A bibliographic review was carried out in a time window between 2010 and 2020 to establish the organic molecules with the most significant biological activity against FOX. It was evidenced that the expression of the antifungal activity in the manuscripts differs concerning the units used or the property defined for this purpose, for example, half-maximal inhibitory concentration (IC50), half-maximal effective concentration (EC50), minimum inhibitory concentration (MIC), or percentage of inhibition (%) at a specific concentration. This review took the IC50, EC50, or MIC value expressed in micromolar as a criterion to select the interest reports. We discarded those reports where the activity was only reported as a percentage of inhibition. They were not conclusive, or merely the employed method did not provide definitive quantitative information for the corresponding molecules.
3. Conclusions and Perspectives
This review allowed us to establish that most of the synthetic methods published for promising antifungal agents usually employ cyclo condensation reactions. These protocols generally tend to have moderate to good yields, which depend on the structural nature of the precursors, the reaction conditions, and the use of catalysts. Among the most used catalysts, the use of porous materials, composites that can cause acidic or basic catalysis, have recently increased, although both inorganic and organic acids and bases are still being used. In addition, numerous protocols evidenced the use of metal catalysts, which tend to improve performance and selectivity under mild conditions. Regarding the energy sources used, although the use of conventional heating is maintained, many methodologies have more frequently used microwave or ultrasound irradiation to achieve better performance. On the other hand, the manuscripts cited and discussed in this review clearly showed that heterocyclic compounds play an essential role in controlling a phytopathogen such as
FOX, being benzothiazole derivatives, the most studied compounds with the highest antifungal activity (
Table 1). Some reports have described biological and environmental effects and their potential activity, degradation pathways, and subproducts characterization of synthetic heterocycles such as podophyllotoxin derivatives
[148][35], rhodamine derivatives and analogs
[149][36], benzothiazole and benzotriazole derivatives—which have emerged as contaminants in aquatic environments and toxic to aquatic organisms
[150,151,152,153][37][38][39][40]—and polycyclic (hetero)aromatic hydrocarbons compounds which recently was demonstrated their predominance in contaminated food samples and their relationship with potential toxicity
[154][41]. However, further studies are necessary to establish these promissory antifungal agents’ potential cytotoxicity and environmental risks.
Future research on this type of heterocyclic compounds could give more promising results in agrochemistry. It is hoped that this information will lead to the design of better molecules with improved antifungal properties and greater specificity as the development of new synthetic strategies. However, there is an urgent need to direct research related to the synthesis and design of new bioactive molecules against
FOX, considering the described antecedents in this review. The design of novel antifungal agents against
FOX should be oriented to inhibit specific enzymes, commonly called molecular targets. Thus, Catharina and Carels (2018) performed a systematic identification of specific enzymes for
FOX [155][42]. In addition, they described the characterization of enzymatic functionalities associated with protein targets that could be considered for the control of root rots induced by
FOX such as chitin synthase
[156][43], UDP-N-acetylglucosamine diphosphorylase
[157][44], the decapping scavenger enzyme (DcpS, m7GpppX diphosphatase)
[158][45], carnitine acetyltransferase
[159][46], hydroxyanthranilate 3,4-dioxygenase
[160[47][48],
161], ureidoglycolate lyase
[162][49], and holocytochrome-c synthase (HCCS, also known as cytochrome c heme lyase)
[163][50]. It is necessary to focus on vital processes such as cell membrane stability, respiration, mitosis and cell division, and signal transduction. The cell membrane performs many biological functions: to prevent the entry of large molecules, provide the cell’s shape, maintain the water potentials in the cell, and participate in signal transduction. It has been established as adverse effects of fungicides, affecting the membrane of microorganisms, which alter their structure and function
[164][51]. Azole fungicides, such as triazoles, interrupt the biosynthesis of ergosterol, an essential sterol of fungal cell membranes, by inhibiting cytochrome P450 eburicol 14α-demethylase (CYP51). This inhibition prevents the demethylation of eburicol, the primary substrate of CYP51 in most filamentous fungi such as
FOX, which leads to a depletion of ergosterol and an accumulation of non-functional 14α-methylated sterols
[165][52]. Inhibition of this enzyme could deplete ergosterol and changes the fluidity of the membrane in the lipid bilayer, which leads to a reduction in the activity of crucial membrane enzymes and, if ergosterol levels are low enough, blocks the “sparking” reaction necessary for the re-initiation of fungus growth
[166][53]. Fungicides that alter cell division processes presumably affect β-tubulin, since these can inhibit the assembly of α- and β-tubulin heterodimers in microtubules, which are vital for various processes such as signaling motility, division cell, and mitosis
[167,168][54][55]. Moreover, fungicides that become inhibitors of this metabolic process can bind to cytochrome b
[169][56], an enzyme that is part of the bc1 complex, which is present in the internal mitochondrial membrane of eukaryotic organisms and is responsible for catalyzing the transfer of electrons from ubiquinol to cytochrome c
[170][57]. Compounds that inhibit mitochondrial respiration block the electron transfer process in the airway and lead to an energy deficit due to a shortage of ATP
[171][58]. Many of the fungicides can cause damage to process such as DNA replication and transcription in phytopathogenic fungi. Within the enzymes that involve these metabolic processes, topoisomerases are ubiquitous enzymes found in various living organisms, including fungi pathogens
[172][59], as they are necessary for the maintenance of DNA topology
[173][60]. The main goal to direct the design of novel bioactive compounds is the molecular characterization of these enzymatic targets and the determination of their quaternary structure, their active site and mainly, successful protocols for their obtention. However, few reports have been published for
FOX enzymatic targets making difficult the access to this information.
Despite this, computational tools such as molecular docking, molecular dynamics, and quantitative structure–activity relationship (QSAR) offer an essential alternative for the rational design of new antifungal agents against
FOX. Recently, in silico molecular docking studies of pyrrolo(1,2-
a)pyrazine-1,4-diones, hexahydro, and pyrrolo(1,2-
a)pyrazine-1,4-diones, hexahydro-3(2-methylpropyl)pyrrolo(1,2-
a)pyrazine-1,4-diones against some enzymatic targets, showed the potential of these compounds as bioactive multitargeting compounds
[174][61]. Hydrazone derivatives bearing imidazole or benzimidazole nucleus were designed, synthesized, and evaluated for their antioxidant, antifungal, and anti-acetylcholinesterase activities. Molecular docking studies of the most active compounds showed reasonable binding modes in the active site of
FOX FGB1 enzyme and acetylcholinesterase, and in silico predictions of ADME and pharmacokinetic parameters indicated that these compounds should have good oral bioavailability
[175][62]. The structure–antifungal activity relationship studies of fusarubin analogs using molecular docking and simulations-allowed establishing these compounds’ possible mechanism against three target enzymes
[176][63]. Finally, molecular docking studies of some Schiff bases derived from 5-(morpholinosulfonyl)indol-2,3-dione and appropriate amines or hydrazide derivatives indicated good binding with the evaluated enzymatic targets lower binding energy of the most promising compounds than a standard drug used
[177][64]. These recent antecedents involving computational tools leading to the generation of structure–activity correlation models will allow the effective obtaining of new agrochemical agents.