Heterocyclic‐Based Fungicides: Emerging Strategies for Viable Plant Disease Control

ABSTRACT

Fungal infections in plants cause significant agricultural losses worldwide, while increasing fungicide resistance and growing environmental concerns have created an urgent need for safer and more effective antifungal agents. Heterocyclic compounds have attracted considerable attention because of their structural diversity, potent antifungal activity, and ability to interact with multiple fungal targets, offering broad‐spectrum protection against phytopathogens. This review summarizes the classification of heterocyclic fungicides, their mechanisms of action targeting fungal cells and enzymes, and their potential for controlling major plant fungal diseases. It also highlights recent advances in the rational design, synthesis, molecular docking, and SAR studies of heterocyclic scaffolds, along with molecular optimization strategies to overcome resistance and improve efficacy and bioavailability. Furthermore, the review emphasizes the potential of heterocyclic moieties for the development of environmentally sustainable plant protection agents. Synthetic and semisynthetic/part‐natural scaffolds, particularly azole, quinoline, indole, cyclotryptamine, and phenazine derivatives, demonstrated promising antifungal activity, with structural optimization further enhancing their efficacy and identifying them as valuable lead candidates for next‐generation sustainable fungicides.

Heterocyclic compounds have attracted considerable attention because of their structural diversity, potent antifungal activity, and ability to interact with multiple fungal targets, offering broad‐spectrum protection against phytopathogens. Synthetic and semisynthetic/part‐natural scaffolds, particularly azole, quinoline, indole, cyclotryptamine, and phenazine derivatives, demonstrated promising antifungal activity, with structural optimization further enhancing their efficacy and identifying them as valuable lead candidates for next‐generation sustainable fungicides.

Abbreviations

A.A.

A. Alternata

A.S.

Alternaria solani

B.C.

Botrytis cinerea

B.M.

Bipolaris maydis

B.S.

Bipolaris sorokiniana

C.A.

Cercospora arachidicola

C.H.

Cercosporaarac hidicolahori

C.J.

Cytospora juglandis

C.L.

Curvularia lunata

C.M.

C. micotianae

C.O.

Colletotrichum orbiculare

EC 50%

Effective concentration: concentration of compound that inhibits the fungi growth by 50%

F.G.

Fusarium graminearum

F.O.

Fusarium oxysporum

G.Z.

Gibberella zeae

H.M.

H. maydis

M.O.

M. oryzae

P.A.

Pythium aphanidermatum

P.A.

Pythium aphanidermatum

P.C.

Phytophthora citrophthora

P.G.

Pyricularia grisea

P.I.

Phytophthora infestans

P.P.

Physalospora piricola

P.S.

Pellicularia sasakii

R.C.

Rhizoctonia cerealis

R.S.

Rhizoctonia solani

S.S.

Sclerotinia sclerotiorum

S.T.

Setosphaeria turcica

T.C.

Thanatephorus cucumeris

V.D.

Verticillium dahliae

V.M.

V. mali

W.A.

Watermelon anthracnose

W.P.

Walnut pythium

1. Introduction

Crop diseases are natural calamity that poses a major threat to agricultural output and cause loss of at least 16%–20% of the world's food output, with some crops suffering losses of up to 30%–50% annually [1] and also a reason for economic losses, approximately USD 220 billion annually, which is roughly equal to one‐third of the world's annual harvest [2, 3]. Plant diseases caused by bacteria, viruses, and fungi, of which two‐thirds are caused by plant pathogenic fungi, are the most widespread and destructive diseases affecting agriculture across the globe [2, 3, 4]. Environmental conditions such as high humidity, poor air circulation, soil saturation, and moderate temperatures often promote fungal proliferation and disease outbreaks [5]. In addition, global climate change has been shown to alter the epidemiology of fungal infections, influencing pathogen virulence, spore dispersal patterns, and host susceptibility. Changes in cropping systems and monoculture practices have also contributed to the emergence of new fungal races and the re‐emergence of resistant strains. In addition to direct yield losses, fungal infections can impair seed germination, reduce photosynthesis, and lower the nutritional and commercial value of crops [6]. Moreover, some pathogenic fungi produce mycotoxins that pose serious health hazards to humans and animals when contaminated food is consumed [7]. To combat these infections, the use of fungicides has become an integral part of integrated pest and disease management [8]. Among these, heterocyclic compounds have emerged as highly effective chemical tools due to their potent antifungal activity, systemic action, and structural versatility [9].

1.1. Heterocycles as Plant Fungicides and Their Agricultural Applications

Heterocyclic compounds comprising nitrogen, oxygen, or sulfur atoms within ring systems play a vital role in modern agriculture owing to their varied structures, notable biological activity, and strong antifungal properties [10, 11, 12, 13]. They serve as active ingredients in insecticidal, acaricidal, fungicidal, and herbicidal agents, offering benefits through a variety of mechanisms of action, which significantly contribute to sustainable agricultural productivity and improve food security worldwide. These compounds interact with fungal enzymes and targets, disrupting essential processes such as membrane synthesis, respiration, and nucleic acid metabolism. This interaction provides broad‐spectrum activity and aids in reducing the development of fungicide resistance, contributing significantly to sustainable crop protection and improved food production worldwide [14, 15, 16, 17]. In addition, structure–activity relationship studies of heterocyclic compounds have shown that different substituents, such as halogens and heteroaryl rings, often enhance fungicidal potency, selectivity, and stability. In addition, hybrid heterocyclic molecules containing multiple pharmacophores have shown promising activity against resistant fungal strains [18]. Commercial fungicides such as triazoles, imidazoles, pyrazolecarboxamides, benzimidazoles, phenylpyrroles, and anilinopyrimidine derivatives clearly demonstrate the agricultural importance of heterocyclic chemistry [19]. Table 1 summarizes various important classes of marketed heterocyclic plant fungicides, along with representative examples and the primary fungal diseases they are employed to control in agricultural practice [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45].

TABLE 1.

Chemical classification of heterocyclic fungicides along with targets and mechanism of action.

Chemical class	Example fungicide	Target fungal diseases	MOA	References
Triazoles	Tebuconazole	Powdery mildew, rusts, leaf spots	Inhibit ergosterol synthesis, disrupting membranes	[20]
	Propiconazole	Powdery mildew, rusts, leaf spots	Inhibit ergosterol synthesis	[21]
	Difenoconazole	Powdery mildew, rusts, leaf spots	Inhibit ergosterol synthesis	[22]
	Prothioconazole	Powdery mildew, rusts, leaf spots	Inhibit ergosterol synthesis	[23]
Imidazoles	Imazalil	Root rot, post‐harvest diseases	Block ergosterol production	[24]
	Prochloraz	Root rot, post‐harvest diseases	Block ergosterol production	[25]
Pyrimidines	Fenarimol	Powdery mildew, leaf spots	Inhibit sterol biosynthesis	[26]
	Ethirimol	Powdery mildew, leaf spots	Inhibit sterol biosynthesis	[27]
Pyrroles	Fludioxonil	Fusarium, Botrytis, Rhizoctonia	Disrupt spore germination	[28]
Pyridines	Fluazinam	Phytophthora, Sclerotinia	Inhibit fungal respiration	[29]
	Pydiflumetofen	Phytophthora, Sclerotinia	Inhibit fungal respiration	[30]
Morpholines	Fenpropimorph	Powdery mildew, rust	Inhibit sterol biosynthesis enzymes	[31]
	Tridemorph	Powdery mildew, rust	Inhibit sterol biosynthesis enzymes	[32]
Thiazoles	Thiabendazole	Fusarium, post‐harvest rots	Disrupt microtubules and cell division	[33]
Oxazoles	Vinclozolin	Blights, rots, molds	Inhibit mitochondrial respiration	[34]
Benzimidazoles	Carbendazim	Botrytis, Fusarium, Sclerotinia	Prevent microtubule formation	[35]
	Thiophanate‐methyl	Botrytis, Fusarium, Sclerotinia	Prevent microtubule formation	[36]
	Benomyl	Botrytis, Fusarium, Sclerotinia	Prevent microtubule formation	[37]
Pyrazoles	Penflufen	Various fungal diseases	Block fungal respiration	[38]
Thiadiazoles	Etridiazole	Pythium ultimum	Inhibit spore germination	[39]
Dicarboximides	Vinclozolin	Blights, rots, molds	Affect cell signaling and membranes	[40]
Oxathiins	Carboxin	Seedling diseases, rusts	Inhibit mitochondrial enzymes	[41]
Oxadiazoles	Oxadiazon	Broad‐spectrum activity	Causes membrane damage	[42]
	Metoxadiazone	Broad‐spectrum activity	Causes membrane damage	[43]
Indoles	Indole Schiff base derivatives	Various fungal pathogens	Disrupt the cell wall and enzyme function	[44]
Lactams	Piperonyl‐containing lactam derivatives	Phytophthora capsici	Inhibit cell wall biosynthesis	[45]

1.2. Rationale of the Study

The increasing prevalence of plant fungal infections, coupled with the emergence of resistance to conventional fungicides, has created an urgent need for the development of novel antifungal agents with unique mechanisms of action. Heterocyclic compounds, owing to their structural diversity and bioactivity, represent a promising class of molecules for the development of next‐generation fungicides. This paper aims to provide a comprehensive overview of both established and emerging heterocyclic antifungal agents used in plant protection, highlighting their chemical classes, mechanisms of action, and potential for future innovation. By consolidating recent advances and identifying research gaps, this review seeks to support the design of more effective and sustainable plant fungicides.

2. Classifying Heterocycles as Phytopathogenic Fungi Inhibitors

2.1. Sarisan Analogues

Xu et al. designed an innovative class of sarisan analogues with 1, 3, 4 oxadiazole scaffold via iodine‐mediated oxidative cyclization reactions (Scheme 1). The structures of the compounds were confirmed using ¹H NMR, IR, and MS The antifungal potential of the compounds was evaluated in vitro against Fusarium graminearum, Fusarium solani, Valsa mali, Alternaria alternate, and Curvularia lunata at 50 µg/mL using the mycelium growth rate method. Among the compounds evaluated, derivative 1 exhibited significant antifungal activity, achieving a percentage inhibition value exceeding 50% (Tables 2 and 3). SAR : Structure‐Activity Relationship (SAR) analysis revealed that the incorporation of a 3‐pyridyl group on the 1,3,4‐oxadiazole ring resulted in agents with enhanced activity and inhibition greater than 50%, surpassing those with 3‐halophenyl or 4‐halophenyl groups, and comparable to hymexazol, the reference drug [46].

SCHEME 1.

Synthesis of sarisan analogues having 1, 3, 4 oxadiazole.

TABLE 2.

Antifungal activities of active compound 1against five phytopathogenic fungi at 50 µg/mL.

Compounds	Antifungal activities (inhibition %)
	V. mali	C. lunata	A. alternate	F. solani	F. graminearum
1	68.8 ± 1.7	69.7 ± 1.4	60.6 ± 0.8	51.0 ± 1.0	52.1 ± 2.9
Sarisan	49.4 ± 5.2	35.2 ± 0.9	65.2 ± 3.3	44.3 ± 1.3	54.3 ± 0.5
Hymexazol	24.3 ± 2.4	34.1 ± 1.4	60.3 ± 1.5	45.4 ± 2.0	54.5 ± 1.1

TABLE 3.

The EC₅₀ of active compound 1 against phytopathogenic fungi.

Compounds	EC50 ± SD (µg/mL)
	V. mali	C. lunata	A. alternate
1	12.6 ± 0.5	14.5 ± 1.2	17.0 ± 0.6
Sarisan	55.2 ± 2.7	87.1 ± 3.0	16.4 ± 1.7
Hymexazol	ND	96.3 ± 2.9	22.7 ± 1.9

ND: not determined.

2.2. N‐butyphthalide

Li et al. developed a new class of 6‐substituted N‐butyphthalide (NBP) via phthalic anhydride under various reaction conditions (Scheme 2). The chemical entities of the synthesized derivatives were validated using different spectral investigations, and their in vitro antifungal effectiveness was assessed against various strains using the mycelium growth rate method at 50 µg/mL. Among the synthesized motifs, Compounds 2 and 3 demonstrated the highest potency in comparison to hymexazol, which served as the reference. The results for these compounds are detailed in Tables 4 and 5. SAR indicated that the introduction of nitro and hydroxyl groups at the NBP (3) position, as well as a nitro group at the C‐6 position of NBP (2), resulted in enhanced activity compared to other compounds containing azo groups [47].

SCHEME 2.

Synthesis of 6‐substituted N‐butyphthalide (NBP).

TABLE 4.

The antifungal properties of 6‐substituted n‐butyphthalide derivatives at 50 µg/mL.

Fungal strains	Compounds (% inhibition)
	2	3	Hymexazol
Fusarium solani	95.0 (± 2.0)	64.9 (± 3.1)	42.9 (± 3.0)
Thanatephorus cucumeris	47.4 (± 1.3)	42.5 (± 5.0)	94.7 (± 0.4)
Fusarium oxysporum	88.2 (± 1.2)	65.1 (± 1.6)	53.5 (± 0.3)
Fusarium graminearum	80.9 (± 0.9)	39.2 (± 2.0)	63.9 (± 1.6)
Botrytis cinerea	32.9 (± 0.9)	100 (± 0.3)	75.6 (± 1.6)
Pyricularia oryzae	42.6 (± 2.3)	97.7 (± 0.6)	88.6 (± 0.3)
Valsa mali	88.9 (± 0.9)	90.9 (± 0.7)	35.8 (± 1.5)
Sclerotiua sclerotiorum	17.5 (± 3.4)	100 (± 0.4)	87.4 (± 1.3)
Alternaria solani	66.7 (± 0.5)	84.9 (± 0.5)	52.9 (± 0.3)

TABLE 5.

EC₅₀ values of active 6‐substituted n‐butyphthalide compounds 2 and 3.

Fungal strains	EC50± SD (µg/mL)
	2	3	Hymexazol
Fusarium solani	6.6 ± 0.5	25.7 ± 1.3	53.8 ± 0.5
Fusarium oxysporum	9.6 ± 1.3	18.2 ± 0.8	39.4 ± 2.0
Fusarium graminearum	16.0 ± 1.2	—	32.4 ± 3.7
Botrytis cinerea	—	6.3 ± 1.8	11.5 ± 3.5
Pyricularia oryzae	—	5.9 ± 0.3	24.3 ± 0.5
Valsa mali	11.2 ± 1.5	10.0 ± 0.5	—
Sclerotiua sclerotiorum	—	4.5 ± 0.9	25.1± 1.7
Alternaria solani	18.6 ± 0.7	8.4 ± 1.3	48.9 ± 0.2

2.3. Sarisan Analogues/Phenylisoxazoline

Liu et al. developed a novel class of sarisan derivatives having 3‐phenylisoxazoline scaffold, using substituted benzaldehydes and hydroxylamine hydrochloride (Scheme 3), their molecular entities were investigated by IR, ¹H/¹³C‐NMR, and MS studies, and their in vitro antifungal potential was further evaluated against F. solani, F. graminearum, C. lagenarium, A. solani, and B. cinerea using mycelium growth rate method at 50 µg/mL then assessed for cytotoxic study through CCK‐8 method (normal NRK‐52E cells). In the series of synthesized derivatives, compounds 4–6 were found to possess strong antifungal properties, surpassing those of hymexazol, as detailed in Tables 6 and 7. These compounds also demonstrated minimal toxicity to benign NRK‐52E cells and exhibited a clear selectivity between phytopathogenic fungi and non‐mutated eukaryotic cells. SAR : SAR study demonstrated that the presence of fluoro (4), chloro (6) group at m‐position and trifluoromethyl at p‐position (5) on the benzene ring increased the antifungal activity with low cytotoxicity [48].

SCHEME 3.

Synthesis of sarisan derivatives having a 3‐phenylisoxazoline scaffold.

TABLE 6.

Antifungal activity of sarisan derivatives against fungi (50 µg/mL).

Compounds	% Inhibition
	B. cinerea	C. lagenarium	A. solani	F. solani	F. graminearum
4	45.5 ± 2.1	39.2 ± 0.03	54.3 ± 4.0	55.0 ± 3.5	55.9 ± 1.1
5	43.7 ± 1.9	27.6 ± 2.2	55.7 ± 2.0	25.0 ± 3.5	50.8 ± 1.1
6	67.9 ± 5.1	59.6 ± 0.04	17.5 ± 4.5	42.2 ± 1.6	45.5 ± 2.6
Sarisan	28.5 ± 2.2	34.4 ± 2.9	35.2 ± 1.3	38.5 ± 3.1	45.3 ± 2.5
Hymexazol	55.3 ± 2.4	42.1 ± 1.4	38.3 ± 1.5	46.4 ± 2.0	54.5 ± 1.1

TABLE 7.

The EC₅₀ values of active molecules 4–6.

Compounds	Antifungal activities
	B. cinerea	C. lagenarium	A. solani	F. solani	F. graminearum
4	/	/	32.9 ± 1.6	35.6 ± 0.3	33.4 ± 0.4
5	/	/	37.0 ± 1.0	/	36.8 ± 0.5
6	30.1 ± 0.7	36.6 ± 0.9	/	/	/
Hymexazol	41.2 ± 0.5	65.7 ± 1.6	69.9 ± 2.0	49.6 ± 1.9	34.6 ± 1.2

50% Effective concentration: concentration of compound that inhibits fungal growth by 50%; /: not detected.

2.4. 4‐Aminoquinolines

Yang et al. synthesized a novel set of 4‐aminoquinolines having a 1,3‐benzodioxole pharmacophore via ammonolysis of acyl chlorides, afterwards nucleophillic substitution reaction (Scheme 4), and characterized their molecular structures by IR, ¹H/¹³C NMR, and Mass spectrometry studies, followed by in vitro antifungal evaluation against P. piricola, C. lunata, P. grisea, A. alternate, and A. brassicae using the mycelium growth rate method at 50 µg/mL. Among the synthesized analogs, compound 7 emerged as the most effective antifungal agent, inducing notable morphological changes in the mycelia of C. lunata. (Tables 8 and 9). SAR: SAR analysis indicated that para‐substituted methyl aniline at the fourth position, along with furyl at the ortho‐position of the primary quinoline pharmacophore, served as highly effective antifungal agents [49].

SCHEME 4.

Synthesis of 4‐aminoquinolines having 1,3‐benzodioxole.

TABLE 8.

Inhibition rates of 1,4‐aminoquinoline compounds against five phytopathogenic fungi at 50 µg/mL.

Compounds	Antifungal activities (inhibition %)
	P. piricola	A. brassicae	C. lunata	P. grisea	A. alternate
7	74.2 ± 0.74	70.0 ± 0.91	76.7 ± 1.6	69.9 ± 1.1	73.7 ± 1.2
Azoxystrobin	68.6 ± 1.7	48.8 ± 0.42	44.9 ± 0.0	52.9 ± 1.0	54.7 ± 0.47

TABLE 9.

Anti‐phytopathogenic results (EC₅₀) of some potent 1,4‐aminoquinoline compounds.

Compounds	EC50 (µg/mL)
	C. lunata	Toxic regression equation	r 2	P. grisea	Toxic regression equation	r 2
7	10.3 ± 0.53	y = 0.7952x + 1.8094	0.9995	14.0 ± 0.35	y = 1.0851x + 0.5004	0.9987
Azoxystrobin	74.9 ± 0.91	y = 0.7624x + 1.2819	0.9982	16.0 ± 0.82	y = 0.2271x + 4.0451	0.9972

2.5. Cylopentapyrazoles

Giray et al. designed a sequence of cylopentapyrazoles having a 1,2,3‐thiadiazole scaffold using [3+2] cycloaddition with thiadiazole‐5‐carboxylic acid hydrazones (Scheme 5), then characterized via ¹H/¹³C‐NMR, LC‐MS, EA, and subsequently tested for in vitro antifungal potential against the tested strains using the mycelium growth rate method. Furthermore, an in silico study was conducted using CYP51B (PDB: 6CR2). Within this series, analogs 8 and 9 demonstrated superior antifungal efficacy compared to ketoconazole, interacting with the hydrophobic cavity residues (Tables 10 and 11). SAR: SAR assessments demonstrated that substituting cylopentylpyrazole ring on the 1,2,3‐thiadiazole moiety significantly enhanced the antifungal potential [15].

SCHEME 5.

Synthesis of cylopentapyrazole having a 1,2,3‐thiadiazole scaffold.

TABLE 10.

Antifungal activity of the pyrazole compounds 8 and 9.

Compounds	Concentrations	F. moniliforme	F. culmorum	F. heterosporum	B. cinerea
8	50 µg/mL	—	—	33 ± 3.4	—
9	50 µg/mL	53 ± 2.7	—	52 ± 3.1	25 ± 1.4
8+9	25 + 50 µg/mL	48 ± 2.6	74 ± 3.1	—	100 ± 1
Ketoconazole	50 µg/mL	93 ± 1	100 ± 0.6	100 ± 0.4	57 ± 2
Cedriks	50 µg/mL	96 ± 2	94 ± 1	91 ± 2	90 ± 3

TABLE 11.

The EC₅₀ results of the most active pyrazole derivatives in combination.

Compounds	F. moniliforme	F. culmorum	B. cinerea
8+9	63.72 µg/mL	13.85 µg/mL	6.37 µg/mL
Cedriks	14.32 µg/mL	11.25 µg/mL	10.92 µg/mL

2.6. Fangchinoline

A novel class of fangchinoline derivatives bearing a carbamate was reported by Wang et al. via the reaction of a phenolic hydroxyl group and an isocyanate (Scheme 6), which was structurally verified via IR, NMR, and MS, and examined for in vitro antifungal activity against tested plant fungus strains using the cross method. All synthesized fangchinoline analogs exhibited antifungal activity against all strains, but compound 10 appeared to be more effective than azoxystrobin, the positive control (Table 12). SAR: The presence of a carbamate group (EWG) and substitution of p‐trifluoromethyl (EDG) at the benzene ring enhanced the antifungal activity, as benzene was found to be essential for stabilizing the process of interaction with fungi [50].

SCHEME 6.

Synthesis of fangchinoline derivatives bearing carbamate.

TABLE 12.

The antifungal results of the most active compound 10.

Compounds	EC50 (mg/L)
	A. alternata	P. adianticola	G. zeae	Pp. adianticola	P. theae	C. fructicola
10	>200	82.6	42.9	13.9	42.1	>200
Tetrandrine	>200	>200	>200	>200	>200	138.7
Fangchinoline	>200	>200	>200	>200	>200	>200
Azoxystrobin	47.3	15.8	95.0	47.7	2.3	10.4

2.7. Imidazo[1,2‐b]Pyridazine

Fan et al. discovered a novel class of 3,6‐disubstituted imidazo[1,2‐b]pyridazine scaffolds via cyclization of chloroacetaldehyde and 3‐amino‐6‐chloropyridazine (Scheme 7), followed by structural examination via MS, ¹H‐NMR, and FTIR, and later assessment of their in vitro antifungal potential using a mycelium linear growth rate method against tested strains. The investigation revealed that the synthesized analogs 11–13 were significantly more effective than the reference (Tables 13 and 14). SAR : The antifungal activity was significantly affected by substitutions on the pyridazine ring. Specifically, activity was enhanced by the presence of an unsubstituted phenyl ring (11), a thiofuran ring at the C‐3 position (12), and an OCH₃ group at the C‐6 position (13) of the main core moiety [51].

SCHEME 7.

Synthesis of 3,6‐disubstituted imidazo[1,2‐b]pyridazine scaffolds.

TABLE 13.

Antifungal activities of imidazo[1,2‐b]pyridazine against tested phyto‐pathogenic fungi.

Fungal strains	(Inhibition % ± SE)
	11	12	13	Hymexazol	Carbendazim
F. solani	98.9 ± 1.1	98.1 ± 0.6	98.7 ± 1.3	63.5 ± 1.4	100 ± 1.0
F. oxysporum f. sp. Vasinfectum	74.2 ± 1.4	92.9 ± 1.4	79.8 ± 1.1	42.8 ± 2.5	99.8 ± 0.2
F. bulbigenum	76.1 ± 2.2	94.3 ± 1.7	84.9 ± 0.7	59.3 ± 2.2	99.6 ± 0.9
F. graminearum	81.3 ± 0.8	73.8 ± 2.2	81.7 ± 1.4	42.8 ± 2.2	99.8 ± 1.2
C. Curvalaria Leaf Spot	97.8 ± 1.8	96.7 ± 0.6	99.7 ± 0.5	63.0 ± 3.4	9.9 ± 2.1
B. berengriana f. sp. Piricola	96.7 ±1.2	96.6 ± 0.4	81.4 ± 0.9	44.8 ±1.9	93.4 ± 1.6
A. alternata	91.1 ± 0.8	98.9 ± 1.3	92.4 ± 1.6	78.4 ± 1.3	1.4 ± 1.2
P. oryzae	87.4 ± 1.6	91.7 ± 2.7	86.3 ± 3.1	72.4 ± 1.6	7.0 ± 0.5
A. brassicae	92.8 ± 1.3	84.1 ± 1.3	94.2 ± 1.3	74.6 ±2.8	2.2 ± 1.2

TABLE 14.

EC₅₀ values of some imidazo[1,2‐b]pyridazine compounds 11–13.

Fungal strains (inhibition % ± SE)	Compounds
	11	12	13	Hymexazol	Carbendazim
F. solani	13.5 ± 0.3	5.1 ± 0.3	8.1 ± 0.1	27.3 ± 0.5	0.7 ± 0.2
F. oxysporum f. sp. Vasinfectum	25.6 ± 1.9	8.4 ± 1.8	18.5 ± 2.2	95.3 ± 1.6	1.2 ± 0.3
F. bulbigenum	18.6 ± 1.6	7.5 ± 0.2	13.0 ± 1.4	29.4 ± 2.0	0.8 ± 0.6
F. graminearum	13.2 ± 0.9	14.3 ± 0.7	10.6 ± 1.5	62.3 ± 4.7	0.5 ± 0.1
C. Curvalaria Leaf Spot	5.6 ± 0.7	6.8 ± 0.5	6.4 ±0.2	33.2 ± 3.5	>100
B. berengriana f. sp. Piricola	13.8 ± 1.0	9.1 ± 2.2	11.8 ± 3.8	65.5 ± 0.5	0.2 ± 0.1
A. alternata	6.7 ± 1.5	8.9 ± 1.6	7.8 ± 1.5	16.7 ± 3.5	>100
P. oryzae	13.5 ± 0.7	11.8 ± 1.4	12.0 ± 1.9	25.5 ± 2.7	>100
A. brassicae	10.0 ± 1.1	13.2 ± 3.1	11.3 ± 0.9	33.9 ± 0.2	>100

2.8. Sydnone

Du et al. synthesized a novel series of trifluoromethyl sydnone derivatives via amine substitution reactions (Scheme 8), characterized them using several spectral/physical techniques, and screened them for in vitro and in vivo fungal inhibition properties using a spore germination method against various tested plant fungal strains. In contrast, compound 14 showed the highest efficiency in inhibiting fungal strains and was comparable to the standard drugs (Table 15). SAR: SAR study indicated that the N(3) benzyl/3‐trifluoromethyl benzene ring of mesoionic sydnone played a substantial role in enhancing antifungal activity [52].

SCHEME 8.

Synthesis of trifluoromethyl sydnone derivatives.

TABLE 15.

In vitro and in vivo antifungal results of the sydnone compound 14.

Compounds	Inhibition rate (%, 25 mg L−1) (in vitro)		Inhibition rate (%) 400 mg L−1 (in vivo)				50 mg L−1
	RB	CGM	CDM	CA	WPM	CSR	tyrosinase
14	0	0	90	70	90	0	44
PSA	/	100
TCA	100	/
KSM			100	/	/	/	/
AZS			/	100	100	100	/
KA			/	/	/	/	92

RB, Phyricularia grisea; CGM, Botrytis cinerea Pers; PSA, Pyrisoxazole; TCA, Tricyclazole; /, not measured. CDM, Pseudoperonospora cubensis; CA, Colletotrichum orbiculare; CSR, Puccinia sorghi; WPM, Blumeria graminis; KSM, Kresoxim‐methyl; AZS, Azoxystrobin; KA, Kojic acid.

2.9. 1,3‐Benzodioxole

Song et al. effectively synthesized a range of γ‐lactam derivatives having 1,3‐benzodioxole scaffolds via amino acid and thionyl chloride as starting materials (Scheme 9), then elucidated by ¹H/¹³C/2D‐NMR and HRMS‐ESI methods, which were later assessed for their in vitro antifungal efficacy against various plant fungus strains using bioassay screening at different concentrations. Compounds 15–17, which incorporate methylethyl ethanoate, 2,2‐dimethylpropyl ethanoate, and 3‐methylpentan‐2‐one groups at the main pharmacophore, demonstrated significant biological profiles (Table 16). SAR: The structural modifications of γ‐lactam hybrids, which incorporate a 1,3‐benzodioxole moiety linked to an alkyl chain, demonstrated enhanced activity as evidenced by the SAR findings [53].

SCHEME 9.

Synthesis of lactam derivatives having 1,3‐benzodioxole.

TABLE 16.

In vitro fungicidal activity of novel γ‐lactam derivatives 15–17.

Fungicidal activity (100%) at 100 mg/L
Compounds	R. solani	A. tenuis Nees	G. theae‐sinensis	F. graminearum
15	28.35	37.99	21.82	65.14
16	34.76	38.64	68.59	52.75
17	47.56	34.73	5.44	40.83
IC50 (mg/L) value
15	—	121.75	—	205.77
16	117.43	159.64	64.47	113.47
17	71.03	115.99	71.89	156.69
Carbendazim	—	182.47	—	—
Piperine	79.01	114.67	49.43	262.91

2.10. 2‐Aminobenzoxazole

A new sequence of 2‐aminobenzoxazole derivatives was reported by Fan et al. through the reduction of 2‐nitrophenols (Scheme 10), subsequently structural determination via NMR, EA, and MS. The antifungal efficacy of analogs was assessed using the mycelial growth inhibitory rate method in vitro at a concentration of 50 µg/mL, followed by in vivo experiments against Botrytis cinerea on tomato at a concentration of 100 µg/mL. In the analysis of results, compound 18, characterized by the presence of a phenyl ring, demonstrated the highest percentage of inhibition against all tested strains in comparison to hymexazol (Tables 17 and 18). The computational analysis of the lipid binding site in Sec14p from Saccharomyces cerevisiae (PDB 6F0E) demonstrated a pi‐pi stacking interaction involving Tyr 151, as well as a pi‐alkyl interaction with Arg208. SAR : SAR studies have demonstrated that the introduction of an appropriate substituent, such as an unsubstituted phenyl ring, at the 5‐position of 2‐aminobenzoxazole can significantly inhibit fungal proliferation and differentiation, thereby exhibiting antifungal properties [54].

SCHEME 10.

Synthesis of 2‐aminobenzoxazole derivatives.

TABLE 17.

In vitro and in vivo fungicidal results of the 2‐aminobenzoxazole compound 18.

Fungal strains	% Inhibition ± SD (in vitro)		% Preventive rate (in vivo)
	18	Hymexazol	18	Hymexazol
Fusarium sulphureum	100 ± 0.3	50.4 ± 1.3
Thanatephorus cucumeris	100 ± 0.1	89.7 ± 0.5
Fusarium oxysporum	100 ± 0.5	53.5 ± 0.9
Fusarium graminearum	70.5 ± 2.7	64.2 ± 1.0
Botrytis cinerea	100 ± 0.1	88.6 ± 0.1	46.7 ± 1.1	23.1 ± 2.3
Valsa mali	93.7 ± 1.2	10.1 ± 1.5
Alternaria alternata	100 ± 0.8	70.2 ± 1.3
Alternaria solani	100 ± 0.2	42.9 ± 0.6

TABLE 18.

EC₅₀ values of some 2‐aminobenzoxazole compounds against eight phytopathogenic fungi.

Fungal strains	Average inhibition rate ± SD (%) (n = 3)
	18	Hymexazol
Fusarium sulphureum	3.96 ± 0.2	43.8 ± 0.6
Thanatephorus cucumeris	5.08 ± 0.2	17.78 ± 2.1
Fusarium oxysporum	4.36 ± 0.4	39.40 ± 1.1
Fusarium graminearum	9.68 ± 1.1	32.36 ± 2.0
Botrytis cinerea	2.40 ± 0.5	6.30 ± 0.2
Valsa mali	5.56 ± 0.2	> 50
Alternaria alternata	6.50 ± 0.7	25.12 ± 0.5
Alternaria solani	3.50 ± 0.2	48.98 ± 2.1

2.11. Pyrazole

Dong et al. reported a series of pyrazole‐4‐carboxamide derivatives using methyl hydrazine and ethyl 4,4‐difluoro‐3‐oxobutanoate as starting materials (Scheme 11), followed by spectral characterization using ¹H/¹³C‐NMR and HRM. In vitro antifungal activity of the derivatives was evaluated against nine phytopathogenic fungi using the mycelial growth inhibition rate method, and in vivo testing was conducted against A. solani on tomato leaves at a concentration of 10 mg/L. The findings demonstrated that 19 exhibited strong inhibitory activity against all strains (Tables 19 and 20). SAR: The SAR study indicated that the presence of a 2‐Cl group on the benzene ring and its strong affinity for the SDH protein Gallus gallus (PDB: 2FBW) due to H‐bond and π–π stacking bindings might be the cause of its higher activity than that of other molecules [55].

SCHEME 11.

Synthesis of pyrazole‐4‐carboxamide derivatives.

TABLE 19.

In vitro antifungal findings of pyrazole‐4‐carboxamides 19.

Fungal strains	Average inhibition (% inhibition) at 100 µg/mL
	19	Boscalid	Fluxapyroxad
F.O.	63 ± 0	83 ± 0.7
P.A.	29 ± 2.0	32 ± 0.5
S.T.	32 ± 0.3	33 ± 0.1
A.S.	100 ± 0	100 ± 0
F.G.	56 ± 0	21 ± 0.9
P.S.	49 ± 2.0	0 ± 0
P.P.	48 ± 0	82 ± 0
S.S.	76 ± 0.6	100 ± 0
B.C.	53 ± 1.5	86 ± 0
Average inhibition (% inhibition) at 50 µg/mL
Fusarium oxysporum	nd	84 ± 1.1	nd
Alternaria solani	93 ± 0.9	94 ± 0.6	38 ± 1.9

TABLE 20.

EC₅₀ and in vivo protective activity of pyrazole‐4‐carboxamide compound (19).

Fungi	Compound	EC50 value			% Inhibition at 10 µg/mL
		Regression equation	R2	EC50 (µg/mL)
A. solani	19	y = − 0.384 + 0.791x	0.982	3.06	100 ± 0
	Boscalid	y = − 0.227 + 0.967x	0.916	1.72	100 ± 0

2.12. 1,3,4‐Oxadiazole

Song et al. synthesized pimprinine having 1,3,4‐oxadiazole‐5‐thioether scaffolds via esterification of indole‐3‐carboxylic acid (Scheme 12) and determined their structures by NMR spectroscopy (¹H, ¹³C, and 2D NMR), followed by in vitro antifungal testing against various fungal strains using Leaf‐piece assays. Among the reported analogs, compound 20 exhibited notable antifungal activity. The results for this active molecule are presented in Table 21. SAR: SAR exploration was favored by the 1,3,4‐oxadiazole‐5‐thioether‐containing pimprinine scaffold, instead of the methylene bridge, which resulted in improved efficacy [56].

SCHEME 12.

Synthesis of pimprinine having a 1,3,4‐oxadiazole‐5‐thioether scaffold.

TABLE 21.

Antifungal activity of pimprinine derivative 20.

Species	Rate	Compound
		20	Streptochlorin	Pimprinine
Phytophthora infestans (on tomato leaf pieces)	200	0	0	0
	60	27	49	0
Septoria tritici (on wheat leaf pieces)	100	0	36	51
Uromyces viciae‐fabae (on bean leaf pieces)	100	27	55	27
Pythium dissimile	20	99	99	0
	2	0	0	0
Alternaria solani	20	55	99	0
	2	0	99	0
Botryo tinia fuckeliana	20	0	99	0
	2	0	0	0
Gibberella zeae (all in artificial media)	20	0	99	0
	2	0	0	0

2.13. Benzoxazepin

Yang et al. reported benzoxazepin‐4(3H)‐one analogs using N‐hydroxyphthalimide as the starting material (Scheme 13), followed by structure confirmation via NMR and MS. The antifungal potency of the compounds was examined against nine fungal strains using the mycelium growth inhibitory test. In this series, compound 21 demonstrated superior inhibitory activity relative to the positive controls, azoxystrobin and trifloxystrobin. The results of the active scaffold are presented in Tables 22 and 23, respectively. SAR : The SAR study demonstrated that aryl substituents revealed improved results compared to alkyl substituents; hence, the presence of p‐dimethylamino at the benzoyl ring of nitrogen‐ and oxygen‐comprising heterocyclic benzoxazepine enhanced the antifungal activity of the compound [57].

SCHEME 13.

Synthesis of benzoxazepin‐4(3H)‐one derivatives.

TABLE 22.

In vitro antifungal activity of oxazepin‐4(3H)‐one compounds against phytopathogens.

Fungus	Mycelium growth inhibition rate (%) at 50 µg/mL
	21	Trifloxystrobin	Azoxystrobin
Alternaria solani	24 ± 2	54 ± 0 9	48 ± 4
Botrytis cinerea	94 ± 0	8 ± 0	96 ± 0
Cercospora arachidicola	17 ± 0	74 ± 0	69 ± 0
Gibberella zeae	52 ± 0	82 ± 8	79 ± 1
Phytophthora infestans	30 ± 4	81 ± 0	76 ± 1
Physalospora piricola	45 ± 0	79 ± 6	82 ± 1
Pellicularia sasakii	24 ± 2	88 ± 0	73 ± 1
Rhizoctonia cerealis	40 ± 2	89 ± 0	63 ± 0
Sclerotinia sclerotiorum	88 ± 0	94 ± 2	100

TABLE 23.

In vitro antifungal EC₅₀ (µg/mL) of the selected oxazepin‐4(3H)‐one compounds.

Fungi	Compound	EC50 value
		Regression equation	R2	EC50 (µg/mL)
Sclerotinia sclerotiorum	21	y = 4.1390 + 1.0330x	0.9823	7.21
	Trifloxystrobin	y = 5.0464 + 0.8075x	0.9839	0.89
	Azoxystrobin	y = 4.4666 + 1.4417x	0.9418	2.52
Botrytis cinerea	21	y = 2.9953 + 2.3250x	0.9894	7.92
	Trifloxystrobin	y = 2.7578 + 1.7124x	0.9144	21.96
	Azoxystrobin	y = 3.4896 + 1.6002x	0.9521	9.43

2.14. 4‐Aminoquinolines

Yang et al. synthesized novel 2‐phenyl‐4‐aminoquinoline compounds using o‐aminoacetophenone as a starting material (Scheme 14) and investigated their antifungal activity against A. alternate, P. grisea, and C. lunata fungal strains using the mycelium growth rate and serial dilution methods. Notably, derivative 22 demonstrated the highest antifungal activity among all the derivatives. These compounds induced significant morphological alterations when compared to azoxystrobin, which was used as a reference drug. The active compound data are presented in Tables 24 and 25. SAR: The SAR study revealed that a para‐substituted (Cl group) aniline ring at the 2‐arylquinoline moiety showed significant enhancement in the antifungal profile compared to ortho‐ or meta‐ derivatives. Additionally, the electronic properties of the substituents on the aniline moiety, whether electron‐donating or electron‐withdrawing, played a role in determining the activity [58].

SCHEME 14.

Synthesis of novel 2‐phenyl‐4‐aminoquinoline.

TABLE 24.

In vitro fungicidal findings of 2‐phenyl‐4‐aminoquinoline (22).

Compounds	Average inhibition rate ± SD (%)
	C. lunata		P. grisea		A. alternate
	100 µg/mL	50 µg/mL	100 µg/mL	50 µg/mL	100 µg/mL	50 µg/mL
22	71.7 ± 1.5	65.0 ± 0.3	84.5 ± 1.4	77.2 ± 0.8	82.6 ± 1.7	76.3 ± 0.2
Azoxystrobin	55.5 ± 1.5	44.9 ± 0.0	57.0 ± 1.6	52.9 ± 1.0	58.7 ± 1.4	54.7 ± 0.5

TABLE 25.

Fungicidal results of 2‐phenyl‐4‐aminoquinoline (22).

Compounds	EC50 (µg/mL)			Mean (µg/mL)
	C. lunata	P. grisea	A. alternate
22	13.3 (12.4–14.2)	14.4 (13.0–15.8)	15.6 (14.1–17.2)	14.4
Azoxystrobin	75.0 (71.8–78.6)	34.5 (31.7–37.6)	16.0 (14.7–17.1)	41.8

2.15. Phenylpyrrole (Alkaloid Lycogalic Acid Analogs)

Zhang et al. created a novel series of phenylpyrrole conjugates derived from the alkaloid lycogalic acid through palladium‐catalyzed Suzuki–Miyaura coupling (Scheme 15) and determined their structures using high‐resolution mass spectrometry (HRMS) and NMR spectroscopy (¹H, ¹³C, and 2D NMR), followed by a fungicidal growth rate test against the seven fungal strains. Among the synthesized derivatives, compounds 23 and 24 exhibited remarkable activity against Rhizoctonia cerealis. Table 26 displays the results for the active compounds. Molecular docking results also demonstrated hydrogen bond interactions and a strong binding affinity of active scaffolds with RcCYP51. SAR : SAR analysis revealed that the indole ring, along with the −CF3 (electron‐withdrawing group) and −OCF3 (electron‐donating group) substituents located at the 3‐position of the phenyl ring, played a crucial role in significantly enhancing the activity [2].

SCHEME 15.

Synthesis of phenylpyrrole conjugates derived from alkaloid lycogalic acid.

TABLE 26.

In vitro fungicidal (% inhibition rate) results of phenylpyrrole derivatives 23 and 24 (50 µg/mL⁻¹).

Compounds	F.C.	C.H.	P.P.	R.C.	A.S.	P.G.	S.S.
23	32 ± 1	47 ± 1	57 ± 1	92 ± 1	13 ± 1	43 ± 1	79 ± 1
24	43 ± 1	44 ± 1	49 ± 1	91 ± 1	19 ± 1	69 ± 1	84 ± 1
Carbendazim	100	52 ± 1	100	100	13 ± 1	100	93 ± 2

2.16. Phenazine‐1‐carboxylic Acid and N‐Phenyl Alanine

Wu et al. synthesized phenazine‐1‐carboxylic acid scaffolds using methyl 2‐bromopropionate and aniline as starting materials (Scheme 16) and then spectrally confirmed them via LC‐MS and ¹H/¹³C NMR. The synthesized compounds were examined for their in vitro antifungal potential using a mycelial growth rate method at 50 µg/mL. Compound 25 exhibited superior in vitro antifungal activity compared to metalaxyl and demonstrated excellent phloem mobility, resulting in substantial phloem formation and accumulation (Tables 27 and 28). SAR: SAR analysis revealed that the substitution of electron‐donating groups, such as chloro, at the para position of the phenyl ring significantly enhanced the activity related to noble phloem mobility, compared to substitutions at the ortho and meta positions [1].

SCHEME 16.

Synthesis of phenazine‐1‐carboxylic acid scaffolds.

TABLE 27.

In vitro antifungal inhibition results of the phenazine‐1‐carboxylic compound 25.

Compounds	S. S	B. S.	Phy. p	P. c	A. s	P. a	R. S	P. i
25	<10	<10	<10	<10	<10	11.11±0.48	<10	<10
Phenazine‐1‐carboxylic acid	98.55 ± 0.51	100.00 ± 0	85.76 ± 0.65	68.00 ± 1.06	75.73 ± 0.29	73.13 ± 0.29	93.07 ± 1.66	89.25 ± 0.98
Metalaxyl	15.58 ± 1.80	<10	80.56 ± 0.71	<10	24.56 ± 0	16.62 ± 0.29	56.11 ± 1.23	<10

Phy. P.: Phytophthora parasitica.

TABLE 28.

EC₅₀ values of phenazine‐1‐carboxylic compounds against S. sclerotiorum.

Compounds	EC50/(µg/mL)	EC50/(µmol/L)	Regression equation	95% confidence interval/(µg/mL)	R 2
25	6.57	16.22	y = 4.0718+1.1352x	5.5046–7.8456	0.9939
Phenazine‐1‐carboxylic acid	3.87	17.28	y = 4.1864+1.3840x	3.218–4.6567	0.9901

2.17. Benzoylurea

An et al. synthesized novel benzoylurea derivatives having a pyrimidine moiety using 2,6‐difluorobenzamide as a starting material (Scheme 17), followed by structure confirmation via HRMS and NMR spectroscopy (¹H, ¹³C, and 2D NMR), and then tested in vitro for their ability to inhibit B. cinerea (cucumber, tobacco, and blueberry), R. solani, and Phomopsis sp. strains using a mycelium growth rate test. Nevertheless, compounds 26 and 27 showed remarkable activity when compared to the other scaffolds (Tables 29 and 30). In addition, the in silico docking examination indicated that the active scaffolds interacted with the succinate dehydrogenase (SDH) receptor (PDB: 2FBW) by forming hydrogen bonds with SER‐17 and SER‐39. SAR: According to SAR examination, the incorporation of 5‐bromo‐2‐chloro and 6‐difluoromethyl groups at the pyrimidine moiety of benzoylurea demonstrated significant antifungal activity [59].

SCHEME 17.

Synthesis of benzoylurea derivatives having a pyrimidine moiety.

TABLE 29.

Antifungal results of the benzoylurea compounds 26 and 27 (50 µg/mL).

Compounds	Inhibition Rate (%)
	B. C. (Cucumber)	R. S.	B. C. (Tobacco)	Phomopsis sp.	B.C. (Blueberry)
26	18.84 ± 1.86	70.27 ± 1.43	46.93 ± 1.46	49.84 ± 1.47	52.20 ± 3.26
27	50.15 ± 1.82	89.74 ± 8.84	47.65 ± 1.21	42.17 ± 1.34	53.77 ± 3.62
Hymexazol	24.64 ± 3.09	71.98 ± 2.00	72.88 ± 2.30	47.09 ± 1.69	71.26 ± 4.43

TABLE 30.

EC₅₀ values of benzoylurea derivatives toward R. solani.

Compounds	Regression equation	R 2	EC50/(µg/mL)
26	y = 0.47x+3.43 0.98	6.72	0.95
27	y = 0.58x+3.49 0.94	5.21	1.04
Hymexazol	y = 0.78x+4.39 0.99	6.11	1.24

2.18. Pyrazole

Zhao et al. developed pyrazole compounds having an aryl‐substituted trifluoromethoxy substructure by oxidative cyclization and aryl substitution (Scheme 18), systematically characterized by IR, NMR, and HRMS, then screened for in vitro antifungal potency towards six fungal strains using a mycelium growth rate test at 100 µg/mL. Derivatives 28 and 29, characterized by a straight‐chain substituent (28) and a cycloalkyl group (29), demonstrated considerable potential against F. graminearum and C. micotianae strains, respectively, and significant activity against all strains against all tested strains in comparison to the other molecules examined (Tables 31 and 32). SAR : The analysis of the structure–activity relationship indicated that the presence of either a straight chain or a cycloalkyl ring on the pyrazole moiety is crucial for activity. Conversely, the inclusion of a phenyl ring, regardless of its steric and electronic characteristics, was found to diminish the activity [4].

SCHEME 18.

Synthesis of pyrazole compounds having an aryl‐substituted trifluoromethoxy substructure.

TABLE 31.

In vitro fungicidal results of pyrazole compounds 28 and 29 (100 µg/mL).

Compounds	Inhibition (%)
	B. C.	M.O.	P. A.	F.G.	C. M.	V.M.
28	29.18 ± 1.34	40.06 ± 0.68	29.82 ± 0.74	65.11 ± 0.61	47.56 ± 4.43	28.14 ± 0.62
29	37.61 ± 3.33	35.33 ± 0.62	38.51 ± 1.31	81.22 ± 0.60	56.03 ± 0.80	41.22 ± 0.65
Pyraclostrobin	77.57 ± 0.93	77.53 ± 0.62	75.57 ± 0.59	80.14 ± 1.16	69.62 ± 0.61	74.38 ± 0.72

TABLE 32.

EC₅₀ values of 98 and 99 against tested species of fungus (µM).

Compounds	EC50 (95%CI) F. graminearum	EC50 (95%CI) C. micotianae
28	0.0735(0.0506–0.1053)	—
29	0.0530(0.0409–0.0669)	0.1430(0.1152–0.1953)
Pyraclostrobin	0.0112(0.0026–0.0211)	0.0352(0.0165–0.0551)

2.19. Cyclotryptamine Alkaloid

Yang et al. synthesized a series of cyclotryptamine alkaloid derivatives from 2‐(1H‐indol‐3‐yl)acetonitrile (Scheme 19), followed by structural analysis using spectral methods (FTIR, NMR, MS), and evaluated their antifungal activity against six plant fungal strains using the filter paper method. In this series, compound 30 demonstrated the highest potency when evaluated against the positive controls, amphotericin B and carbendazim (Table 33). SAR : SAR investigations revealed that incorporation of 6‐chloropyridine and 3‐fluoro‐benzyl groups significantly improved the compound's potency [60].

SCHEME 19.

Synthesis of cyclotryptamine alkaloid derivatives from 2‐(1H‐indol‐3‐yl) acetonitrile.

TABLE 33.

Antifungal results of cyclotryptamine alkaloid compound 30.

Compounds	MIC (µgmL−1)
	S. S.	A. S.	V. d.	F. O.	W. p.	C. L.
30	1.90	1.90	3.90	—	31.30	250.00
Carbendazim	7.80	62.50	15.16	62.50	31.30	125.00
Amphotericin B	3.90	15.60	125.00	125.00	125.00	62.50

2.20. N‐acyl‐N‐arylalanines

Kalinina et al. synthesized a library of novel N‐acyl‐N‐arylalanines hybrids using N‐alkylation of substituted anilines (Scheme 20), then characterized their structure using spectral means and later tested for in vitro antifungal activity against B. cinerea, R. solani, and S. sclerotiorum using a mycelium growth rate test and in vivo against A. brassicicola‐infected rape leaves. All synthesized compounds exhibited moderate activity against all strains. However, compound 31 demonstrated restrained activity against the tested strains while enhancing the protective properties of the rapeseed plant at a concentration of 200 µg/mL, surpassing the effects of tiadinil in vivo (Table 34). SAR: Research into the SAR has revealed that the incorporation of 1,2,3‐thiadiazole and 2,6‐dimethylbenzyl rings plays a crucial role in enhancing the antifungal properties of conjugates. These chemical structures are effective in eliminating leaf damage, halting the development of necrotic patches, and boosting overall activity [61].

SCHEME 20.

Synthesis of novel N‐acyl‐N‐arylalanines hybrids.

TABLE 34.

The effectiveness of the N‐acyl‐N‐arylalanines compound on A. brassicicola‐infected rape leaves (in vivo).

Compounds	Protecting efficiency (%)	Spot width (mm)
31	92.16	1.33 ± 0.48
Isotianil	40.78	10.05 ± 3.31
Tiadinil	91.57	1.23 ± 1.90
Negative control	—	16.97 ± 4.84

2.21. Triterpene Conjugates With 1,2,3‐Triazole

Chen et al. developed novel triterpene conjugates with 1H‐1,2,3‐triazole analogs using oleanolic acid as the starting material (Scheme 21). The conjugates were structurally confirmed using x‐ray crystallography, NMR, UV, HRMS, and MS. Antifungal screening was performed on six strains using a mycelial growth rate assay. Compounds 32–37 exhibited the most potent activity against S. sclerotiorum, achieving an inhibition rate exceeding 50% at a concentration of 50 µg/mL, in comparison to chlorothalonil, which served as the reference drug (Table 35). SAR: The incorporation of a methyl or benzyl ring at the R₁ position demonstrated superior activity compared to a methoxy chain. Furthermore, antifungal effectiveness was improved by substituting the electron‐withdrawing group (EWG) at the benzene ring (R₂) instead of an alkyl chain [62].

SCHEME 21.

Synthesis of novel triterpene conjugates with 1H‐1,2,3‐triazole analogs.

TABLE 35.

Inhibition rate of 1,2,3‐triazole compounds against six fungal species (% control at 50 µg/mL).

Compounds	Inhibition ratio (100%)
	S. sclerotiorum	P. boehmeriae Saw	B. cinerea Pers	R. solani Kuhn	P. oryzae Cav.	F. oxysporum Schl. F. sp. vasinfectum (Atk.) Snyd. & Hans.
32	85.6	66.8	66.9	69.6	39.4	31.4
33	83.1	60.8	70.5	72.5	37.8	27.6
34	87.6	57.9	71.6	75.6	36.6	23.5
35	86.8	50.8	75.9	75.8	20.5	23.8
36	87.7	55.7	77.4	78.9	22.4	26.7
37	89.6	54.1	78.9	79.7	30.5	25.4
Chlorothalonil	92.7	94.2	98	98.4	89.2	94.2

2.22. Coumarin

Using resorcinol and cyanoacetic acid, Xu et al. synthesized 4‐amino coumarin‐based derivatives (Scheme 22), followed by spectral characterization via MS and ¹H/¹³C‐NMR, and tested in vitro for mycelium growth inhibition activity against B. cinerea, A. alternata, A. salani, and F. oxysporum strains. All compounds showed significant growth‐inhibitory potential against all strains; however, 38 and 39 exhibited the highest activity relative to the others (Tables 36 and 37). In addition, in silico analyses revealed that the synthesized inhibitor 39 was entirely confined within the binding pocket of SDH (PDB: 1YQ3), establishing a predictable hydrogen bond with the TYR58 amino acid residue. The presence of the substituent was pivotal in determining the docking process, as it influenced both the binding configuration and the interaction energy. SAR : According to SAR research, the presence of 3‐methyl‐2‐butylene (38), a prevalent coumarin‐based natural component, and a six‐carbon chain, such as 2‐bromo‐1‐oxo‐hexyl, combined with an 8‐methyl group (39), indicated outstanding activity and beneficial effects [63].

SCHEME 22.

Synthesis of 4‐amino coumarin‐based derivatives.

TABLE 36.

Antifungal activity of 4‐amino coumarin scaffolds 38 and 39 (200 µg/mL).

Compounds	% Inhibition (96 h)
	B. C.	A. S.	F. O.	A. A.
38	44.80 ± 0.6	76.00 ± 2.5	40.20 ± 2.0	73.70 ± 3.4
39	38.34 ± 4.3	45.00 ± 4.9	38.00 ± 0.7	49.28 ± 4.3
Chlorothalonil	78.36 ± 0.0	58.25 ± 0.1	66.85 ± 0.0	56.69 ± 0.1
Carbendazim	91.88 ± 0.0	15.16 ± 0.2	86.81 ± 0.0	14.67 ± 0.2

TABLE 37.

In vitro EC₅₀ values of 4‐amino coumarin derivatives at different conc.

Compounds	EC50 (µg/mL)
	A. Alternata	A. Salani
38	107.4	96.7
39	144.5	92.1

2.23. Thiochromanone

Xiao et al. synthesized thiochromanone with a carboxamide moiety using 4‐substituted thiophenol as a preliminary material (Scheme 23), followed by characterization via NMR and IR spectrometric analysis and screening for mycelial growth inhibition rate against Phomopsis sp, B. cinerea, and B. dothidea. The results showed that 40 exhibited significant activity against both species compared to pyrimethanil and carbendazim. Table 38 presents the antifungal activity results. SAR: The SAR study revealed that the substitution of smaller electron‐withdrawing groups at R₁ (‐Cl) and R₂ (‐F) increased the antifungal activity [64].

SCHEME 23.

Synthesis of thiochromanone with a carboxamide moiety.

TABLE 38.

In vitro antifungal activities of the thiochromanone compounds against B. dothidea, Phomopsis sp., and B. cinerea at 50 µg/mL.

Compounds	Inhibition rate (%)
	B. dothidea	Phomopsis sp	B. cinerea
40	22 ± 2.2	60 ± 1.6	88 ± 1.5
Pyrimethanil	80 ± 1.3	84 ± 1.3	81 ± 2.4
Carbendazim	86 ± 2.2	100 ± 0.3	100 ± .5

2.24. Tetrahydro‐ß‐carbolines

Buaban et al. designed tetrahydro‐ß‐carbolines from the Pictet–Spengler reaction of tryptamine with substituted aldehydes (Scheme 24), then structurally validated via MS and NMR spectroscopy, and later examined for in vitro antifungal activity against F. fujikuroi, F. semitectum, B. oryzae, and C. Lutana using agar well diffusion assay, MIC assessment, and fungal radial growth inhibitory activity. Among the investigated molecules, 41 exhibited significant antifungal efficacy against all the phytopathogenic strains of Oryza sativa (Tables 39 and 40). SAR: The SAR revealed that substituting the piperidine nitrogen with an alkyl chain (N‐octyl analog) at the main pharmacophore increased the antifungal activity relative to amphotericin B, which served as the reference drug [65].

SCHEME 24.

Synthesis of tetrahydro‐ß‐carbolines.

TABLE 39.

In vitro MIC (µg/mL) and zones of inhibition (cm) of THßC derivative 41.

Rice fungal strains		41	Amphotericin B
B. oryzae	Zone of Inhibition	0.10 ± 0.0	0.21 ± 0.1
	MIC	28 ± 0.0	0.78 ± 0.0
F. fujikuroi	Zone of Inhibition	0.1 ± 0.0	0.00
	MIC	>512	>512
F. semitectum	Zone of Inhibition	0.1 ± 0.1	0.13 ± 0.1
	MIC	>512	>512
C. lutana	Zone of Inhibition	0.15 ± 0.1	0.15 ± 0.1
	MIC	200 ± 0.0	0.33 ± 0.1

TABLE 40.

Zone of inhibition of 41 against phytopathogenic fungi.

Compounds	Conc.	Width of Collection (cm)
		B. oryzae	F. fujikuroi	F. semitectum	C. lutana
None (control)	—	7.77 ± 0.15	5.48 ± 0.08	5.17 ± 0.23	5.00 ± 0.27
41	1000	NG1 (100%)	NG (100%)	NG (100%)	NG (100%)
	500	0.85 ± 0.05 (89.1%)	1.30 ± 0.35 (76.3%)	0.90 ± 0.07 (82.6%)	0.90 ± 0.12 (82.0%)
	250	1.43 ± 0.11 (81.7%)	2.23 ± 0.08 (59.4%)	3.08 ± 0.04 (40.6%)	1.98 ± 0.11 (60.5%)
	100	2.48 ± 0.13 (68.2%)	3.43 ± 0.04 (37.4%)	5.90 ± 0.21	3.00 ± 0.07 (40%)
Amphotericin B	0.6	3.30 ± 0.14 (57.6%)	5.68 ± 0.04 (−3.7%)	2.45 ± 0.17 (52.7%)	4.03 ± 0.08 (19.5%)

NG¹: no growth.

2.25. Benodanil

Yang et al. designed novel benodanil‐heterocyclic carboxamide hybrids via a chloroaniline as a starting material (Scheme 25). The structures were initially validated via IR, ¹H/¹³C NMR, and HRMS spectroscopy and evaluated for in vitro antifungal activity against F. oxysporum, A. solani, A. tenuissima, and R. solani using the mycelium growth rate method. Compounds 42 and 43 exhibited the highest antifungal efficacy against R. solani compared to that of benodanil (Table 41). In silico analysis demonstrated that compound 42 occupies the cavity formed by subunits B, C, and D of SDH. Additionally, the primary interaction identified was a hydrogen bond between scaffold 42 and the residue C/Trp‐73. SAR: SAR analysis revealed that the incorporation of 3‐CH(CH₃)₂ (42) and 3‐CF₃ (43) functional groups on the phenyl ring enhanced the activity of derivatives. These derivatives exhibited uneven mycelial development, characterized by relatively weak, wrinkled, and covering colonies [66].

SCHEME 25.

Synthesis of novel benodanil‐heterocyclic carboxamide hybrids.

TABLE 41.

IC₅₀ (mg/L), inhibition rate (%), and EC₅₀ values of carboxamide compounds 42 and 43 against SDH of R. solani.

Compounds	IC50 (mg/L)	EC50	Inhibition rate (%)
42	52.58 ± 1.2	6.32 ± 0.4	90.30 ± 1.5
43	56.86 ± 1.7	6.06 ± 0.7	83.58 ± 1.1
Benodanil	62.02 ± 1.2	6.38 ± 0.6	—

2.26. Pyridine‐linked 1,2,4‐oxadiazole

Yang et al. designed an innovative series of benzamides containing pyridine‐linked 1,2,4‐oxadiazole derivatives through esterification, cyanation, cyclization, and aminolysis reactions (Scheme 26), structurally described using IR, ¹H/¹³C NMR, HRMS, and EA, and subsequently investigated for in vitro antifungal activity against eight fungal strains using a mycelial growth inhibition assay. The antifungal outcomes validated that scaffold 44 exhibited superior antifungal efficacy in comparison to the positive control, fluxapyroxad (Tables 42 and 43). SAR : SAR exploration demonstrated that the incorporation of a 2‐fluoro group onto the benzene ring enhanced the phytopathogenic activity of the synthesized molecule [67].

SCHEME 26.

Synthesis of benzamides containing pyridine‐linked 1,2,4‐oxadiazole derivatives.

TABLE 42.

Fungicidal activities of benzamide compound 44.

Compounds	% Inhibition (at 50 mg/L)
	A.S.	F.G.	CA	PC	S.S.	B.C.	TC	F.O.
44	50.0	44.4	40.0	8.3	80.8	90.5	84.8	22.7
Fluxapyroxad	88.9	30.3	100	38.1	96.4	63.6	88.4	44.4

PC: Phytophthora capsica.

TABLE 43.

EC₅₀ of benzamide compound 44.

Fungus	y = a+bx	r 2	EC50/(µgmL−1)
S.S.	y = 1.5805x+3.3168	0.9836	11.61
B.C.	y = 2.1065x+2.3871	0.9758	17.39
T.C.	y = 1.8992x+2.6489	0.9815	17.29

2.27. Pimprinine and Streptochlorin (Indole Alkaloids)

Liu et al. synthesized pimprinine and streptochlorin derivatives using an acylation reaction of indole (Scheme 27), characterized them via ultraviolet‐visible spectroscopy, ¹H/¹³C‐NMR, ESR, and MS, and subsequently tested their in vitro antifungal potency against six different pathogenic strains using the mycelium growth rate method. Compounds 45–48 demonstrated greater potency than the reference drugs azoxystrobin and boscalid at a concentration of 50 µg/mL. The results for these active substances are detailed in Tables 44 and 45. Molecular docking models suggest that compound 45 interacts with leucyl‐tRNA synthetase (PDB: 2V0C) in a manner analogous to AN2690. This finding provides insight into the mechanism of action relevant to its antifungal activity. SAR : SAR analysis showed that adding different substituents to the indole ring, such as methyl and halogen (47, 48), and halogenating with chloro‐ and bromo‐ groups at the fourth position, as well as H or methyl substituents at the second site of oxazole (45, 46), enhanced the antifungal efficacy of the active compounds [68].

SCHEME 27.

Synthesis of pimprinine and streptochlorin derivatives.

TABLE 44.

Antifungal activity of pimprinine and streptochlorin derivatives.

Compounds	% Progression inhibition (at 50 µg/mL)
	ALS	A.S.	B.T.	COL	G.B.	R.S.
45	85.5	65.4	99.9	94.6	99.9	82.4
46	99.9	69.9	99.9	88.3	98.7	96.1
47	37.8	24.8	35.9	90.1	37.5	46.4
48	79.0	37.0	86.0	91.2	75.3	68.5
Osthole	31.3	61.2	70.4	92.3	57.0	66.5
Boscalid	92.8	57.6	99.9	25.5	40.9	87.3
Carbendazim	6.4	59.6	99.9	99.9	99.9	99.9

ALS: Alternaria Leaf Spot; COL: Colletotrichum lagenarium.

TABLE 45.

EC₅₀ determination of active pimprinine and streptochlorin compounds.

Pathogen	Compounds	Toxic Regression	R	EC50 (µg/mL)	95% confidence interval
ALS	45	Y = 2.7969+1.7139X	0.9802	19.2928	10.2574∼36.2873
	46	Y = 3.9921+1.8926X	0.9974	3.4086	3.1301∼3.7119
	48	Y = 1.9984+2.0046X	0.9904	31.4339	24.7935∼39.8527
	Boscalid	Y = 5.1084+1.0376X	0.9935	0.7862	0.6462∼0.9566
	Carbendazim	Y = ‐1.8843+5.7567X	0.9265	15.6994	5.6810∼43.3849
A.S.	46	Y = 3.8271+1.0526X	0.9977	13.0099	11.8507∼14.2825
	Boscalid	Y = 4.3437+0.4903X	0.9806	21.8016	12.7424∼37.3012
	Carbendazim	Y = 3.2290+2.5855X	0.9688	4.8412	3.3993∼6.8947
B.C.	45	Y = 5.5662+1.2805X	0.9413	0.3613	0.0753∼1.7329
	46	Y = 4.6370+6.9223X	0.9167	1.1283	0.4899∼2.5988
	48	Y = 0.7267+3.0369X	0.9837	25.5341	19.8748∼32.8049
	Boscalid	Y = 5.2263+0.7489X	0.9810	0.4986	0.3268∼0.7608
	Azoxystrobin	Y = 4.4507+0.8502X	0.9921	4.3516	3.4330∼5.5160
COL	45	Y = 4.1129+1.5735X	0.9967	3.6625	3.2373∼4.1435
	46	Y = 3.6409+1.494X	0.9232	8.1215	4.8507∼13.5978
	47	Y = 4.8309+1.5299X	0.9954	1.2899	1.0572∼1.5739
	48	Y = 2.8392+2.2448X	0.9997	9.1740	8.8047∼9.5588
	Azoxystrobin	Y = 4.2298+0.4299X	0.9968	61.8611	49.2272∼77.7376
	Boscalid	Y = 2.9242+1.351X	0.9673	34.3930	18.9576∼62.3960
G.Z.	46	Y = 5.1780+1.0649X	0.9090	0.6805	0.2148∼2.1553
	Carbendazim	Y = 6.1001+8.7644X	0.9653	0.7490	0.4996∼1.1228
R.S.	46	Y = 5.1533+0.7519X	0.9603	0.6215	0.1817∼2.1250
	Boscalid	Y = 5.1182+0.5510X	0.9942	0.6103	0.4943∼0.7535
	Carbendazim	Y = 5.2412+4.4774X	0.9993	0.8833	0.8410∼0.9279

2.28. Dihydroquinoline

Cheng et al. developed a novel series of 2, 3‐dihydroquinolin‐4(1H)‐one via a Claisen–Schmidt condensation reaction of substituted benzaldehyde with 2‐aminoacetophenone (Scheme 28), and their structures were studied using ultraviolet‐visible, ¹H/¹³CNMR, ESR, and MS, then assessed for in vitro antifungal activity using the mycelium growth rate method against S. sclerotiorum, F. graminearum, R. solani, B. cinerea, and H. maydis. Compound 49 demonstrated significant antifungal activity relative to the positive control, fluopyram, at a concentration of 20 mg/L, as shown in Tables 46 and 47. Molecular modelling results indicated that compound 49 exhibited a stronger binding affinity and interaction with the binding sites of SDH from Botrytis cinerea (PDB: 4YTP) compared to fluopyram. SAR: The SAR investigation revealed that the incorporation of semicarbazide and amino groups, along with the attachment of the electron‐donating methyl group at the 5th position of the thiophene ring, substantially enhanced the antifungal efficacy of the synthesized derivatives [69].

SCHEME 28.

Synthesis of 2, 3‐dihydroquinolin‐4(1H)‐one.

TABLE 46.

Antifungal results of 2, 3‐dihydroquinolin‐4(1H)‐one compound 49.

Compounds	% Inhibition (20 mg/L)
	R.S.	F. G.	H. M.	S.S.	B.C.
49	57.3 ± 1.4	62.6 ± 0.5	77.5 ± 2.7	88.5 ± 2.9	100.0 ± 0.0
Fluopyram	71.4 ± 1.9	62.9 ± 1.0	100.0 ± 0.0	100.0 ± 0.0	100.0 ± 0.0

TABLE 47.

EC₅₀ (mg/L) of the 2, 3‐dihydroquinolin‐4(1H)‐one compound (49) that is effective against B. cinerea.

Compounds	EC50
49	0.132 ± 0.021
Fluopyram	0.879 ± 0.121

2.29. Biphenyl Azoles

Wang et al. successfully synthesized a series of 2‑(2‐arylphenyl)azoles via cobalt‐catalyzed C−H/C−H cross‐coupling reactions, as illustrated in Scheme 29. The structures of these compounds were confirmed using elemental analysis (EA), Fourier‐transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance (¹H‐NMR) methods. Subsequently, their in vitro fungicidal properties were evaluated against F. graminearum, P. piricola, R. cerealis, B. maydis, and W. anthracnose strains, with bixafen serving as the positive control. Compounds 50–53 demonstrated significant efficacy against all tested strains, as detailed in Table 48. SAR: SAR analysis revealed that the antifungal activity was enhanced by incorporating a heteroarene ring into the biphenyl structure [70].

SCHEME 29.

Synthesis of 2‐(2‐arylphenyl)azoles.

TABLE 48.

In vitro antifungal activity of synthetic azole analogues.

Compounds	Fungicidal activity (%) at 50 µg/mL
	F.G.	P.P.	R.C.	B.M.	W.A.
50	42 ± 2	84 ± 1	46 ± 1	33 ± 1	29 ± 2
51	47 ± 1	79 ± 2	43 ± 1	31 ± 2	36 ± 1
52	63 ± 2	79 ± 1	57 ± 3	23 ± 2	24 ± 2
53	45 ± 1	69 ± 1	11 ± 1	28 ± 2	21 ± 1
Bixafen	58 ± 2	79 ± 1	61 ± 1	67 ± 3	57 ± 2

2.30. Indole

Tan et al. produced a novel series of N‐substituted chiral indoles using L‐tryptophan as the starting material, as depicted in Scheme 30, followed by framework validation using different spectral methods. The antifungal potential was assessed in vitro using the mycelial growth rate method against six different fungal strains. Among the synthesized compounds, derivative 54 exhibited potent efficacy compared to the conventional antifungal agents carbendazim and amphotericin B. The results of the active derivatives are presented in Table 49. SAR: The inclusion of 2‐chloronicotinoyl in the main pharmacophore increased the antifungal potential of the active molecule [3].

SCHEME 30.

Synthesis of N‐substituted chiral indoles.

TABLE 49.

MIC values of chiral indole compound 54 against a phytopathogenic fungus.

Compounds	S. S.	A. S.	V. D.	C. O.	C. J.	C. L.
54	1.95	3.9	1.95	15.63	3.9	15.63
Carbendazim	7.8	62.5	15.16	62.5	31.3	125
Amphotericin B	3.9	15.16	125	125	125	62.5

2.31. Quinoxaline

Teng et al. discovered a novel sequence of quinoxaline‐2‐oxyacetate hydrazide scaffolds using phenylenediamine as a precursor (Scheme 31). They thoroughly validated the structure using IR, NMR, MS, and EA and examined their in vitro antifungal potential against various strains using the mycelial growth rate method, and in vivo on R. solani in rice leaves and against B. cinerea on tomato fruits. Compounds 55 and 56 showed potent in vitro results compared to the reference (ridylbacterin and pyrimethanil), while molecules 57 and 58 showed significant in vivo results compared to carbendazim, as detailed in Tables 50, 51, 52. In comparison to those treated with DMSO, mycelia exposed to compound 57 developed noticeable lesions. This observation implies that compound 57 might alter the growth trajectory and condition of the mycelia by impacting the cell membrane structure of R. solani. SAR: The inclusion of a para‐positioned EWG halogen on the phenyl ring of the quinoxaline‐2‐oxyacetate hydrazide core has been found to increase activity, as validated by SAR analysis. This enhancement is likely attributable to the size and electrical properties of the substituents [71].

SCHEME 31.

Synthesis of quinoxaline‐2‐oxyacetate hydrazide scaffolds.

TABLE 50.

Inhibitory activities of quinoxaline‐2‐oxyacetate hydrazide compounds 55 and 56.

Compounds	B. C.	A. S.	G. Z.	R. S.	C. O.	A. A.
55	86.1 ± 1.4	89.5 ± 1.2	95.8 ± 0.8	91.9 ± 0.9	100	96.4 ± 0.5
56	80.6 ± 1.7	6.4 ± 0.7	92.2 ± 1.2	98.0 ± 0.7	91.7 ± 0.6	63.2 ± 0.7
Pyrimethanil	75.1 ± 1.0	43.1 ± 0.7	32.6 ± 1.8	89.4 ± 0.7	15.2 ± 1.1	27.2 ± 1.5

TABLE 51.

Antifungal EC₅₀ values of quinoxaline‐2‐oxyacetate hydrazide compounds against phytopathogenic fungi.

Pathogen	Compounds	EC50	Regression equation	Confidence	R2
G. zeae	55	0.94 ± 0.03	Y = 1.3200X+5.0329	0.84–1.06	0.9973
	56	0.87 ± 0.03	Y = 1.1326X+5.0682	0.75–1.00	0.9962
	Pyrimethanil	2.20 ± 0.11	Y = 1.5239X+4.4782	1.81–2.67	0.9885
C. orbiculare	55	1.84 ± 0.07	Y = 1.7837X+4.5261	1.60–2.13	0.9923
	56	1.01 ± 0.11	Y = 1.6068X+4.9917	0.75–1.37	0.9805
	Carbendazim	2.32 ± 0.11	Y = 2.3102X+4.1532	1.65–4.60	0.9815
A. alternata	55	1.54 ± 0.12	Y = 1.4515X+4.7261	1.14–2.10	0.9706
	Pyrimethanil	2.07 ± 0.15	Y = 0.6205X+4.7564	1.65–2.41	0.9732
R. solani	55	0.20 ± 0.07	Y = 0.6613X+5.6581	0.05–0.32	0.9877
	56	0.16 ± 0.04	Y = 0.6309X+5.5750	0.06–0.23	0.9845
	Pyrimethanil	0.21 ± 0.10	Y = 0.7552X+5.5126	0.10–0.43	0.9736

TABLE 52.

In vivo antifungal results of compounds 57 and 58.

Compounds	Treatment (µg/mL)	% Protection efficacy
57	200	66.1 ± 3.5
Carbendazim	200	90.1 ± 1.2
58	100	52.7 ± 1.2
58	200	73.3 ± 2.0
Carbendazim	200	95.6 ± 0.7

2.32. Bromoindoles

Munoz et al. synthesized a novel series of 3‐acyl‐6‐bromoindole scaffolds using 6‐bromoindole as a starting material (Scheme 32), then structurally confirmed using ¹H/¹³C NMR and ESI‐MS, and consequently screened for their in vitro antifungal activity against M. fructicola and B. cinerea using mycelial growth and conidial germination inhibition tests. All derivatives showed notable efficacy toward the tested strain, but compounds 59 and 60 showed potent activity, inhibiting mycelial growth in a dose‐dependent manner and reducing spore germination, thereby minimizing the risk of developing fungal resistance (Table 53). The antifungal activity of these compounds is directly associated with their potential to bind to the enzymes SDH (PDB: 2FBW) and MfCat2. SAR study showed that the presence of an acetyl group at the main moiety enhanced the antifungal potential by increasing confined hydrophobicity, which may improve membrane permeation toward fungi. Halogenation of potential molecules can significantly improve biological efficacy by modifying steric and electronic properties, which enhances both the efficiency and stability of the scaffolds [72].

SCHEME 32.

Synthesis of 3‐acyl‐6‐bromoindoles scaffold.

TABLE 53.

In vitro antifungal activity of active compounds 59 and 60.

Compounds	B. cinerea		M. fructicola
	EC50 (µg/mL)	ICG (%)	EC50 (µg/mL)	ICG (%)
59	11.62 ± 0.05	7	18.84 ± 0.23	0
60	98.42 ± 0.68	100	31.78 ± 0.40	96
BC‐1000	95.13 ± 0.67	100	<10	84
Captan	82.89 ± 0.69	100	—	—
Mystic 520 SC	—	—	<10	85

2.33. Calycanthaceous Alkaloid

Zheng et al. synthesized a series of calycanthaceous alkaloid compounds featuring a tetrahydropyrroloindole structure, utilizing indole‐3‐acetonitrile as a preparatory reactant through acylation at the N3 position (Scheme 33) and structurally determined by IR, ¹H/¹³C‐NMR, and MS, then tested for in vitro antifungal activity against various fungal strains via microdilution assay employing amphotericin B and carbendazim as standard drugs. In this study, scaffold 61 showed more potent antifungal activity than other compounds. SAR: By enhancing electron density and lipophilicity, the aliphatic group substituent on the calycanthaceous alkaloid ring demonstrated the highest inhibition, according to the SAR research. Table 54 shows the results of synthesized compounds [73].

SCHEME 33.

Synthesis of calycanthaceous alkaloid compounds featuring tetrahydropyrroloindol.

TABLE 54.

MIC and MFC of active compound 61 against various plant fungus species.

Compounds	MIC (µg/mL)
	P. ca	V. d	F. s	C. o.	P.c.	C. j.	A. sf.	A. s.	C. l.	F. o.	A. n.
61	31.25	62.5	256	62.5	62.5	—	15.63	—	—	31.25	125
Amhotericin B	3.9	62.5	256	125	15.63	256	7.81	—	7.81	125	0.97
Carbendazim	1.95	256	125	0.97	0.97	62.5	0.97	—	—	7.81	—
	MFC
61	62.5	125	—	125	125	—	31.25	—	—	62.5	256
Amhotericin B	7.81	125	—	256	31.25	—	15.63	—	15.63	256	1.93
Carbendazim	3.9	—	256	1.95	1.95	125	1.95	—	—	15.63	—

P.ca.: P. capsici, V.d.: V. dahlia, F.s.: F. oxysperium sp. vasinfectum, C.o.: C. orbiculare, P.c.: P. citrinum, C.j.: Cytospora juglandis, A.sf.: A. sflavu, A.s.: A. solani, C.l.: C. lunaia, F.o.: F. oxysporum, A.n.: A. niger, MIC: minimal inhibitory concentration; MBC: Minimum Bactericidal Concentration.

2.34. Calycanthaceous Alkaloid

Using indole‐3‐acetonitrile as a starting material, Zhu et al. synthesized an innovative class of calycanthaceous alkaloid derivatives (Scheme 34) which were structurally verified via ESI MS, ¹H/¹³C NMR, followed by antifungal screening against various fungal strains via a microdilution study. Among the studied compounds, 62 emerged as the most potent antifungal agent against aspergillu sflavu than amphotericin B and showed good to moderate antifungal activity against all mentioned fungal strains. SAR: In the SAR investigation, calycanthaceous alkaloid‐containing hexahydropyrroloindole molecules exhibited enhanced antifungal activity, whereas adding a 4‐trifluoromethyl substitution on the benzyl moiety (R₁ ) and substitution of an aliphatic chain having a ketone group at the main pharmacophore (R₂ ) increased the lipophilicity, which likely facilitates cell penetration and interaction with fungal targets (Table 55) [74].

SCHEME 34.

Synthesis of calycanthaceous alkaloid derivatives.

TABLE 55.

Antifungal activity of synthesized compound 62 against various plant fungus strains.

Compounds	MIC (µg/mL)
	V. d	F. v.	C. j.	A. s.	P.c.	F. o.	C. o.	A. n.	B. p.	C. l.
62	250	—	250	15.63	—	250	250	250		125
Amphotericin B	1.9	—	250	31.3	31.3	62.5	250	3.9	—	7.8
Chlorothalonil	31.3	250	62.5	7.8	15.6	62.5	250	15.6	31.3	125

MIC, minimal inhibitory concentration; V.d, Verticillium dahliae; F.v, Fusarium oxysporum sp. vasinfectum; C.j, Cytospora juglandis; A.s, Aspergillus flavus; P.c, Penicillium citrinum; F.o, Foxysporum; C.o, Colletotrichum orbiculare; A.n, Aspergillus niger; B.p, Bcinerea pers; C.l, Curvularia lunaia.

3. Outcomes of the Paper

This review brings together and evaluates a wide range of recent studies showing that many types of heterocyclic compounds, such as oxadiazoles, pyrazoles, benzoxazoles, quinolines, triazoles, and various hybrid structures, show strong antifungal activity against major plant pathogens. Consistent SARs were observed; for instance, adding halogen atoms, using para‐position electron‐withdrawing or CF₃ groups, and attaching heteroaryl rings often improved potency or enhanced movement within plant tissues. Table 56 summarizes the origin‐ and scaffold‐based classification of heterocyclic plant fungicides, highlighting key structural modifications identified through SAR studies and their influence on antifungal activity as evaluated by different inhibitory assays. Among the synthetic compounds evaluated for plant antifungal activity, several heterocyclic scaffolds demonstrated remarkable efficacy. Sarisan‐based derivatives showed promising activity, with compounds 1 and 6 exhibiting EC₅₀ values of 12.6 and 30.1 µg/mL, respectively, together with inhibition rates of 69.7% and 67.9%. Quinoline‐based derivatives exhibited enhanced antifungal performance, with compounds 7, 22, and 49 showing EC₅₀ values of 10.3, 13.3, and 0.132 µg/mL, respectively, and corresponding inhibition rates of 76.7%, 84.5%, and 100%. Similarly, the indole‐based derivative, compound 59, with an EC₅₀ value of 11.62 µg/mL, and compound 60, with 96%–100% inhibition, demonstrated outstanding antifungal efficacy and showed the potential of indole‐containing molecules as effective fungicidal leads. Among all synthetic scaffolds, azole‐based derivatives exhibited the most consistent and potent antifungal activity. Compounds 11, 12, 13, and 19 achieved inhibition rates of 98.9%, 98.9%, 98.7%, and 100%, respectively, corresponding EC₅₀ values of 5.6, 5.1, 7.8, and 3.06 µg/mL. Notably, compounds 28 and 29 showed exceptionally low EC₅₀ values of 0.0736 and 0.0530 µg/mL, despite exhibiting comparatively lower inhibition rates of 65.11% and 81.22%, respectively, under the reported assay conditions.

TABLE 56.

Origin‐based classification, SAR analysis, and inhibitory assay for evaluating heterocyclic plant fungicides.

S. No.	Molecular structures	Heterocyclic Core	Inhibitory Assay/Method	Unified SAR Analysis	Std. drug	Reference
Synthetic Origin
Classification based on Heterocyclic Core
Sarisan
1.		Sarisan	Mycelium growth rate	3‐Pyridyl group on the 1,3,4‐oxadiazole	Sarisan, Hymexazol	[46]
2.		Sarisan	Mycelium growth rate	Fluoro (4), chloro (6) group at m‐position and trifluoromethyl at p‐position (5) on benzene	Sarisan, Hymexazol	[48]
Quinolines
3.		4‐ Aminoquinoline	Mycelium growth rate	para‐Substitution of methyl at aniline and furyl at the o‐positions	Azoxystrobin	[49]
4.		4‐Aminoquinoline	Mycelium growth rate	para‐Substituted (Cl group) aniline ring at the 2‐arylquinoline moiety	Azoxystrobin	[58]
20.		Dihydro‐quinoline	Mycelium growth rate	Inclusion of semicarbazide and amino groups as well EDG methyl group at fifth position of the thiophene ring	Fluo‐pyram	[69]
Azoles
5.		Cyclopenta‐pyrazole	Mycelium growth rate	Cylopentylpyrazole ring on the 1,2,3 thiadiazole moiety	Ketoconazole, Cedriks	[15]
6.		Pyrazole	Mycelium growth rate	A straight chain or cycloalkyl ring on the pyrazole moiety	Pyraclostrobin	[4]
7.		Pyrazole	Mycelial growth rate	Substitution with 2‐chloro Benzene	Boscalid	[55]
8.		Imidazo[1,2‐b] pyridazine	Mycelium linear growth rate	Unsubstituted phenyl (11), thiofuran ring (12) at the C‐3 site), and OCH3 (13) at the C‐6 position	Hymexazol, Carbendazim	[51]
9.		Syndone	Spore germination	3‐Trifluoromethyl benzene ring of sydnone	Pyrisoxazole, Tricyclazole, Kresoxim‐methyl; Azoxystrobin; Kojic acid	[52]
21.		Biphenyl azoles	% Fungicidal activity	Heteroarene ring to the biphenyl structure	Bixafen	[70]
10.		N‐Butylphthalide	Mycelium growth rate	Nitro on the C‐6 (R1) position of NBP (2) and nitro (R2) and hydroxyl (R1) groups at NBP (3)	Hymexazol	[47]
Oxole/oxazoles
11.		1,3‐Benzo‐dioxole with γ‐lactam	Bioassay screening at different conc.	Alterations at γ‐lactam hybrids with an alkyl chain	Carbendazim, Piperine	[53]
12.		2‐Amino‐Benzo‐oxazole	Mycelial growth rate	Unsubstituted phenyl ring, at the 5‐position of 2‐aminobenzoxazole	Hymexazol	[54]
13.		1,2,4‐Oxadiazole	Mycelium growth rate	Attachment of 2‐F group to the benzene ring	Fluxapyroxad	[67]
14.		1, 3, 4‐Oxadiazole	Leaf piece assays	1,3,4‐Oxadiazole‐5‐thioether‐containing pimprinine scaffold	Pimprinine	[56]
Indole
24.		Bromoindole	Mycelial growth and conidial germination test	Presence of acetyl group at indole	Captan, BC‐1000	[72]
22.		Tryptophan Indole	Mycelium growth rate	2‐Chloronicotinoyl	Carbendazim, Amphotericin B	[3]
Miscellaneous
15.		Benz‐oxazepin	Mycelium growth rate	p‐Dimethylamino benzoyl ring	Trifloxystrobin, Azoxystrobin	[57]
16.		Benzoylurea	Mycelium growth rate	5‐Bromo‐2‐chloro (26) and 6‐diflouromethyl (27) at the pyrimidine moiety	Hymexazol	[59]
17.		Coumarin	Mycelium growth rate	Presence of 3‐methyl‐2‐butylene (38) and a six‐carbon chain, 2‐bromo‐1‐oxo‐hexyl, combined with an 8‐methyl group (39)	Chlorothaloni, Carbendazim	[63]
18.		Thiocramanone	Mycelium growth rate	Electron‐withdrawing ‐Cl and ‐F groups	Pyrimethanil, Carbendazim	[64]
19.		Benodanil	Mycelium growth rate	3‐CH(CH3)2 (42) and 3‐CF3 (43) functional groups on the phenyl ring	Benodanil	[66]
23.		Quinoxaline	Mycelium growth rate	para‐Positioned EWG halogen in the phenyl ring of the core quinoxaline‐2‐oxyacetate hydrazide moiety	Pyrimethanil, carbendazim	[71]
Chemically modified natural/Partial‐Synthetic Compounds
25.		Phenazine‐1‐carboxylic acid	Mycelium growth rate	EDG, chloro, in the fourth position of the phenyl ring	Metalaxyl, Phenazine‐1‐carboxylic acid	[1]
26.		Lycogalic acid	Fungicidal growth rate	Indole ring and −CF3 (EWG, 23) and −OCF3 (EDG, 24) substituents at the 3‐position of the phenyl ring	Carbendazim	[2]
27.		Fangchinoline	Cross method	Carbamate group and substitution of p‐trifluoromethyl at the benzene ring	Tetrandrine, Fangchinoline, Azoxystrobin	[50]
28.		Cyclotryptamine	Filter paper method	6‐Chloro pyridine and 3‐floro benzyl groups	Amphotericin B, Carbendazim	[60]
29.		Arylalanine and thiadiazole	Mycelium growth rate	1,2,3‐Thiadiazole and 2,6‐dimethylbenzyl rings	Isotianil, Tiadinil	[61]
30.		Beta Carboline	Agar well diffusion assay, MIC and fungal radial growth inhibitory activity	Substituting piperidine nitrogen with an alkyl chain (N‐octyl analog)	Amphotericin B	[65]
31.		Triterpene conjugates with Triazole	Mycelium growth rate	Methyl (32‐34)/benzyl ring (35‐37) at R1 and EWG (halogen or nitro) groups (R2) at other ring	Chlorothalonil	[62]
32.		Pimprinine (Indole alkaloid)	Mycelium growth rate	Methyl and Br (47, 48) at indole as well as H or methyl substituents and chloro & bromo groups at the fourth position, at the second site of oxazole (45, 46)	Azoxy‐strobin, boscalid	[68]
33.		Calycanthaceous alkaloid	Microdilution assay	Aliphatic group substituent on calycanthaceous alkaloid	Amphotericin B, Carbendazim	[73]
34.		Calycanthaceous alkaloid	Microdilution assay	Hexahydropyrroloindole having 4‐triflouro methyl substitution on benzyl moiety (R1) and substitution of aliphatic chain having ketone group at main pharmacophore (R2 ) increases lipophilicity	Amphotericin B, Chlorothalonil	[74]

Among partially synthetic compounds, the cyclotryptamine derivative (compound 30) exhibited the highest potency, with an MIC of 1.90 µg/mL, indicating strong antifungal activity. In contrast, calycanthaceous alkaloid derivatives showed comparatively moderate efficacy, with compounds 61 and 62 displaying MIC values of 31.25 µg/mL and 15.63 µg/mL, respectively. The fangchinoline derivative (compound 10) also demonstrated promising antifungal activity, achieving an EC₅₀ of 13.9 µg/mL and 98.9% inhibition of fungal growth, suggesting that structural modification of this alkaloid effectively enhances its fungicidal performance. Phenazine‐1‐carboxylic acid derivative (compound 25) has an EC₅₀ of 6.57 µg/mL, but cycogalic acid derivatives (compounds 23 and 24) demonstrated high inhibition rates of 92% and 91%, respectively.

4. Future Prospects

The future landscape of plant antifungal development is witnessing a significant shift toward novel heterocyclic scaffolds with innovative mechanisms of action to combat resistance and improve efficacy. Among the most promising candidates is Quinofumelin, a quinoline derivative that inhibits dihydroorotate dehydrogenase (DHOD) in the pyrimidine biosynthesis pathway, offering potent activity against Pyricularia oryzae and Fusarium species [75]. Similarly, Metyltetraprole, a tetrazolinone compound, disrupts electron transport by binding to the Qo site of the same complex and shows potential against Zymoseptoria tritici [76]. Advances in lipid transport inhibition have introduced new classes such as Fluoxapiprolin, an isoxazoline‐thiazole hybrid that targets oxysterol‐binding proteins (OSBPs) [77], and Oxathiapiprolin‐like molecules, which interfere with OSBP‐related pathways to compromise membrane integrity in oomycetes like Phytophthora infestans and Pythium species [78]. Other promising leads include indole Schiff base derivatives, which demonstrate broad‐spectrum activity through disruption of cell membranes and enzyme systems [79], and 1,3,4‐oxadiazole analogs, which impair key metabolic enzymes and electron transport functions [88]. Additionally, experimental sulfoximines are being evaluated for their ability to inhibit lipid biosynthesis and mitochondrial enzyme activity in fungi such as Sclerotinia and Fusarium [80]. Hybrid heterocycles like triazole‐pyrazole hybrids exhibit dual action by targeting ergosterol synthesis and inducing oxidative stress, offering an approach to tackle multidrug‐resistant phytopathogens [81]. These research‐stage heterocyclic agents represent a forward‐looking strategy for sustainable and resistance–resilient plant disease management, offering a new generation of safer and more effective antifungal solutions.

5. Field Consensus

Looking ahead, several clear opportunities emerge from the findings presented in this review. One key direction is to refine new generations of heterocyclic compounds that act on different or multiple biochemical targets, such as Complex III inhibitors at the Qo and Qi sites, and OSBP inhibitors, specifically compounds such as oxathiapiprolin and fluoxapiprolin, which are well‐recognised inhibitors of oxysterol‐binding protein rather than modulators, and hybrid molecules that combine features targeting ergosterol and respiration. Another promising approach involves using hybrid design strategies to minimize the risk of resistance development. In parallel, integrating modern computational methods, including structure‐based design and machine learning‐guided structure‐activity analysis, with faster phenotypic screening can help identify compounds that demonstrate strong activity, effective crop translocation, and favorable safety profiles. Progress in formulation science, particularly through nano‐ and controlled‐ release systems, along with integrated strategies that combine heterocyclic compounds with biological control agents, offers additional ways to improve field performance and sustainability. Together, these directions expand upon the core research themes and candidate compound classes outlined in the review.

5.1. Environmental Sustainability and Green Aspects

Environmental safety and functional residue/residency are important considerations in the agricultural use of heterocyclic compounds [82]. Many modern heterocyclic agrochemicals are designed to provide high biological activity at low application doses, which helps reduce the total chemical load released into soil, water, and surrounding ecosystems [83]. Their selective mechanisms of action against fungal targets such as ergosterol biosynthesis, mitochondrial respiration, and specific enzymes also minimize unnecessary toxicity to crops and, potentially, to non‐target organisms when properly used [84]. Recent research has emphasized the importance of green synthesis, computational modelling, molecular docking, artificial intelligence, and nanotechnology in accelerating the discovery of next‐generation heterocyclic fungicides capable of targeting resistant fungal strains. Novel compounds with improved environmental safety and unique modes of action are being developed to overcome resistance problems and provide sustainable crop protection solutions [17, 85]. Newer heterocyclic compounds are being optimized to avoid long‐term harmful residues in crops and the environment by improving biodegradability and metabolic breakdown after their protective action is complete [86]. Therefore, heterocyclic compounds offer strong potential for safer and more efficient crop protection; continued evaluation of residue persistence, non‐target safety, and environmental impact remains essential for sustainable agricultural use [87].

6. Research‐Gap Analysis

Despite significant progress, several key gaps remain in developing promising heterocyclic compounds into reliable field‐ready products. Many new molecules still lack a clear understanding of their mechanisms, as definitive target‐level validation through biochemical or genetic studies is often missing. Evidence from laboratory tests is not always matched by data on systemic activity, crop movement, or consistent performance in the field. Research on resistance is limited, with few systematic studies on cross‐resistance or long‐term selection pressure. Evaluations of environmental impact and non‐target effects are often incomplete, with little information on ecotoxicology, soil microbiome interactions, or metabolic fate at early stages of discovery. In addition, formulation and scale‐up challenges are rarely addressed, and few studies consider industrial feasibility, stability, or manufacturability. Addressing these gaps will require collaboration across multiple fields, combining target identification, standardized testing from laboratory to field, resistance monitoring, environmental safety assessment, and formulation development to ensure that new heterocyclic fungicides are both effective and sustainable.

6.1. Significance of the Review

The present review provides a comprehensive and up‐to‐date evaluation and covers existing literature on heterocyclic compounds as plant protectant fungicides, which aims to guide rational agrochemical discovery for the management of plant diseases caused by phytopathogenic fungi. This study is distinguished from the existing literature surveys by providing a broad, integrated, and forward‐looking analysis of heterocyclic compounds in plant fungal disease management rather than only listing individual fungicides or focusing on a single chemical class. It systematically combines established commercial fungicides with newly synthesized and research‐stage heterocyclic scaffolds, covering their chemistry, summarizing known modes of action and biological targets, and highlighting key SAR trends, synthetic methods that support their antifungal potential, and comparative biological performance against major phytopathogens. Additionally, it offers a critical evaluation of in vitro and in vivo efficacy data in light of environmental and resistance factors. This review serves as a vital resource for those developing next‐generation, resistance‐robust plant antifungal agents by including well‐established scaffolds and some currently in the research phase that are already used in agriculture. In addition, it includes research‐gap analysis, future prospects, and expert consensus to identify challenges such as limited mechanistic validation, insufficient field data, residue concerns, and formulation barriers. By linking historical commercial success with next‐generation innovation, this paper offers a more comprehensive roadmap for designing sustainable, resistance–resilient, and eco‐friendly heterocyclic fungicides for modern agriculture.

7. Conclusion

Heterocyclic compounds continue to play a pivotal role in plant disease management due to their broad structural diversity and ability to disrupt key fungal processes such as ergosterol biosynthesis, mitochondrial respiration, and cell division. Their central role in modern fungicide chemistry is evidenced by the fact that many of the most successful and long‐standing commercial fungicide classes are defined by, and named after, their heterocyclic frameworks. Examples include phenylpyrroles (e.g., fludioxonil), anilinopyrimidines (e.g., pyrimethanil, cyprodinil), pyrazole carboxamides (e.g., bixafen, fluxapyroxad), methyl benzimidazole carbamates (e.g., carbendazim), triazole and imidazole DMIs (e.g., tebuconazole, prothioconazole), and morpholine SBIs (e.g., fenpropimorph). These classes have shaped modern crop protection by delivering exceptional selectivity, systemic activity, and field reliability, demonstrating the proven translational success of heterocycle‐driven chemical innovation.

Their integration into fungicide development has led to the creation of several effective and selective agents targeting a wide range of phytopathogens. While many heterocyclic fungicides are already in commercial use, emerging resistance among fungal species and environmental safety concerns necessitate the discovery of novel chemotypes. Historically effective fungicide families illustrate that successful innovation arises not only from discovering entirely new scaffolds but also from intelligently modifying existing heterocycles to achieve improved target affinity, metabolic stability, and cross‐resistance avoidance. Research efforts are increasingly focused on designing new heterocyclic frameworks, hybrid molecules, and derivatives that offer improved efficacy, reduced phytotoxicity, and novel modes of action. Future progress will depend on integrating structural biology, resistance‐mechanism mapping, AI‐assisted molecular design, and insight gained from successful legacy fungicide classes to guide rational scaffold optimization. This review reinforces the importance of heterocycles as a foundation for current and next‐generation plant antifungal agents, emphasizing their continued relevance in sustainable agricultural protection and highlighting that the strategic design of heterocycle‐based fungicides remains one of the most promising routes to overcoming global resistance challenges.

Author Contributions

ST, MK, SS: original draft writing, review, investigation, editing of the original draft, and supervision. HD, KCP: review and investigation. The final manuscript was read and approved by all writers.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.