolin-3-one-1,1-dioxide1,2-benzisothiazolin-3-one-1,1- Barley/Cucumber/Barley/oryzaeBlumeriaBlumeriaoryzaeColletotrichum pv. graminisOryzaepv. graminisOryzae f. lagenarium sp. f. Hordei sp. Hordei [75–78] dioxide (BIT, Saccharin) (Field)(Laboratory) [75–78] [75–78] (BIT,dioxide Saccharin) (BIT, Saccharin) Bean/(Laboratory)(Laboratory)Uromyces(Field) faba 1,2-benzisothiazolin-3-one-1,1- Barley/Cucumber/BlumeriaColletotrichum graminis f. sp. Hordeilagenarium 1,2-benzisothiazolin-3-one-1,1- Barley/Cucumber/Cucumber/BlumeriaColletotrichum(Laboratory)Colletotrichum graminis f. lagenarium sp. Hordei lagenarium [75–78] dioxide (BIT, Saccharin) Bean/(Laboratory)Uromyces faba [75–78] dioxide (BIT, Saccharin) Bean/Soybean/Bean/Uromyces(Laboratory)PhakosporaUromyces faba fabapachirhizi (Laboratory) Cucumber/Colletotrichum(Laboratory) lagenarium Soybean/Cucumber/PhakosporaColletotrichum(Laboratory)(Laboratory) pachirhizi lagenarium(Laboratory) Soybean/Bean/UromycesPhakospora faba pachirhizi Rice/Soybean/XanthomonasBean/(Laboratory)PhakosporaUromyces oryzae pachirhizifaba pv. oryzae, Rice/Xanthomonas(Laboratory) oryzae pv. oryzae, Soybean/MagnaporthePhakospora(Laboratory) pachirhizi grisea Magnaporthe grisea (Field) Rice/Soybean/Xanthomonas(Laboratory)Phakospora(Field) oryzae pachirhizi pv. oryzae, Rice/Wheat/Wheat/XanthomonasBlumeriaMagnaportheBlumeria(Laboratory) oryzae graminis graminis pv. grisea oryzae, f. sp. f. Tritici sp. Tritici Magnaporthe grisea [71] [71] (Laboratory)(Laboratory)Rice/XanthomonasMagnaporthe Cucumber/ Cucumber/(Field) grisea oryzae Colletotrichum pv.Colletotrichum oryzae, Wheat/orbiculareBlumeria,(Field)Xanthomonas graminis f. sp. campestris Tritici pv. orbiculareWheat/BlumeriaMagnaporthe, Xanthomonas graminis grisea campestris f. sp. Tritici pv. [71] Wheat/(Laboratory)BlumeriaCucurbitae Cucumber/ graminis (Laboratory)f. sp.Colletotrichum Tritici [71] (Laboratory) Cucumber/Cucurbitae(Field) Colletotrichum [71] 3,4-dichloro-23,4-dichloro0-cyano-1,2-thiazole-5-carboxanilide-2′-cyano-1,2- (Laboratory)orbiculare ,Cucumber/ XanthomonasColletotrichum campestris pv. orbiculareWheat/Blumeria, Xanthomonas(Laboratory) graminisAlternaria campestris f. sp. Tritici brassicaepv. thiazole-5-carboxanilide orbiculareChinese, Xanthomonas cabbage/ campestris pv. [71] Isothianil (Isotianil/Stout®) (Laboratory)Chinese cabbage/ Cucumber/CucurbitaeAlternaria Colletotrichum brassicae Isothianil3,4-dichloro (Isotianil/Stout®-2′-cyano-1,2- ) Cucurbitae(Laboratory) 3,4-dichloro3,4-dichloro-2′-cyano-2′-cyano-1,2-1,2- - (Laboratory) thiazole-5-carboxanilide orbicularePumpkin/,(Laboratory) Xanthomonas(Laboratory)(Laboratory)Sphaerotheca campestris fuliginea pv. thiazolethiazole-5-carboxanilide-5-carboxanilide Chinese cabbage/Alternaria brassicae Isothianil (Isotianil/Stout® ) ChineseChinesePumpkin/ cabbage/ cabbage/CucurbitaeSphaerothecaAlternaria(Laboratory)Alternaria brassicae fuliginea brassicae Isothianil3,4-dichloroIsothianil (Isotianil/Stout®- 2(Isotianil/Stout®′-cyano-1,2- ) ) (Laboratory) [79–81] (Laboratory)(Laboratory)(Laboratory) thiazole-5-carboxanilide Strawberry/Colletotrichum acutatum [79–81] ChinesePumpkin/Strawberry/Pumpkin/ cabbage/SphaerothecaSphaerothecaColletotrichumAlternaria fuliginea fuliginea acutatumbrassicae Isothianil (Isotianil/Stout® ) (Laboratory) (Laboratory)(Laboratory)(Laboratory) Peach/Xanthomonas(Laboratory) campestris pv.[79Pruni–81][79 –81] Strawberry/Strawberry/ColletotrichumColletotrichum acutatum acutatum [79–81] Peach/Strawberry/Pumpkin/XanthomonasColletotrichumSphaerotheca(Laboratory) campestris fuliginea acutatum pv. Pruni (Laboratory) (Laboratory)(Laboratory) Peach/Xanthomonas campestris pv. Pruni [79–81] Peach/Strawberry/Apple/XanthomonasApple/ErwiniaColletotrichumErwinia campestris amylovora acutatum pv. (Field)Pruni [82] (Laboratory) [82] (Laboratory)(Field) Citrus/Apple/XanthomonasErwinia(Laboratory) amylovora citri, Xanthomonas Apple/Erwinia amylovora [82] [83] Peach/Citrus/axonopodisXanthomonasApple/Xanthomonas(Field)Erwiniapv. campestris citri, Citruculaamylovora Xanthomonas pv. (Field) Pruni [82] (Field) [82] Citrus/Xanthomonasaxonopodis(Laboratory)(Field) citri, pv. Xanthomonas Citrucula [83] Rape/Citrus/PseudomonasXanthomonas citri, syrngae Xanthomonaspv. maculicola, Citrus/axonopodisApple/XanthomonasErwinia pv.(Field) Citrucula citri, amylovora Xanthomonas [83] [84] leptosphaera maculans (Laboratory) [82] Rape/axonopodisPseudomonas(Field)(Field) pv. Citrucula syrngae pv. [83] Citrus/Rape/maculicola,JapaneseXanthomonasPseudomonas leptosphaera pear/(Field) syrngae citri,Venturia Xanthomonas pv. maculans nashicola [84] [85] Benzo-1,2,3-thiadiazole-7- maculicola,Rape/axonopodisPseudomonas leptosphaera(Laboratory)(Laboratory) pv. maculansCitrucula syrngae pv. [84] [83] (Laboratory) carbothionicBenzo-1,2,3 acibenzolar-thiadiazole-S--7- maculicola,Japanese pear/ leptosphaera(Field)Venturia maculans nashicola [84] carbothionic acibenzolar-S- JapaneseCowpea/ pear/(Laboratory)ColletotrichumVenturia nashicola destructivum [85] Benzo-1,2,3methyl-thiadiazole ester -7- Rape/Pseudomonas(Laboratory)(Laboratory) syrngae pv. [85] [86] Benzo-1,2,3-thiadiazole-7-carbothionicmethyl ester (Laboratory)(Laboratory) carbothionic(BTH/Bion® acibenzolar /Actigrad®-S ) - Cowpea/Japanesemaculicola,Colletotrichum pear/ leptosphaeraVenturia destructivum maculansnashicola [84] acibenzolar-(BTH/Bion®S-methyl /Actigrad® ester ) Cowpea/Colletotrichum destructivum [85][86] methyl ester Tobacco/TMV,(Laboratory)(Laboratory) CMV, Tomato spotted[86] wilt (BTH/Bion®/Actigrad®)Benzo-methyl1,2,3-thiadiazole ester -7- (Laboratory)(Laboratory) [87,88] (BTH/Bion® /Actigrad® ) Cowpea/Colletotrichum destructivum carbothionic(BTH/Bion® acibenzolar /Actigrad®- )S - Tobacco/TMV,Tobacco/TMV,Cowpea/JapaneseColletotrichum virusCMV,pear/ CMV, VenturiaTomato (Laboratory) Tomato destructivum spotted nashicola spotted [86] (Laboratory) [85][86] methyl ester Cucumberwilt/Colletotrichum(Laboratory) wiltvirus virus orbiculare[87,88], CMV [87,88] Tobacco/TMV, CMV, Tomato spotted Agronomy(BTH/Bion® 2018, 8, 5 /Actigrad® ) Tobacco/TMV,Cowpea/(Laboratory)Colletotrichum(Laboratory) CMV, Tomato destructivum spotted 8 of 21 [85,89] (Laboratory) [86] CucumberCucumber/Colletotrichum/Colletotrichum(Laboratory)wilt virus orbiculare, orbiculare, [87,88] Tomato/Clavibacter(Laboratory)CMV michighanensis [85,89]subs. Tomato/Tobacco/TMV,Clavibacter(Laboratory) CMV,CMV michighanensis Tomato spotted subs. [85,89] Cucumbermichiganensis,(Laboratory)/Colletotrichum Verticillium orbiculare, dahliae [90,91] Cucumbermichiganensis,/Colletotrichum(Laboratory)wilt Verticillium virus orbiculare, dahliae [90,91][87,88] (Laboratory/Field)CMV [85,89] (Laboratory/Field)(Laboratory)CMV [85,89] (Laboratory) OilCucumberOil seed seed rape/ rape//Colletotrichum(Laboratory)LeptosphaeriaLeptosphaeria orbiculare, maculans maculans [92] [92] (Laboratory/Field)(Laboratory/Field)CMV [85,89] (Laboratory)

2,2-2trifluoroethylbenzo(d) Cucumber/Erysiphae cichoracearum, 2,2-2triﬂuoroethylbenzo(d) (1,2,3) Cucumber/Erysiphae cichoracearum, (1,2,3) thiadiazole-7-carboxylatic Colletotrichum lagenarium [93] [93] thiadiazole-7-carboxylatic acid Colletotrichum lagenarium (Field) acid (Field)

Rice/Magnoporthe grisea [80] (Field) Tobacco/Tobacco mosaic virus, N-(3-Chloro-4-Methylphenyl)-4- Pseudomonas syringae pv. tabaci, Methyl-1,2,3-thiadiazole-5- [66,94] Erysiphae cichoracearum Carboxamide Tiadinil (TDL, V- (Laboratory) GET® ) Tea/Colletotrichum theaasinensis, Pestalotiopsis longista [95] (Field)

2,5-bis (pyridi-2-yl)-1,3,4- Tomato/Verticillium dahliae [96] thiadiazol (Laboratory)

Bis(μ-2,5-bis(pyridin-2-yl)-1,3,4- Tomato/Verticillium dahliae thiadiazoleκ4N2,N3:N4,N5)bis(d [96] (Laboratory) ihydrato-κO)nickel(II)) (NiL2)

bis(azido-κN)bis(2,5-bis(pyridin- Tomato/Verticillium dahliae 2-yl)-1,3,4-thiadiazole-κ2N2, [97] (Laboratory) N3)nickel(II) (NiL2(N3)2)

Bis((2,5-bis(pyridine-2-yl)-1,3,4- Tomato/Verticillium dahliae, thiadiazole-di-azido copper(II)) Agrobacterium tumefaciens [98] (CuLN3)2 (Laboratory)

The thiazolic compound probenazole (PBZ) (3-allyloxy-1,2-benzisothiazole-1,1-dioxide) is an inducer of plant defense that was developed by Meiji Seika Ltd. (Tokyo, Japan) to control the fungal rice blast disease for more than four decades (Table 4). It was the first commercialized inducer of resistance under the trade name of Oryze mate® . PBZ inhibits hyphal penetration into the host tissue, lesion expansion and sporulation [70]. It provides an excellent blast control lasting for more than two months. Despite of its direct antifungal activity, it is able to dramatically enhance the activity of several enzymes that are involved in plants defenses, such as peroxidase (POX), polyphenol oxidase (PPO), phenyl alanine ammonia lyase (PAL), tyrosine ammonia lyase (TAL), and catechol-O-

AgronomyAgronomy 201 20188, ,8 8, ,5 5 88 of of 21 21 Agronomy 2018, 8, 5 8 of 21 Agronomy 2018, 8, 5 Tomato/Clavibacter michighanensis subs. 8 of 21 Tomato/Tomato/ClavibacterClavibacter michighanensis michighanensis subs. subs. Tomato/michiganensis,Clavibacter Verticillium michighanensis dahliae subs. [90,91] michiganensis,michiganensis, Verticillium Verticillium dahliae dahliae [90,91][90,91] michiganensis,(Laboratory/Field) Verticillium dahliae [90,91] Tomato/Clavibacter(Laboratory/Field)(Laboratory/Field) michighanensis subs. Oilmichiganensis, seed (Laboratory/Field)rape/Leptosphaeria Verticillium maculansdahliae [90,91] OilOil seed seed rape/ rape/LeptosphaeriaLeptosphaeria maculans maculans [92] Oil seed (Laboratory/Field)rape/(Laboratory/Field)Leptosphaeria maculans [92][92] (Laboratory/Field)(Laboratory/Field) [92] Oil seed rape/(Laboratory/Field)Leptosphaeria maculans [92] (Laboratory/Field) Agronomy 2018, 8, 5 8 of 20 2,2-2trifluoroethylbenzo(d) Cucumber/Erysiphae cichoracearum, 2,22,2--2trifluoroethylbenzo2trifluoroethylbenzo((dd)) Cucumber/Cucumber/ErysiphaeErysiphae cichoracearum cichoracearum, , (1,2,32,2)- 2trifluoroethylbenzothiadiazole-7-carboxylatic(d) Cucumber/ColletotrichumErysiphae lagenarium cichoracearum , [93] ((1,2,31,2,3)) thiadiazole thiadiazole--77--carboxylaticcarboxylatic ColletotrichumColletotrichum lagenarium lagenarium [93][93] (1,2,3) thiadiazoleacid- 7-carboxylatic Colletotrichum(Field) lagenarium [93] 2,2-2trifluoroethylbenzoacidacid (d) Cucumber/Erysiphae(Field)(Field) cichoracearum , (1,2,3) thiadiazoleacid-7 -carboxylatic Table 4. Cont. Colletotrichum(Field) lagenarium [93] acid (Field)

Rice/Magnoporthe grisea Plant/PathogenRice/Rice/MagnoportheMagnoporthe grisea Interactiongrisea [80] Chemical/Trade Name Chemical Structure Rice/Magnoporthe(Field) grisea [80][80] Reference (Laboratory/Field(Field)(Field) Experiments) [80] Tobacco/TobaccoRice/Magnoporthe(Field) mosaic grisea virus, N-(3-Chloro-4-Methylphenyl)-4- Tobacco/TobaccoTobacco/Tobacco mosaic mosaic virus, virus, [80] NN--(3(3--ChloroChloro--44--Methylphenyl)Methylphenyl)--44-- Tobacco/TobaccoPseudomonasRice/Magnoporthe(Field) syringae mosaic pv. grisea tabacivirus,(Field), [80] N-(3Methyl-Chloro-1,2,3-4-Methylphenyl)-thiadiazole-5--4- PseudomonasPseudomonas syringae syringae pv. pv. tabaci tabaci, , [66,94] MethylMethyl--1,2,31,2,3--thiadiazolethiadiazole--55-- PseudomonasErysiphae syringae cichoracearum pv. tabaci , [66,94][66,94] CarboxamideMethyl-1,2,3 Tiadinil-thiadiazole (TDL,-5- V- Tobacco/TobaccoTobacco/TobaccoErysiphaeErysiphae cichoracearum cichoracearum mosaic mosaic virus, virus, [66,94] N-(3-Chloro-4-Methylphenyl)-4-NCarboxamide-(3-Chloro-4 -TiadinilMethylphenyl) (TDL, V-4-- Erysiphae(Laboratory) cichoracearum Carboxamide Tiadinil (TDL, V- Pseudomonas(Laboratory) syringae pv. tabaci, Methyl-1,2,3-thiadiazole-5-Methyl-1,2,3GET®GET®-thiadiazole )) -5- Pseudomonas(Laboratory) syringae pv. tabaci, Erysiphae[66,94] [66,94] GET® ) Tea/ErysiphaeColletotrichum(Laboratory) cichoracearum theaasinensis, CarboxamideGET® Tiadinil Tiadinil ) (TDL, V- Tea/Tea/ColletotrichumcichoracearumColletotrichum theaasinensis, theaasinensis,(Laboratory) Tea/ColletotrichumPestalotiopsis(Laboratory) longistatheaasinensis, [95] (TDL, V-GET®)GET® ) PestalotiopsisPestalotiopsis longista longista [95][95] Tea/PestalotiopsisColletotrichum(Field) longista theaasinensis, [95] Tea/Colletotrichum(Field)(Field) theaasinensis, [95] PestalotiopsisPestalotiopsis(Field) longista (Field) [95] (Field) 2,5-bis (pyridi-2-yl)-1,3,4- Tomato/Verticillium dahliae 2,52,5--bisbis (pyridi (pyridi--22--yl)yl)--1,3,41,3,4-- Tomato/Tomato/VerticilliumVerticillium dahliae dahliae [96] 2,5-bis (pyridithiadiazol-2-yl) -1,3,4- Tomato/(Laboratory)Verticillium dahliae [96] thiadiazol Verticillium(Laboratory) dahliae [96] 2,5-bis (pyridi-2-yl)-1,3,4-thiadiazolthiadiazol Tomato/ (Laboratory) (Laboratory) [96] 2,5-bis (pyridi-2-yl)-1,3,4- Tomato/Verticillium dahliae [96] thiadiazol (Laboratory)

Bis(μ-2,5-bis(pyridin-2-yl)-1,3,4- Bis(µBB-2,5-bis(pyridin-2-yl)-1,3,4-isis((μμ--2,52,5--bis(pyridinbis(pyridin--22--yl)yl)--1,3,41,3,4-- Tomato/Verticillium dahliae thiadiazoleκ4Bis(μ-2,5-bis(pyridinN2,N3:N-24,-yl)N5-)1,3,4bis(d- Tomato/Tomato/VerticilliumVerticillium dahliae dahliae [96] thiadiazolethiadiazoleκ4thiadiazoleκ4κ4N2,NNN2,2,3:NN3:N3:N4,N4,N4,NN5)bis55))bisbis((dd Tomato/Tomato/Verticillium(Laboratory)Verticillium dahliae dahliae(Laboratory) [96][96] [96] thiadiazoleκ4ihydrato-κON)nickel(II)2,N3:N4,)N (NiL5)bis2()d (Laboratory) [96] Bihydratois(μ-2,5-bis(pyridin-κO)nickel(II)-2-)yl) (NiL-1,3,42) - (Laboratory) (dihydrato-ihydratoκO-)nickel(II))κO)nickel(II) (NiL) (NiL)2) Tomato/(Laboratory)Verticillium dahliae thiadiazoleκ4ihydrato-κON)nickel(II)2,N3:N4,N) (NiL5)bis2 2()d [96] (Laboratory) ihydrato-κO)nickel(II)) (NiL2)

bis(azido-κN)bis(2,5-bis(pyridinbis(azido-bis(azidobis(azidoκN)bis(2,5-bis(pyridin-2-yl)---κκNN)bis)bis((2,52,5--bis(pyridinbis(pyridin-- Tomato/Verticillium dahliae bis(azido2-yl)-1,3,4-κN-thiadiazole)bis(2,5-bis(pyridin-κ2N2, - Tomato/Tomato/VerticilliumVerticillium dahliae dahliae [97] 1,3,4-thiadiazole-22--yl)yl)--1,3,41,3,4-κ-thiadiazolethiadiazole2N2,N3)nickel(II)--κκ22NN2,2, Tomato/Tomato/Verticillium(Laboratory)Verticillium dahliae dahliae(Laboratory) [97][97] [97] 2-yl)N3-)1,3,4nickel(II)-thiadiazole (NiL2(N-κ32)2N) 2, (Laboratory) [97] bis(azidoN3)nickel(II)-κN)bis( 2,5(NiL-bis(pyridin2(N3)2) - (Laboratory) N(NiL3)nickel(II)2(N3) 2(NiL) 2(N3)2) Tomato/(Laboratory)Verticillium dahliae 2-yl)N3-1,3,4)nickel(II)-thiadiazole (NiL2(N-κ32)N2) 2, [97] (Laboratory) N3)nickel(II) (NiL2(N3)2)

Bis((2,5-bis(pyridine-2-yl)-1,3,4- Tomato/Verticillium dahliae, Bis((2,5-bis(pyridine-2-yl)-1,3,4-thiadiazole-di-azidoBBisis(((2,5(2,5--bis(pyridinebis(pyridine--22--yl)yl)--1,3,41,3,4-- Tomato/Tomato/Tomato/VerticilliumVerticilliumVerticillium dahliae, dahliae, dahliae, Agrobacterium Bthiadiazoleis((2,5-bis(pyridine-di-azido- copper(II)2-yl)-1,3,4-) Tomato/AgrobacteriumVerticillium tumefaciens dahliae, [98] [98] thiadiazolethiadiazolecopper(II))--didi (CuLN--azidoazido copper(II) copper(II)) )) AgrobacteriumAgrobacteriumtumefaciens tumefaciens tumefaciens(Laboratory) [98][98] thiadiazole-di-azido3 2 3copper(II)2 ) Agrobacterium tumefaciens [98] Bis((2,5-bis(pyridine(CuLN3 )2- 2-yl)-1,3,4- Tomato/(Laboratory)Verticillium dahliae, (CuLN(CuLN3))2 (Laboratory)(Laboratory) thiadiazole-(CuLNdi-azido3)2 copper(II)) Agrobacterium(Laboratory) tumefaciens [98] (CuLN3)2 (Laboratory)

The thiazolic compound probenazole (PBZ) (3-allyloxy-1,2-benzisothiazole-1,1-dioxide) is an TheThe thiazolic thiazolic compound compound probenazole probenazole (PBZ) (PBZ) (3(3--allyloxyallyloxy--1,21,2--benzisothiazolebenzisothiazole--1,11,1--dioxide)dioxide) is is an an Theinducer thiazolicThe of thiazolic plant compound defense compound thatprobenazole was probenazole developed (PBZ) by (PBZ) Meiji (3- allyloxy (3-allyloxy-1,2-benzisothiazole-1,1-dioxide)Seika Ltd.-1,2 (-Tokyobenzisothiazole, Japan) to- 1,1control-dioxide) the fungal is an is an inducerinducer ofof plantplant defensedefense thatthat waswas developeddeveloped byby MeijiMeiji SeikaSeika Ltd.Ltd. ((TokyoTokyo,, JapanJapan)) toto controlcontrol thethe fungalfungal inducerinducerrice of plantblastThe of thiazolicdisease plant defense defense for compound thatmore that wasthan was probenazole developedfour developed decades (PBZ) by by(Table Meiji (3 Meiji- allyloxySeika4). It Seika wasLtd.-1,2 the(-Tokyo Ltd.benzisothiazole first (Tokyo,, Japancommercialized) to- Japan) 1,1control-dioxide) inducerthe to controlfungal is anof the fungal ricerice blastblast diseasedisease forfor moremore thanthan fourfour decadesdecades (Table(Table 44)).. ItIt waswas thethe firstfirst commercializedcommercialized inducerinducer ofof inducerriceresi stanceblast of diseaseunderplant defense the for trade more that name than was of four developed Oryze decades mate® by (Table .Meiji PBZ Seikainhibits4). It wasLtd. hyphal (theTokyo first penetration, Japancommercialized) to into control the hostinducerthe fungal tissue, of rice blastresiresi diseasestancestance under under for the the more trade trade than name name fourof of OryzeOryze decades mate® mate®.. PBZ (TablePBZ inhibits inhibits4). Ithyphalhyphal was penetration penetration the first commercializedintointo the the host host tissue, tissue, inducer of riceresilesion stanceblast expansion disease under the andfor trade moresporulation name than offour [70] Oryze .decades It provides mate® (Table. PBZ an excellentinhibits4). It was hyphal blast the controlfirst penetration commercialized lasting into for themore hostinducer than tissue, two of resistancelesionlesion under expansionexpansion the trade andand sporulationsporulation name of [70][70] Oryze.. ItIt providesprovides mate® anan. PBZ excellentexcellent inhibits blastblast controlcontrol hyphal lastinglasting penetration forfor moremore thanthan into twotwo the host tissue, resilesionmonths.stance expansion Despite under the andof tradeits sporulation direct name antifungal of [70] Oryze. It provides mate®activity,. PBZ anit excellentis inhibits able to hyphal blast dramatically control penetration lasting enhance into for themore the host activity than tissue, two of months.months. Despite Despite ofof itsits direct direct antifungal antifungal activity,activity, itit isis able able to to dramaticallydramatically enhanceenhance the the activity activity of of lesion expansionlesionmonths.several expansion enzymes Despite and andthat sporulationof its sporulationare direct involved antifungal [ 70[70] in]. .plants It It provides providesactivity, defenses, an it excellentis an such able excellent as to peroxidaseblast dramatically control blast (POX lasting control enhance), polyphenol for lasting more the activity than oxidase for two more of than two severalseveral enzymesenzymes thatthat areare involvedinvolved inin plantsplants defenses,defenses, suchsuch asas peroxidaseperoxidase ((POXPOX)),, polyphenolpolyphenol oxidaseoxidase months.months.several(PPO Despite), enzymes phenyl Despite of its alanine thatof direct its are direct ammoniainvolved antifungal antifungal in lyase plants activity, activity, (PAL defenses,), it tyrosineitis is such able able ammoniaas to to peroxidase dramatically lyase (POX (enhanceTAL) enhance, polyphenol), and the catechol activitythe oxidase activity- O ofof several ((PPOPPO)),, phenylphenyl alanine alanine ammonia ammonia lyase lyase ( (PALPAL)),, tyrosinetyrosine ammonia ammonia lyase lyase ( (TALTAL)),, andand catechol catechol--OO-- several( PPO), enzymesphenyl alanine that are ammoniainvolved in lyase plants (PAL defenses,), tyrosine such as ammonia peroxidase lyase (POX (TAL), polyphenol), and catechol oxidase-O- enzymes that are involved in plants defenses, such as peroxidase (POX), polyphenol oxidase (PPO), ( PPO), phenyl alanine ammonia lyase (PAL), tyrosine ammonia lyase (TAL), and catechol-O- phenylalanine ammonia lyase (PAL), tyrosine ammonia lyase (TAL), and catechol-O-methyltransferase, as well as transcript accumulation of OsPR1a and PBZ1, a gene belonging to PR10 family that is used as a marker for responses to the synthetic elicitor. 1,2-benzisothiazoline-3-one-1,1-dioxide (BIT) is the derivative metabolite of PBZ. It is well known as saccharin and it also induces resistance against a broad spectrum of pathogens in cereals and leguminous plants. In rice, PBZ-induced defense is independent from the accumulation of SA. PBZ enhances transcripts of SA glucosyltransferase b(OsSGT1), which is involved in the conversion of free SA to SAG [99]. However, in A. thaliana and tobacco, PBZ mimics the effects of SA since it stimulates the expression of PR genes and induces SA accumulation. Since PBZ failed to induce plant defense responses in npr1 mutants or nahG transgenic plants, it seems to interfere only with defense signaling steps upstream from SA accumulation [70,100]. The isotianil compound 3,4-dichloro-20-cyano-1,2-thiazole-5-carboxanilide is an isothiazole derivative that was developed by Bayer Crop Science (Monheim am Rhei, Germany) and the Japanese company Sumitomo Chemical Co., Ltd (Tokyo, Japan) (Table4). It is registered under the trade name Agronomy 2018, 8, 5 9 of 20 of Stout®(Sumitomo Chemical Co., Ltd, Tokyo, Japan) to fight against rice blast. Isotianil does not show any direct antimicrobial activity [79,80], but it is able to activate defense responses against a wide range of pathogens in various plants even at very low concentrations. These include rice blight and powdery mildew in wheat, anthracnose, and bacterial leaf spot in cucumber, alternaria leaf spot in chinese cabbage, powdery mildew in Pumpkin, anthracnose in strawberry, and bacterial shot hole in peach [79,81]. In rice, it was reported to enhance the accumulation of defense-related enzymes such as PAL and lipoxygenase (LOX) in rice [79,80]. However, several, isotianil-responsive genes that are involved in SA pathway were identified. These include, NPR1, NPR3, the transcription factors OsWRYK45, OsWRYK62, OsWRYK70, OsWRYK76, as well as genes that are involved in SA catabolism such as OsSGT1 and OsBMST1 leading to the mobile signal MeSA [81]. Several benzothiadiazoles have been found to behave as functional analogues of SA. The Benzo- 1,2,3-thiadiazole-7-carbothionic acid-S-methyl ester (BTH) or ASM (for acibenzolar-S-methyl) was the first commercialized thiadiazole derivative. It was registered under the tradename of BION®(Syngenta, Bâle, Switzerland) in Europe in 1989 and Actigard®(Syngenta, Bâle, Switzerland) in the US in 1990 [70]. BTH is effective against a broad spectrum of pathogens, it does not show antimicrobial activity at the concentration used for in planta protection (Table4). BTH seems to activate SA-dependent signaling pathways by interfering as SA agonists with targets that are located downstream from SA accumulation, and can activate the same PR genes that are induced by SA. However, BTH treatment induces SAR in nahG transgenic plants, which fail to accumulate SA, suggesting that accumulation of SA is not required for BTH-induced SAR [101]. In Arabidopsis, BTH triggers NPR1-dependent SAR [102]. It inhibits catalase and APX, which lead to enhanced H2O2 content and to activation of plant defenses [103]. It was suggested that BTH is converted into acibenzolar by SABP2, which, in turn, activates a disease resistance signaling pathway that is similar to that activated by SA [104]. In addition, a BTH-binding protein kinase (BBPK) isolated from tobacco leaves was reported to regulate NPR1 activity through phosphorylation. Until now, BTH has been tested in more than 120 pathosystems. These include resistance against E. amylovora, the causal agent of fire blight in apple and pear [82] and against bacterial canker that is caused by Clavibacter michiganensis subsp. michiganensis in tomato [90]. When applied as foliar spray or soil drench, in the field, BTH was able to reduce the lesions produced in grapefruit by Xanthomonas citri and X. axonopodis pv. Citrumelo [83]. BTH enhanced resistance against the bacterial pathogen Pseudomonas syringae pv. maculicola and the fungal pathogen Leptosphaeria maculans in Brassica napus in SA dependent manner [84]. In Japanese pear, BTH reduced scab disease caused by Venturia nashicola and was correlated with enhancement of several lines of plant defenses, including antioxidant defenses, polygalacturonase-inhibiting proteins (PGIP), MAPK, and leucin-rich repeat Receptor like kinase [85,105,106]. BTH enhanced resistance against the anthracnose pathogens Colletotrichum destructivum in cowpea seedlings [86] and Colletotrichum orbiculare in cucumber [107]. BTH also induced resistance in oil seedrape against phoma stem canker caused by Leptosphaera maculans [92]. In tomato, BTH significantly reduced disease incidence and severity against Verticillium dahliae [91] and Botrytis cinerea [108]. It is also relatively effective in controlling various viral diseases in tobacco, such as TMV, tobacco necrosis virus (TNV), and tomato spotted wilt virus (TSWV) [87,88]. Its efficacy was also reported in tomato against cucumber mosaic virus (CMV), and TSWV [89,109]. Because disease reduction conferred by BTH in the field is generally incomplete Du et al. performed several modifications in the 7-ester group of BTH to enhance its efficacy. They found that adding fluorine resulted in compounds with enhanced protective ability against cucumber Erysiphe cichoracearum and Colletotrichum lagenarium [93]. N-(3-Chloro-4-Methylphenyl)-4-Methyl-1,2,3-thiadiazole-5-Carboxamide known as tiadinil (TDL), is the second commercialized thiadiazole derivative. It was registered under the trade name of V-GET®in 2003 by Nihon Nohyaku Co., Ltd. (Tokyo, Japan) (Table4). It confers rice blight resistance without exhibiting any antimicrobial activity [80,110]. Its metabolite, 4-methyl-1,2,3-thiadiazole-5- carboxylic acid (SV-03), seems to be responsible for SAR activation [94]. TDL also protects tea Agronomy 2018, 8, 5 10 of 20 plants in the field against the fungal diseases that are caused by Colletotrichum theaesinensis and Pestalotiopsis longiseta [95]. In tobacco, TDL and SV-03 induce resistance against TMV, the wildfire bacterial pathogen, and the powdery mildew. TDL acts in similar way to BTH by activating signals downstream of SA [66,94]. They failed to induce accumulation of SA in tobacco or to activate defense genes in Arabidopsis npr1 mutants. However, they enhanced resistance against TMV and P. syringae pv. tabaci, as well as PR gene expression in NahG transgenic tobacco plants. Recently, several derivatives of the isomer 1,3,4-thiadiazole were synthetized and tested as SAR inducers against Verticillium wilt and crown gall diseases (Table4). The derivative 2,5-bis(pyridin-2-yl)- 1,3,4-thiadiazole was reported to enhance tomato disease resistance and to activate plant defense mediated by ROS [96]. Furthermore, several metallic complexes harboring Ni or Cu as transient metal were synthetized and proved to activate SAR against Verticillium wilt. Their protection ability was associated with modulation of ROS accumulation and priming the activity of several plant defense-related enzymes, including peroxidase and polyphenol oxidase [96–98]. However, further experiments are needed to determine whether they act in similar way to BTH or not.

3.5. Pyrimidine Derivatives A new plant defense activator, 5-(cyclopropylmethyl)-6-methyl-2-(2-pyridyl)pyrimidin-4-ol, named PPA (pyrimidin-type plant activator), belonging to the pyridyl-pyrimidine derivative family was reported to enhance the expression of genes related to ROS, defenses, and SA in A. thaliana. PPA was able to reduce disease symptoms that were caused by P. syringae pv. maculicola and to enhance plant defenses against pathogen invasion through the plant redox system [111]. Recently, Narusaka and Narusaka identiﬁed several thienopyrimidine-type compounds that enhance disease resistance against Colletotrichum higginsianum and P. syringae pv. maculicola in A. thaliana. However, they induce the expression of both PR1 and PDF1.2 [112].

3.6. Neonicotinoid Compounds The neonicotinoid imidacloprid (IMI) and clothianidin (CLO) basically used to control crop pests have also been reported to induce plant defenses that are associated with SA and to inhibit the growth of powdery mildew in A. thaliana [113]. However, their effect was mainly due to their respective metabolites; 6-chloropyridinyl-3-carboxylic acid and 2-chlorothiazolyl-5-carboxylic acid. While CLO enhanced SA accumulation through the upregulation of ICS transcripts, and activated the expression of PR1 gene, IMI does not induce endogenous synthesis of SA, but it is further transformed to 6-chloro-2-hydroxypyridinyl-3-carboxylic acid, a potent inducer of PR1 and inhibitor of SA-sensitive enzymes [113]. In addition, IMI activates PR2 gene expression and induces high and long-lasting levels of resistance against the bacterial canker of Citrus X. citri [114].

4. Limitations of the Use of Functional Analogues of SA: Towards a New Generation of Compounds

4.1. Allocation Fitness Cost Limitations of the use of SA analogues in the field include their transient effect and their limited disease spectrum and target crops. However, the major drawback is related to their phytotoxicity when applied at higher doses. These effects are likely to be caused by the strong induction of defense responses, which is associated with growth inhibition [115]. Resources used in the primary metabolism are deviated and used for synthesis of defensive compounds, resulting in plant growth inhibition, a phenomenon known as ‘allocation fitness cost’ or ‘trade-off’ [116–119]. This notion comes from the use of Arabidopsis mutants and the observation that higher doses of SA or its functional analogues are often associated with direct inhibition of plant growth and seed production [10,120,121]. While mutants of Arabidopsis expressing constitutively PR genes were dwarfed and severely affected in seed production [11,122], those that are affected in SA accumulation, such as NahG or ICS1, showed Agronomy 2018, 8, 5 11 of 20 enhanced growth and seed production [121,123]. High concentrations of BTH in sunflower resulted in light chlorosis and reductions in fresh weight [124]. Repetitive application of BTH also provoked yield reduction in pepper [124]. The beneficial effects of SA-regulated defenses were particularly apparent under low-nutrient conditions [125], which supports the theory of allocation costs as a driver of the evolution of inducible defenses. BTH-treated wheat exhibited reduced growth and decreased seed production, mainly under deficiency of nitrogen [120]. Since reduced vigor observed after treatment with BTH was alleviated in npr1 mutants, it was suggested that NPR1 plays a pivotal role in inhibiting plant growth when SA-dependent resistance mechanisms are activated [10]. In addition to SA pathway, several interconnecting signals interacting synergistically or antagonistically, such as JA, ethylene, ABA, auxins, cytokinins, and ROS regulate development and disease resistance. For instance, BTH inhibits the growth by the suppression of auxin and the down regulation of several genes involved in auxin perception, transport and signaling [126,127]. In addition, BTH affects auxin homeostasis through the activation of the expression of gene encoding GH3.5. This family of adenylating enzymes conjugates acyl substrates, such as IAA to the Asp amino-acid [128].

4.2. Priming Effect Several researchers attempted to identify compounds that induce SAR without affecting plant growth in the field [129]. Another form of plant defense is priming, a phenomenon, which is defined as the enhancement of the basal level of resistance in plants, resulting in a faster and stronger resistance response following subsequent pathogen attack [130]. Defense priming can be regarded as an efficient mechanism to manipulate the “trade-off” machinery, resulting in minimizing the allocation fitness cost [129]. The discovery of immune-priming compounds started accidently with the use of probenazole to protect paddy field rice from the blast fungus and the bacterial leaf blight, and prompted the development of similar compounds, such as tiadinil and isotianil [70,79,80]. However, most of the classical activators of plant defenses can induce priming when used at lower doses that are insufficient to trigger detectable levels of defense responses. For instance, BABA primes host plants to activate SA-dependent signaling system [45,46] or other signaling systems, depending on the nature of challenging pathogen [131]. BTH and INA were able to prime a wide range of cellular responses, including alterations in ion transport across the plasma membrane, enhanced synthesis of phytoalexins, cell wall phenolics and lignin-like polymers, and activation of various defense genes [106,132]. Although still poorly understood, the molecular basis of priming started to be unraveled. NPR1 plays important role in inducing high levels of chromatin modification on promoters of the transcription factor genes. Priming involves a cyclic non-protein amino acid pipecolic acid as mobile signal and MAPK. Beckers et al. [133] showed that pre-stress deposition of MAPK3 and MAPK6 plays an important role during BTH-induced priming in A. thaliana. Exposure to the challenges of stressors results in the phosphorylation and activation of these two kinases in primed plants relative to non-primed plants, which is linked to enhanced defense gene expression. Priming is controlled epigenetically and relies on the ability of plant to reprogram the pattern of expression of thousands of genes. The process is initiated through the Arabidopsis subtilase SBT3.3, a proteolytic extracellular enzyme, which is involved in activation of chromatin remodeling, covalent histone modifications and defense genes become poised for enhanced activation following pathogen attack [3,134]. During priming, BTH increased acetylation of histone H3 at Lys-9 (H3K9ac) and trimethylation of histone H3 at Lys-4 (H3K4me3) in the promoter regions of the transcription factors WRKY6, WRKY29, and WRKY52 [135]. In addition, DNA methylation and histone modifications are regulated by RNA Polymerase V [136] and are involved in the transmission of a priming state or stress memory, suggesting that plants may inherit priming sensitization [137]. Transgenerational epigenetic effect of priming was reported to be triggered by BABA in Arabidopsis [138], and more recently in the potato relative Solanum physalifolium [139]. This effect could be considered as robust and a broadly distributed Agronomy 2018, 8, 5 12 of 20 mechanism of phenotypic plasticity to plant diseases. Therefore, screening for new immune-priming compounds is highly needed.

4.3. Screening for New Compounds Evaluation of new compounds requires a large quantity of chemicals and is time and space consuming, thus restricting the range of chemicals that can be tested. Large-scale screening of a broad range of compounds led to the identification of several functional SA analogues that could be used as plant activators in the field of crop protection [11,138]. The first high-throughput screening method involves young seedlings that are grown in liquid, facilitating the uniform application of chemicals from small-molecule libraries in standard 96-well plates [54]. This system is based on the use of β-glucuronidase (GUS) histochemical staining assay and the promoter of CaBP22 of A. thaliana gene, which encode a putative calmodulin-like binding protein. Screening of collection of 42,000 various molecules allowed the identification of the plant defense inducers DCA and 2-(5-bromo-2-hydroxy-phenyl)-thiazolidine-4-carboxylic acid (BHTC), which act, respectively in NPR1 independent and in NPR1 dependent manners [54,140]. By using the same system Bektas et al. identified a new compound named 2,4-dichloro-6-{(E)- ((3-methoxyphenyl)imino)methyl}phenol (DPMP), which acts as a partial agonist of SA [141]. A combination of this system with GUS fused to the promoters of A. thaliana defense-related genes that are involved in SA and JA/ET signaling allowed the identification of PPA [142,143] and thienopyrimidine-type compounds [112]. To avoid unfavorable side effects, such as phytotoxicity, and to distinguish between compounds that directly activate plant defenses responses from those doing so exclusively in the presence of the pathogen, Noutoshi et al., established a new high throughput screening technique based on the use of the pathosystem Arabidopsis suspension-cultured cells/P. syringae with 96 well plates [11]. This system allowed for the elimination of compounds that induce cell death, evaluated after Evans blue staining and identification of compounds that promote pathogen resistance in Arabidopsis by invoking the hypersensitive cell death pathway in response to pathogen attack. Five new immune-priming compounds were selected from a chemical library of 10,000 molecules were called imprimatins A1, A2, A3, B1, and B2 (Table5). Two of them acted by inhibiting SAGT, allowing then, SA accumulation. To access the effect of these new immune-priming compounds on the growth, Arabidopsis seeds were germinated and grown in liquid MS media containing imprimatins. In contrast to tiadinil, which prominently inhibited seedling growth, imprimatin A2, B1, and B2 exhibited only moderate growth inhibitory effects, in a concentration-dependent manner. However, imprimatin A1 and A3 did not affect at all the growth at the concentration range effective for immune priming [12]. Using this screening strategy, Noutoshi et al. isolated imprimatins C that behave as functional analogues of SA [12]. They effectively induce the expression of PR1 gene and enhance disease resistance in A. thaliana, however, they lack antagonistic activity against JA [12]. Furthermore, structure-activity relationship analyses implicated that the potential downstream metabolites of imprimatin C compounds, including 4-chlorobenzoic acid, 3,4-dichlorobenzoic acid, and their derivative 3,5-DCBA also act as partial agonists of SA with various potencies [13]. Therefore, imprimatin C compounds can potentially assist to better understand the molecular events that are involved in SA defense signaling and their putative functional metabolites can serve as valuable tools to address the complexity intrinsic on the activities of SA receptors, providing insights into the mechanisms governing early SA perception and NPR1 regulation and its role in plant immune signaling. Agronomy 2018, 8, 5 13 of 21 Agronomy 2018, 8, 5 13 of 21 Agronomy 2018, 8, 5 13 of 21 Agronomy 2018, 8, 5 13 of 21 Agronomy 2018, 8, 5 13 of 21 Agronomystructure 201-activity8, 8, 5 relationship analyses implicated that the potential downstream metabolites13 of 21 of structure-activity relationship analyses implicated that the potential downstream metabolites of structureimprimatin-activity C compounds, relationship including analyses 4implicated-chlorobenzoic that the acid, potential 3,4-dichlorobenzoic downstream acid metabolites, and their of structureimprimatin-activity C compounds, relationship including analyses 4 implicated-chlorobenzoic that acid, the potential 3,4-dichlorobenzoic downstream acid metabolites, and their of imprimatinstructurederivative-activity 3,5 C - compounds,DCBA relationship also act including analyses as partial 4 implicated-chlorobenzoic agonists thatof SA acid, the with potential 3,4 various-dichlorobenzoic downstream potencies acid [13] metabolites,. and Ther efore, their of imprimatinderivative 3,5 C- DCBA compounds, also act including as partial 4- chlorobenzoic agonists of SA acid, with 3,4 various-dichlorobenzoic potencies acid[13]., Therand efore, their derivativeimprimatinimprimatin 3,5 C- DCBAcompounds compounds, also actcan including aspotentially partial 4- chlorobenzoicagonists assist to ofbetter SA acid, understand with 3,4 various-dichlorobenzoic the potencies molecular [13] acid events., Therand that efore, their are derivativeimprimatin 3,5 C -compoundsDCBA also can act potentially as partial agonistsassist to better of SA understand with various the potenciesmolecular [13] events. Ther thatefore, are imprimatinderivativeinvolved in 3,5 CSA -compoundsDCBA defense also signaling can act potentially as and partial their agonistsassistputative to betterfunctional of SA understand with metabolites various the potencies molecularcan serve as [13]events valuable. Ther thatefore, tools are imprimatininvolved in SAC compounds defense signaling can potentially and their putativeassist to functionalbetter understand metabolites the canmolecular serve as events valuable that tools are involvedimprimatinto address in SAC the compounds defense complexity signaling can intrinsic potentially and their on the putativeassist activi to ties functionalbetter of SAunderstand metabolites receptors, the providing canmolecular serve as insights events valuable that into tools are the involvedto address in theSA defense complexity signaling intrinsic and ontheir the putative activities functional of SA receptors,metabolites providing can serve insightsas valuable into tools the toinvolvedmechanisms address in theSA governing defense complexity signaling early intrinsic SA and perception ontheir the putative activi andties functional NPR1 of SA regulation receptors, metabolites and providing can its serve role ininsightsas plantvaluable into immune tools the tomechanisms address the governing complexity early intrinsic SA perception on the activi andties NPR1 of SA regulation receptors, and providing its role in insights plant immune into the mechanismstosignaling. address the governing complexity early intrinsic SA perception on the activi and ties NPR1 of SA regulation receptors, and providing its role in insights plant immune into the Agronomymechanismssignaling.2018 , governing8, 5 early SA perception and NPR1 regulation and its role in plant immune 13 of 20 signaling. signaling. Table 5. Imprimatins as new immune priming compounds. Table 5. Imprimatins as new immune priming compounds. Table 5. Imprimatins as new immune priming compounds. Table 5. Imprimatins as new immune priming compoundsPlant/Pathogen. Chemical/Trade NameTable 5. Imprimatins as newChemical immune Structure priming compoundsPlant/Pathogen. Reference Chemical/Trade NameTable 5. ImprimatinsChemical as Structure new immune primingPlant/PathogenInteraction compounds. Reference Chemical/Trade Name Chemical Structure Plant/PathogenInteraction Reference Chemical/Trade Name Chemical Structure Plant/PathogenInteraction Reference Chemical/Trade Name Chemical Structure Plant/PathogenInteraction Reference Chemical/Trade Name Chemical Structure InteractionArabidopsis Reference InteractionArabidopsis 2-((E)Chemical/Trade-2-(2-bromo-4-hydroxy Name-5- Chemical Structure Plant/Pathogenthaliana/PseudomoArabidopsis Interaction Reference 2-((E)-2-(2-bromo-4-hydroxy-5- thaliana/PseudomoArabidopsis methoxyphenyl)ethenyl2-((E)-2-(2-bromo-4-hydroxy) quinolin-5--8-ol: thaliana/PseudomonasArabidopsis syringae pv. methoxyphenyl)ethenyl2-((E)-2-(2-bromo-4-hydroxy) quinolin-5--8-ol: thaliana/PseudomonasArabidopsis syringae pv. methoxyphenyl)ethenyl2-((E)-2-(2 Imprimatin-bromo-4-hydroxy) quinolinA1 -5--8-ol: thaliana/Pseudomonastomato syringae DC3000 pv. methoxyphenyl)ethenyl2-2-((E)-2-(2-bromo-4-hydroxy-5-((E)-2- (2Imprimatin-bromo-4-hydroxy) A1 quinolin -5--8-ol: thaliana/Pseudomonastomato syringae DC3000 pv. methoxyphenyl)ethenyl Imprimatin) A1 quinolin -8-ol: Arabidopsisnastomato syringaeavrRp DC3000 thaliana/Pseudomonas m1 pv. methoxyphenyl)ethenylmethoxyphenyl)ethenyl) Imprimatin )A1 quinolin quinolin-8-ol:-8-ol: nastomatoavrRp syringae DC3000 m1 pv. Imprimatin A1 syringaetomatopv.avrRptomato DC3000 m1 DC3000 avrRp m1 ImprimatinImprimatin A1 A1 tomatoavrRp DC3000 m1 avrRp m1 ArabidopsisavrRp m1 Arabidopsis 7-chloro-2-((E)-2- (4- thaliana/PseudomoArabidopsis 7-chloro-2-((E)-2- (4- thaliana/PseudomoArabidopsis nitrophenyl)ethenyl7-chloro-2-((E)-2-) -(44H- -3,1- thaliana/PseudomonasArabidopsis syringae pv. nitrophenyl)ethenyl7-chloro-2-((E)-2)-- 4(4H--3,1- thaliana/PseudomonasArabidopsis syringae pv. benzoxazinnitrophenyl)ethenyl7-chloro7-chloro-2-((E)-2--4--one:2-((E) Imprimatin-2)-- 4(4H--3,1- A2 thaliana/Pseudomonastomato syringae DC3000 pv. nitrophenyl)ethenyl7-chloro-2-((E)-2)- 4(4H--3,1- Arabidopsisthaliana/Pseudomonas syringae thaliana/Pseudomonas pv. benzoxazinnitrophenyl)ethenyl-4-one: Imprimatin)-4H-3,1 -A2 nastomato syringae DC3000 pv. (4-nitrophenyl)ethenyl)-4benzoxazinnitrophenyl)ethenyl-4-one: Imprimatin)-4HH-3,1-benzoxazin--3,1 -A2 nastomato syringaeavrRp DC3000 m1 pv. benzoxazin-4-one: Imprimatin A2 syringaetomatopv.avrRptomato DC3000 m1 DC3000 avrRp m1 benzoxazin4-one:-4-one: Imprimatin Imprimatin A2 A2 tomatoavrRp DC3000 m1 benzoxazin-4-one: Imprimatin A2 tomatoavrRpArabidopsis DC3000 m1 ArabidopsisavrRp m1 thaliana/PseudomoArabidopsisavrRp m1 4-((E)-2-(quinolin-2-yl)ethenyl)phenol: thaliana/PseudomoArabidopsis 4-((E)-2-(quinolin-2-yl)ethenyl)phenol: thaliana/PseudomonasArabidopsis syringae pv. [11] 4-((E)-2-(quinolinImprimatin-2-yl)ethenyl A3 )phenol: thaliana/PseudomoArabidopsis 4-((E)-2-(quinolin-2-yl)ethenyl)phenol: thaliana/Pseudomonas syringae pv. [11] 44-((E)-2-(quinolin-2-yl)ethenyl)phenol:-((E)-2-(quinolinImprimatin-2-yl)ethenyl A3 )phenol: Arabidopsisthaliana/Pseudomonastomato syringae thaliana/PseudomonasDC3000 pv. [11] 4-((E)-2-(quinolinImprimatin-2-yl)ethenyl A3 )phenol: nastomato syringae DC3000 pv. [11] [11] ImprimatinImprimatin A3 A3 syringaenastomatopv. syringaeavrRptomato DC3000 m1 pv. DC3000 avrRp[11] m1 Imprimatin A3 nastomatoavrRp syringae DC3000 m1 pv. [11] Imprimatin A3 tomatoavrRp DC3000 m1 tomatoavrRp DC3000 m1 avrRpArabidopsis m1 2-(3-(2-furyl)-3-phenylpropyl) ArabidopsisavrRp m1 2-(3-(2-furyl)-3-phenylpropyl) thaliana/PseudomoArabidopsis benzo2-(3(c-)(2azoline-furyl)--1,33-phenylpropyl)-dione: Imprimatin thaliana/PseudomoArabidopsis benzo2-(3(c)-azoline(2-furyl)-1,3-3--phenylpropyl)dione: Imprimatin thaliana/PseudomonasArabidopsis syringae pv. benzo2-2-(3-(2-furyl)-3-phenylpropyl)((3c)-azoline(2-furyl)-1,3-3B1--phenylpropyl)dione: Imprimatin Arabidopsisthaliana/PseudomonasArabidopsis syringae thaliana/Pseudomonas pv. benzo2-((3c)-azoline(2-furyl)-1,3-3B1--phenylpropyl)dione: Imprimatin thaliana/Pseudomonastomato syringae DC3000 pv. benzo(c)azoline-1,3-dione:benzo(c)azoline-1,3B1-dione: Imprimatin Imprimatin B1 syringaethaliana/Pseudomonastomatopv. syringaetomato DC3000 pv.DC3000 avrRp m1 benzo(c)azoline-1,3B1-dione: Imprimatin nastomato syringaeavrRp DC3000 m1 pv. B1 nastomato syringae DC3000 pv. B1 avrRp m1 tomatoavrRp DC3000 m1 tomatoavrRp DC3000 m1 avrRp m1 ArabidopsisavrRp m1 Arabidopsis thaliana/PseudomoArabidopsis 3-(2-furyl)-3-phenylpropylamine: thaliana/PseudomoArabidopsis 3-3-(2-furyl)-3-phenylpropylamine:(2-furyl)-3-phenylpropylamine: Arabidopsisthaliana/PseudomonasArabidopsis syringae thaliana/Pseudomonas pv. 3-(2-furyl)-Imprimatin3-phenylpropylamine: B2 thaliana/PseudomonasArabidopsis syringae pv. 3-(2-furyl)Imprimatin-3Imprimatin-phenylpropylamine: B2 B2 syringaethaliana/Pseudomonastomatopv. syringaetomato DC3000 pv.DC3000 avrRp m1 3-(2-furyl)Imprimatin-3-phenylpropylamine: B2 thaliana/Pseudomonastomato syringae DC3000 pv. 3-(2-furyl)Imprimatin-3-phenylpropylamine: B2 nastomato syringaeavrRp DC3000 m1 pv. Imprimatin B2 nastomatoavrRp syringae DC3000 m1 pv. Imprimatin B2 tomatoavrRp DC3000 m1 tomatoavrRp DC3000 m1 avrRp m1 avrRp m1 Arabidopsis Arabidopsis ((E)-(1-amino-2-(2-oxopyrrolidin-1-yl)((E)-(1-amino-2-(2-oxopyrrolidin-1- thaliana/PseudomoArabidopsis ((E)-(1-amino-2-(2-oxopyrrolidin-1- Arabidopsisthaliana/PseudomoArabidopsis thaliana/Pseudomonas yl)ethylidene((ethylidene)amino)E)-(1-amino)amino-2-(2-oxopyrrolidin) 4- 4-chlorobenzoate:chlorobenzoate:-1- thaliana/PseudomonasArabidopsis syringae pv. [144] [144] yl)ethylidene((E)-(1-amino)amino-2-(2-)oxopyrrolidin 4-chlorobenzoate:-1- syringaethaliana/Pseudomonaspv.Arabidopsis syringaetomato pv. DC3000 avrRp[144] m1 yl)ethylidene((E)-(1-aminoImprimatin)aminoImprimatin-2-(2-)oxopyrrolidin 4-chlorobenzoate: C1 C1 -1- thaliana/Pseudomonastomato syringae DC3000 pv. [144] yl)ethylidene((E)-(1-aminoImprimatin)amino-2-(2-)oxopyrrolidin 4-chlorobenzoate: C1 -1- thaliana/Pseudomonastomato syringae DC3000 pv. [144] yl)ethylideneImprimatin)amino) 4-chlorobenzoate: C1 nastomato syringaeavrRp DC3000 m1 pv. [144] yl)ethylideneImprimatin)amino) 4-chlorobenzoate: C1 nastomatoavrRp syringae DC3000 m1 pv. [144] Imprimatin C1 tomatoavrRp DC3000 m1 Imprimatin C1 tomatoavrRp DC3000 m1 avrRp m1 avrRp m1

5. Conclusions5. Conclusions 5. Conclusions 5. ConclusionsThe activation of induced resistance using functional analogues of SA requires large energy 5. ConclusionsThe activation of induced resistance using functional analogues of SA requires large energy inputTheThe, and activation activation thus compromises of of induced induced other resistance resistance metabolic using processes. functional using functional Therefore, analogues theirof analogues SA success requires may of large depend SA energy requires on large energy inputThe, and activation thus compromises of induced other resistance metabolic using processes. functional Therefore, analogues their of SA success requires may large depend energy on input,inputmanagingThe, and and activation thus the tradeoff compromises compromises of induced between other resistance defense other metabolic using metabolicand processes. growth. functional processes. There Therefore, analogues are many their Therefore,of SA evidencessuccess requires may their that large depend signalingsuccess energy on may depend on inputmanaging, and the thus tradeoff compromises between other defense metabolic and processes.growth. There Therefore, are many their evidences success may that depend signaling on managinginputcrosstalks, and theare thus involvedtradeoff compromises between in the other tradeoff. defense metabolic Ide andntification growth.processes. of There signalingTherefore, are many components their evidences success that may thatdirectly depend signaling affect on managingmanagingcrosstalks are the involved tradeoff tradeoff betweenin thebetween tradeoff. defense defense Ide andntification growth. and of growth. There signaling are manycomponents There evidences are that many thatdirectly evidencessignaling affect that signaling crosstalksmanagingthese crosstalk are the involved tradeoffand designing inbetween the tradeoff.new defense compounds Ide andntification growth. that will of There signalingaffect are these manycomponents components evidences that will thatdirectly be signaling the affect most crosstalkscrosstalksthese crosstalk are involved involvedand designing in thein thenew tradeoff. tradeoff.compounds Identification Identiﬁcationthat will of signalingaffect these of components signalingcomponents that components will directly be the affectmost that directly affect thesecrosstalksimportant crosstalk arechallenge involvedand designing for incrop the protection. new tradeoff. compounds IdeThentification discovery that will of NPR1affect signaling asthese receptor components components of SA thatwill will bedirectly be very the helpful affectmost theseimportant crosstalk challenge and designingfor crop protection. new compounds The discovery that will of NPR1 affect asthese receptor components of SA will will be verybe the helpful most theseimportantthesefor future crosstalk crosstalk challengechemical and and designingforscreening designing crop protection. newof immune newcompounds The compounds-priming discovery that compounds will of NPR1 thataffect as willthatthese receptor destabilize affectcomponents of SA these NPR1will will componentsbe by verybe binding the helpful most to will be the most importantfor future challengechemical screeningfor crop protection. of immune The-priming discovery compounds of NPR1 asthat receptor destabilize of SA NPR1 will be by very binding helpful to importantfoimportantr future challengechemicalchallenge screening for for crop crop protection. of protection.immune The-priming discovery The compounds discovery of NPR1 asthat of receptor destabilize NPR1 of as SA receptorNPR1 will be by very binding of helpful SA willto be very helpful for future chemical screening of immune-priming compounds that destabilize NPR1 by binding to for future chemical screening of immune-priming compounds that destabilize NPR1 by binding to

SA [145]. Understanding of the molecular mechanisms underlying priming may also help to design new chemicals that stimulate the plant’s inherent disease resistance mechanisms.

Acknowledgments: This work was supported by the University Chouaib Doukkali, El Jadida, Morocco. Author Contributions: M.F. wrote the first draft. L.F. contributed to the overall preparation of the manuscript and provided the technical guidance and editing support. Conflicts of Interest: The authors declare no conflict of interest.

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