An Insight into All Tested Small Molecules against Fusarium oxysporum f. sp. Albedinis: A Comparative Review

Bayoud disease affects date palms in North Africa and the Middle East, and many researchers have used various methods to fight it. One of those methods is the chemical use of synthetic compounds, which raises questions centred around the compounds and common features used to prepare targeted molecules. In this review, 100 compounds of tested small molecules, collected from 2002 to 2022 in Web of Sciences, were divided into ten different classes against the main cause of Bayoud disease pathogen Fusarium oxysporum f. sp. albedinis (F.o.a.) with structure–activity relationship (SAR) interpretations for pharmacophore site predictions as (δ−···δ−), where 12 compounds are the most efficient (one compound from each group). The compounds, i.e., (Z)-1-(1.5-Dimethyl-1H-pyrazole-3-yl)-3-hydroxy but-2-en-1-one 7, (Z)-3-(phenyl)-1-(1,5-dimethyl-1H-pyrazole-3-yl)-3-hydroxyprop-2-en-1-one 23, (Z)-1-(1,5-Dimethyl-1H-pyrazole-3-yl)-3-hydroxy-3-(pyridine-2-yl)prop-2-en-1-one 29, and 2,3-bis-[(2-hydroxy-2-phenyl)ethenyl]-6-nitro-quinoxaline 61, have antifungal pharmacophore sites (δ−···δ−) in common in N1---O4, whereas other compounds have only one δ− pharmacophore site pushed by the donor effect of the substituents on the phenyl rings. This specificity interferes in the biological activity against F.o.a. Further understanding of mechanistic drug–target interactions on this subject is currently underway.


Introduction
Bayoud disease [1][2][3][4][5], caused by the telluric fungus pathogen Fusarium oxysporum f. sp. albedinis (F.o.a) [6][7][8][9], represents the leading dangerous agent of date palms cultivation, having killed more than 15 million Moroccan and Algerian date palm trees. Fungal infection causes significant implications, threatening date palms with high morbidity and mortality every year worldwide. Therefore, new antifungal inhibitors must be discovered urgently, especially those with new modes of action, low toxicity, and bioavailability, and are effective for responsive and drug-resistant fungi [10][11][12][13][14][15]. Due to their biological activity and chemical properties in recent years, fused heterocyclic compounds containing bridgehead nitrogen or oxygen donor atoms have drawn further interest. Indeed, several classes are reported in this review as pyrazole-and imidazole-based derivatives [16] presented in different biomolecules, such as histidine [17], histamine [18], and natural products [19]; this is an exciting building block [20]. Specifically, in recent decades, 4,5-diarylpyrazoles [21] and 2,5-diarylimidazoles [22] have gained interesting recognition as possible biomolecules in  Compared with literary works, we found that the pyrazole skeleton and its derivatives exhibited excellent inhibitory activity against Fusarium oxysporum [66].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].

17
--As presented in Table 2, the fungal activity of 7 is very substantial, though it decreases slightly in the case of 10 because of ethoxy phenyl groups, which commonly have pharmacophore sites (δ − ···δ + ), as presented in Figure 1, due to their physicochemical properties and their ability to penetrate the envelope of fungal cells and enter their cellular place of action, thus displaying more excellent activity in [27].
The agar diffusion technique was tested for in vitro antifungal function (ADT), where the literature reported the protocol details [7]. The optical density values were measured  The agar diffusion technique was tested for in vitro antifungal function (ADT), where the literature reported the protocol details [7]. The optical density values were measured for each culture at 625 nm, and the inhibition percentage (%) is expressed as (D 0 − Dx)/D 0 × 100. D 0 is the diameter of the mycelial growth of the culture witness, and Dx is the diameter of the mycelial growth ( Table 3). The target biomolecules 18-23 based on βketo-enol and pyrazole entities and pyridine were prepared using a one-pot in situ condensation method, similar to the procedures in the literature [24]. Table 3. Volume is withdrawn, a diameter of the strain and inhibition percentages of the tested (Z)-3(3-bromophenyl)-1-(1,5-dimethyl-1H-pyrazole-3yl)-3-hydroxyprop-2-en-1-one derivatives 18-23 against F.o.a. enol and pyrazole entities and pyridine were prepared using a one-pot in situ condensation method, similar to the procedures in the literature [24]. Table 3. Volume is withdrawn, a diameter of the strain and inhibition percentages of the tested (Z)- As presented in Table 3, only compounds 22 and 23 reach values close to the standard (benomyl), as they belong to the same family. Such variations depend on the radical group attached to the fragment of pyrazole keto-enol, where compound 23 has a phenyl ring attached instead of the methyl group in compound 22. In addition, numerous molecular improvements are currently being made to these compounds as antifungal candidates [25]. The in vitro antifungal potential of ten prepared βKeto-enol pyrazolic compounds against the pathogen F.o.a was determined by the agar diffusion technique reported in the literature [26], and the half-maximal inhibitory concentration (IC50) was determined using a non-linear regression algorithm of the concentration-inhibition percentage graph, with benomyl used as a positive control. In addition, the target biomolecules 24-30 based on βketo-enol and pyrazole entities were prepared by a one-pot in situ condensation method, which is similar to the procedures given in the literature [24].

ID
On the other hand, most of these molecules demonstrate potent antifungal action against F.o.a, as seen in Table 4. These were based on the structure-activity relationships (S.A.R.s). Where a stimulating effect is exerted against F.o.a of the substitution pattern, we found compound 28 in the 3-thiophene group. In contrast, compound 30 with the 2naphthalene group led the same inhibition percentage of 94% as the benomyl fungicide, while the best antifungal activity was found for compound 29 containing the 2-pyridine enol and pyrazole entities and pyridine were prepared using a one-pot in situ condensation method, similar to the procedures in the literature [24]. Table 3. Volume is withdrawn, a diameter of the strain and inhibition percentages of the tested (Z)- As presented in Table 3, only compounds 22 and 23 reach values close to the standard (benomyl), as they belong to the same family. Such variations depend on the radical group attached to the fragment of pyrazole keto-enol, where compound 23 has a phenyl ring attached instead of the methyl group in compound 22. In addition, numerous molecular improvements are currently being made to these compounds as antifungal candidates [25]. The in vitro antifungal potential of ten prepared βKeto-enol pyrazolic compounds against the pathogen F.o.a was determined by the agar diffusion technique reported in the literature [26], and the half-maximal inhibitory concentration (IC50) was determined using a non-linear regression algorithm of the concentration-inhibition percentage graph, with benomyl used as a positive control. In addition, the target biomolecules 24-30 based on βketo-enol and pyrazole entities were prepared by a one-pot in situ condensation method, which is similar to the procedures given in the literature [24].
On the other hand, most of these molecules demonstrate potent antifungal action against F.o.a, as seen in Table 4. These were based on the structure-activity relationships (S.A.R.s). Where a stimulating effect is exerted against F.o.a of the substitution pattern, we found compound 28 in the 3-thiophene group. In contrast, compound 30 with the 2naphthalene group led the same inhibition percentage of 94% as the benomyl fungicide, while the best antifungal activity was found for compound 29 containing the 2-pyridine enol and pyrazole entities and pyridine were prepared using a one-pot in situ condensation method, similar to the procedures in the literature [24]. Table 3. Volume is withdrawn, a diameter of the strain and inhibition percentages of the tested (Z)- As presented in Table 3, only compounds 22 and 23 reach values close to the standard (benomyl), as they belong to the same family. Such variations depend on the radical group attached to the fragment of pyrazole keto-enol, where compound 23 has a phenyl ring attached instead of the methyl group in compound 22. In addition, numerous molecular improvements are currently being made to these compounds as antifungal candidates [25]. The in vitro antifungal potential of ten prepared βKeto-enol pyrazolic compounds against the pathogen F.o.a was determined by the agar diffusion technique reported in the literature [26], and the half-maximal inhibitory concentration (IC50) was determined using a non-linear regression algorithm of the concentration-inhibition percentage graph, with benomyl used as a positive control. In addition, the target biomolecules 24-30 based on βketo-enol and pyrazole entities were prepared by a one-pot in situ condensation method, which is similar to the procedures given in the literature [24].
On the other hand, most of these molecules demonstrate potent antifungal action against F.o.a, as seen in Table 4. These were based on the structure-activity relationships (S.A.R.s). Where a stimulating effect is exerted against F.o.a of the substitution pattern, we found compound 28 in the 3-thiophene group. In contrast, compound 30 with the 2naphthalene group led the same inhibition percentage of 94% as the benomyl fungicide, while the best antifungal activity was found for compound 29 containing the 2-pyridine enol and pyrazole entities and pyridine were prepared using a one-pot in situ condensation method, similar to the procedures in the literature [24]. Table 3. Volume is withdrawn, a diameter of the strain and inhibition percentages of the tested (Z)-3(3-bromophenyl)-1-(1,5-dimethyl-1H-pyrazole-3yl)-3-hydroxyprop-2-en-1-one derivatives 18-23 against F.o.a. As presented in Table 3, only compounds 22 and 23 reach values close to the standard (benomyl), as they belong to the same family. Such variations depend on the radical group attached to the fragment of pyrazole keto-enol, where compound 23 has a phenyl ring attached instead of the methyl group in compound 22. In addition, numerous molecular improvements are currently being made to these compounds as antifungal candidates [25]. The in vitro antifungal potential of ten prepared βKeto-enol pyrazolic compounds against the pathogen F.o.a was determined by the agar diffusion technique reported in the literature [26], and the half-maximal inhibitory concentration (IC50) was determined using a non-linear regression algorithm of the concentration-inhibition percentage graph, with benomyl used as a positive control. In addition, the target biomolecules 24-30 based on βketo-enol and pyrazole entities were prepared by a one-pot in situ condensation method, which is similar to the procedures given in the literature [24].

ID
On the other hand, most of these molecules demonstrate potent antifungal action against F.o.a, as seen in Table 4. These were based on the structure-activity relationships (S.A.R.s). Where a stimulating effect is exerted against F.o.a of the substitution pattern, we found compound 28 in the 3-thiophene group. In contrast, compound 30 with the 2naphthalene group led the same inhibition percentage of 94% as the benomyl fungicide, while the best antifungal activity was found for compound 29 containing the 2-pyridine enol and pyrazole entities and pyridine were prepared using a one-pot in situ condensation method, similar to the procedures in the literature [24]. Table 3. Volume is withdrawn, a diameter of the strain and inhibition percentages of the tested (Z)-3(3-bromophenyl)-1-(1,5-dimethyl-1H-pyrazole-3yl)-3-hydroxyprop-2-en-1-one derivatives 18-23 against F.o.a. As presented in Table 3, only compounds 22 and 23 reach values close to the standard (benomyl), as they belong to the same family. Such variations depend on the radical group attached to the fragment of pyrazole keto-enol, where compound 23 has a phenyl ring attached instead of the methyl group in compound 22. In addition, numerous molecular improvements are currently being made to these compounds as antifungal candidates [25]. c β-Keto-enol pyrazolic compounds

ID
The in vitro antifungal potential of ten prepared βKeto-enol pyrazolic compounds against the pathogen F.o.a was determined by the agar diffusion technique reported in the literature [26], and the half-maximal inhibitory concentration (IC50) was determined using a non-linear regression algorithm of the concentration-inhibition percentage graph, with benomyl used as a positive control. In addition, the target biomolecules 24-30 based on βketo-enol and pyrazole entities were prepared by a one-pot in situ condensation method, which is similar to the procedures given in the literature [24].
On the other hand, most of these molecules demonstrate potent antifungal action against F.o.a, as seen in Table 4. These were based on the structure-activity relationships (S.A.R.s). Where a stimulating effect is exerted against F.o.a of the substitution pattern, we found compound 28 in the 3-thiophene group. In contrast, compound 30 with the 2naphthalene group led the same inhibition percentage of 94% as the benomyl fungicide, while the best antifungal activity was found for compound 29 containing the 2-pyridine enol and pyrazole entities and pyridine were prepared using a one-pot in situ condensation method, similar to the procedures in the literature [24]. Table 3. Volume is withdrawn, a diameter of the strain and inhibition percentages of the tested (Z)- As presented in Table 3, only compounds 22 and 23 reach values close to the standard (benomyl), as they belong to the same family. Such variations depend on the radical group attached to the fragment of pyrazole keto-enol, where compound 23 has a phenyl ring attached instead of the methyl group in compound 22. In addition, numerous molecular improvements are currently being made to these compounds as antifungal candidates [25]. c β-Keto-enol pyrazolic compounds The in vitro antifungal potential of ten prepared βKeto-enol pyrazolic compounds against the pathogen F.o.a was determined by the agar diffusion technique reported in the literature [26], and the half-maximal inhibitory concentration (IC50) was determined using a non-linear regression algorithm of the concentration-inhibition percentage graph, with benomyl used as a positive control. In addition, the target biomolecules 24-30 based on βketo-enol and pyrazole entities were prepared by a one-pot in situ condensation method, which is similar to the procedures given in the literature [24].
On the other hand, most of these molecules demonstrate potent antifungal action against F.o.a, as seen in Table 4. These were based on the structure-activity relationships (S.A.R.s). Where a stimulating effect is exerted against F.o.a of the substitution pattern, we found compound 28 in the 3-thiophene group. In contrast, compound 30 with the 2naphthalene group led the same inhibition percentage of 94% as the benomyl fungicide, while the best antifungal activity was found for compound 29 containing the 2-pyridine Benomyl , x FOR PEER REVIEW 5 of 20 enol and pyrazole entities and pyridine were prepared using a one-pot in situ condensation method, similar to the procedures in the literature [24]. Table 3. Volume is withdrawn, a diameter of the strain and inhibition percentages of the tested (Z)- As presented in Table 3, only compounds 22 and 23 reach values close to the standard (benomyl), as they belong to the same family. Such variations depend on the radical group attached to the fragment of pyrazole keto-enol, where compound 23 has a phenyl ring attached instead of the methyl group in compound 22. In addition, numerous molecular improvements are currently being made to these compounds as antifungal candidates [25]. c β-Keto-enol pyrazolic compounds The in vitro antifungal potential of ten prepared βKeto-enol pyrazolic compounds against the pathogen F.o.a was determined by the agar diffusion technique reported in the literature [26], and the half-maximal inhibitory concentration (IC50) was determined using a non-linear regression algorithm of the concentration-inhibition percentage graph, with benomyl used as a positive control. In addition, the target biomolecules 24-30 based on βketo-enol and pyrazole entities were prepared by a one-pot in situ condensation method, which is similar to the procedures given in the literature [24].
On the other hand, most of these molecules demonstrate potent antifungal action against F.o.a, as seen in Table 4. These were based on the structure-activity relationships (S.A.R.s). Where a stimulating effect is exerted against F.o.a of the substitution pattern, we found compound 28 in the 3-thiophene group. In contrast, compound 30 with the 2naphthalene group led the same inhibition percentage of 94% as the benomyl fungicide, while the best antifungal activity was found for compound 29 containing the 2-pyridine As presented in Table 3, only compounds 22 and 23 reach values close to the standard (benomyl), as they belong to the same family. Such variations depend on the radical group attached to the fragment of pyrazole keto-enol, where compound 23 has a phenyl ring attached instead of the methyl group in compound 22. In addition, numerous molecular improvements are currently being made to these compounds as antifungal candidates [25].
The in vitro antifungal potential of ten prepared βKeto-enol pyrazolic compounds against the pathogen F.o.a was determined by the agar diffusion technique reported in the literature [26], and the half-maximal inhibitory concentration (IC 50 ) was determined using a non-linear regression algorithm of the concentration-inhibition percentage graph, with benomyl used as a positive control. In addition, the target biomolecules 24-30 based on βketo-enol and pyrazole entities were prepared by a one-pot in situ condensation method, which is similar to the procedures given in the literature [24].
On the other hand, most of these molecules demonstrate potent antifungal action against F.o.a, as seen in Table 4. These were based on the structure-activity relationships (S.A.R.s). Where a stimulating effect is exerted against F.o.a of the substitution pattern, we found compound 28 in the 3-thiophene group. In contrast, compound 30 with the 2-naphthalene group led the same inhibition percentage of 94% as the benomyl fungicide, while the best antifungal activity was found for compound 29 containing the 2-pyridine group IC 50 of 60.84 µg/m. The existence of the R substituent should be further exploited [8] to evaluate the S.A.R.s for this novel class of antifungal agents.

Imidazothiazole Derivatives
The synthesis of various types of imidazothiazoles 31-35 is potentially helpful for developing biologically active heterocycles. The synthetic methods are practical and straightforward and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur [30,[75][76][77][78][79][80][81][82]. The antifungal action of five imidazothiazole derivatives 31-35 is carried out on an F.o.a using the concentrations C1, C2, C3, C4, and C5 as 5.0, 1.0, 0.2, 0.05, and 0.01 mg/mL, respectively. Each compound was prepared at various concentrations in the potato dextrose agar (PDA) before the fungus was cultured using the protocol described in the literature [28]. The IC50 was calculated using the linear regression equation between the normal logarithm concentrations and growth inhibition percentages.
From Table 5, the antifungal test of the five imidazothiazole derivatives tested against F.o.a. at five different concentrations acted differently, while all the molecules showed interesting results. Indeed, the best antifungal activity is found for compound 33 due to three methyl substituents on the ortho and para positions of the phenyl ring with IC50 not exceeding 20.00 μg/mL [28]. --

25
Molecules 2022, 27, x FOR PEER REVIEW 6 of 20 group IC50 of 60.84 μg/m. The existence of the R substituent should be further exploited [8] to evaluate the S.A.R.s for this novel class of antifungal agents.

Imidazothiazole Derivatives
The synthesis of various types of imidazothiazoles 31-35 is potentially helpful for developing biologically active heterocycles. The synthetic methods are practical and straightforward and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur [30,[75][76][77][78][79][80][81][82]. The antifungal action of five imidazothiazole derivatives 31-35 is carried out on an F.o.a using the concentrations C1, C2, C3, C4, and C5 as 5.0, 1.0, 0.2, 0.05, and 0.01 mg/mL, respectively. Each compound was prepared at various concentrations in the potato dextrose agar (PDA) before the fungus was cultured using the protocol described in the literature [28]. The IC50 was calculated using the linear regression equation between the normal logarithm concentrations and growth inhibition percentages.
From Table 5, the antifungal test of the five imidazothiazole derivatives tested against F.o.a. at five different concentrations acted differently, while all the molecules showed interesting results. Indeed, the best antifungal activity is found for compound 33 due to three methyl substituents on the ortho and para positions of the phenyl ring with IC50 not exceeding 20.00 μg/mL [28].

Imidazothiazole Derivatives
The synthesis of various types of imidazothiazoles 31-35 is potentially helpful for developing biologically active heterocycles. The synthetic methods are practical and straightforward and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur [30,[75][76][77][78][79][80][81][82]. The antifungal action of five imidazothiazole derivatives 31-35 is carried out on an F.o.a using the concentrations C1, C2, C3, C4, and C5 as 5.0, 1.0, 0.2, 0.05, and 0.01 mg/mL, respectively. Each compound was prepared at various concentrations in the potato dextrose agar (PDA) before the fungus was cultured using the protocol described in the literature [28]. The IC50 was calculated using the linear regression equation between the normal logarithm concentrations and growth inhibition percentages.
From Table 5, the antifungal test of the five imidazothiazole derivatives tested against F.o.a. at five different concentrations acted differently, while all the molecules showed interesting results. Indeed, the best antifungal activity is found for compound 33 due to three methyl substituents on the ortho and para positions of the phenyl ring with IC50 not exceeding 20.00 μg/mL [28]. --

27
Molecules 2022, 27, x FOR PEER REVIEW 6 of 20 group IC50 of 60.84 μg/m. The existence of the R substituent should be further exploited [8] to evaluate the S.A.R.s for this novel class of antifungal agents.

Imidazothiazole Derivatives
The synthesis of various types of imidazothiazoles 31-35 is potentially helpful for developing biologically active heterocycles. The synthetic methods are practical and straightforward and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur [30,[75][76][77][78][79][80][81][82]. The antifungal action of five imidazothiazole derivatives 31-35 is carried out on an F.o.a using the concentrations C1, C2, C3, C4, and C5 as 5.0, 1.0, 0.2, 0.05, and 0.01 mg/mL, respectively. Each compound was prepared at various concentrations in the potato dextrose agar (PDA) before the fungus was cultured using the protocol described in the literature [28]. The IC50 was calculated using the linear regression equation between the normal logarithm concentrations and growth inhibition percentages.
From Table 5, the antifungal test of the five imidazothiazole derivatives tested against F.o.a. at five different concentrations acted differently, while all the molecules showed interesting results. Indeed, the best antifungal activity is found for compound 33 due to three methyl substituents on the ortho and para positions of the phenyl ring with IC50 not exceeding 20.00 μg/mL [28]. --

28
Molecules 2022, 27, x FOR PEER REVIEW 6 of 20 group IC50 of 60.84 μg/m. The existence of the R substituent should be further exploited [8] to evaluate the S.A.R.s for this novel class of antifungal agents.

Imidazothiazole Derivatives
The synthesis of various types of imidazothiazoles 31-35 is potentially helpful for developing biologically active heterocycles. The synthetic methods are practical and straightforward and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur [30,[75][76][77][78][79][80][81][82]. The antifungal action of five imidazothiazole derivatives 31-35 is carried out on an F.o.a using the concentrations C1, C2, C3, C4, and C5 as 5.0, 1.0, 0.2, 0.05, and 0.01 mg/mL, respectively. Each compound was prepared at various concentrations in the potato dextrose agar (PDA) before the fungus was cultured using the protocol described in the literature [28]. The IC50 was calculated using the linear regression equation between the normal logarithm concentrations and growth inhibition percentages.
From Table 5, the antifungal test of the five imidazothiazole derivatives tested against F.o.a. at five different concentrations acted differently, while all the molecules showed interesting results. Indeed, the best antifungal activity is found for compound 33 due to three methyl substituents on the ortho and para positions of the phenyl ring with IC50 not exceeding 20.00 μg/mL [28].

29
Molecules 2022, 27, x FOR PEER REVIEW 6 of 20 group IC50 of 60.84 μg/m. The existence of the R substituent should be further exploited [8] to evaluate the S.A.R.s for this novel class of antifungal agents.

Imidazothiazole Derivatives
The synthesis of various types of imidazothiazoles 31-35 is potentially helpful for developing biologically active heterocycles. The synthetic methods are practical and straightforward and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur [30,[75][76][77][78][79][80][81][82]. The antifungal action of five imidazothiazole derivatives 31-35 is carried out on an F.o.a using the concentrations C1, C2, C3, C4, and C5 as 5.0, 1.0, 0.2, 0.05, and 0.01 mg/mL, respectively. Each compound was prepared at various concentrations in the potato dextrose agar (PDA) before the fungus was cultured using the protocol described in the literature [28]. The IC50 was calculated using the linear regression equation between the normal logarithm concentrations and growth inhibition percentages.
From Table 5, the antifungal test of the five imidazothiazole derivatives tested against F.o.a. at five different concentrations acted differently, while all the molecules showed interesting results. Indeed, the best antifungal activity is found for compound 33 due to three methyl substituents on the ortho and para positions of the phenyl ring with IC50 not exceeding 20.00 μg/mL [28]. 60

Imidazothiazole Derivatives
The synthesis of various types of imidazothiazoles 31-35 is potentially helpful for developing biologically active heterocycles. The synthetic methods are practical and straightforward and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur [30,[75][76][77][78][79][80][81][82]. The antifungal action of five imidazothiazole derivatives 31-35 is carried out on an F.o.a using the concentrations C1, C2, C3, C4, and C5 as 5.0, 1.0, 0.2, 0.05, and 0.01 mg/mL, respectively. Each compound was prepared at various concentrations in the potato dextrose agar (PDA) before the fungus was cultured using the protocol described in the literature [28]. The IC50 was calculated using the linear regression equation between the normal logarithm concentrations and growth inhibition percentages.
From Table 5, the antifungal test of the five imidazothiazole derivatives tested against F.o.a. at five different concentrations acted differently, while all the molecules showed interesting results. Indeed, the best antifungal activity is found for compound 33 due to three methyl substituents on the ortho and para positions of the phenyl ring with IC50 not exceeding 20.00 μg/mL [28]. 181. 30 53.00

Imidazothiazole Derivatives
The synthesis of various types of imidazothiazoles 31-35 is potentially helpful for developing biologically active heterocycles. The synthetic methods are practical and straightforward and are conceivably applicable to analogous heterocyclic systems possessing nitrogen and sulfur [30,[75][76][77][78][79][80][81][82]. The antifungal action of five imidazothiazole derivatives 31-35 is carried out on an F.o.a using the concentrations C 1 , C 2 , C 3 , C 4 , and C 5 as 5.0, 1.0, 0.2, 0.05, and 0.01 mg/mL, respectively. Each compound was prepared at various concentrations in the potato dextrose agar (PDA) before the fungus was cultured using the protocol described in the literature [28]. The IC 50 was calculated using the linear regression equation between the normal logarithm concentrations and growth inhibition percentages.
From Table 5, the antifungal test of the five imidazothiazole derivatives tested against F.o.a. at five different concentrations acted differently, while all the molecules showed interesting results. Indeed, the best antifungal activity is found for compound 33 due to three methyl substituents on the ortho and para positions of the phenyl ring with IC 50 not exceeding 20.00 µg/mL [28].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC50).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC50 = 86 μM and 168 μM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC50 = 284 μM. The two other pyrazoles tested demonstrated low antifungal function [31].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC50).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC50 = 86 μM and 168 μM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC50 = 284 μM. The two other pyrazoles tested demonstrated low antifungal function [31].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC50).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC50 = 86 μM and 168 μM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC50 = 284 μM. The two other pyrazoles tested demonstrated low antifungal function [31].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC50).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC50 = 86 μM and 168 μM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC50 = 284 μM. The two other pyrazoles tested demonstrated low antifungal function [31].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC50).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC50 = 86 μM and 168 μM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC50 = 284 μM. The two other pyrazoles tested demonstrated low antifungal function [31].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC 50 ).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC 50 = 86 µM and 168 µM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC 50 = 284 µM. The two other pyrazoles tested demonstrated low antifungal function [31].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC50).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC50 = 86 μM and 168 μM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC50 = 284 μM. The two other pyrazoles tested demonstrated low antifungal function [31].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC50).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC50 = 86 μM and 168 μM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC50 = 284 μM. The two other pyrazoles tested demonstrated low antifungal function [31].

Pyrazolic Compounds
Monopyrazolic heterocyclic compounds 36-55 were prepared in excellent yields by condensing one equivalent of hydroxymethylpyrazole with one equivalent of primary amines [83][84][85]. The antifungal behavior, as defined in the literature, was calculated by the agar diffusion technique [31], with the linear regression equation between the normal logarithm of the concentrations and the growth inhibition percentages calculated at the half-maximal inhibitory concentration (IC50).
The pyrazolic derivatives 50, 51, and 53-55 were screened in vitro for their antifungal potential against F.o.a and collected in Table 6, where compounds 50 and 55 showed an excellent efficacy of IC50 = 86 μM and 168 μM, respectively, arguably due to the presence of the two phenyl moieties. Due to the (-Br) group, which is an essential source of electronegativity, compound 53 showed a moderate potential with an IC50 = 284 μM. The two other pyrazoles tested demonstrated low antifungal function [31].
Based on Table 7, the most effective inhibitor is nitroquinoxaline 61, which produces 51% inhibition of the growth of Fusarium at a concentration of 72 mg/L due to its small nitro groups that disturb the cell membrane, with some intracellular target and electronwithdrawing solid group. At the same time, compounds 56, 60, and 59 are less effective but produce appreciable growth inhibition at comparable concentrations [48].
Based on Table 7, the most effective inhibitor is nitroquinoxaline 61, which produces 51% inhibition of the growth of Fusarium at a concentration of 72 mg/L due to its small nitro groups that disturb the cell membrane, with some intracellular target and electronwithdrawing solid group. At the same time, compounds 56, 60, and 59 are less effective but produce appreciable growth inhibition at comparable concentrations [48].
Based on Table 7, the most effective inhibitor is nitroquinoxaline 61, which produces 51% inhibition of the growth of Fusarium at a concentration of 72 mg/L due to its small nitro groups that disturb the cell membrane, with some intracellular target and electronwithdrawing solid group. At the same time, compounds 56, 60, and 59 are less effective but produce appreciable growth inhibition at comparable concentrations [48].
Based on Table 7, the most effective inhibitor is nitroquinoxaline 61, which produces 51% inhibition of the growth of Fusarium at a concentration of 72 mg/L due to its small nitro groups that disturb the cell membrane, with some intracellular target and electronwithdrawing solid group. At the same time, compounds 56, 60, and 59 are less effective but produce appreciable growth inhibition at comparable concentrations [48].
Based on Table 7, the most effective inhibitor is nitroquinoxaline 61, which produces 51% inhibition of the growth of Fusarium at a concentration of 72 mg/L due to its small nitro groups that disturb the cell membrane, with some intracellular target and electronwithdrawing solid group. At the same time, compounds 56, 60, and 59 are less effective but produce appreciable growth inhibition at comparable concentrations [48].
The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. The eight new benzimidazole-1,2,3-triazole hybrid molecules were tested against F.o.a using the method described in the literature [49], and their linear growth and sporulation inhibitory rates are presented in Table 8. Based on Table 8, all compounds were tested at a 20 mg/mL concentration, with Pelt, a systemic fungicide and benzimidazole precursor (70% of methyl thiophanate), as the positive control. Compound 66 shows a significantly increased rate with (17.01 and 30.62%) (p < 0.05) against F.o.a, which uniquely holds a CF 3 group fixed to the benzimidazole core, a lipophilic group known to modulate absorption and metabolism, and may explain the enhanced activity [49].
As stated in the literature, in vitro antibacterial and antifungal activity is tested by the agar diffusion technique [50] using pathogenic strains of F.o.a. In contrast, streptomycin was used in the antibacterial assay as a reference compound for quality reasons. Therefore, the minimal concentration of inhibition (M.I.C.) is the lowest concentration of the tested compound that has inhibited the development of the micro-organism.
As presented in Table 9, four tested compounds showed differential anti-proliferative activity against F.o.a, as the best M.I.C. value was found for compound 71 of 5 µg/mL. These results are explained by the piperazine ring spacer and the carboxylate moiety at the three-position of the pyrazole rings that considerably increases the antifungal activity [50].

Bipyrazolic Tripodal Derivatives
A series of novel bipyrazolic tripodal derivatives 74-81 was prepared in one step, with good and excellent yields. Then, one equivalent of the appropriate amine derivatives was added to a solution of two equivalents of the substituted hydroxymethylpyrazole in acetonitrile, and the mixture was continued under stirring at room temperature for 4-5 days. Finally, the crude material was evaporated, washed with water and CH2Cl2, and purified by silica gel column flash chromatography to give the target product 74-81 [52].
The eight compounds containing bipyrazolic tripod derivatives are tested in vitro for their efficacy against Fusarium oxysporum f. Isolated from a date palm with vascular fusariosis, F.o.a was used as the protocol described in the literature [52]. The minimum inhibition concentration (M.I.C.) is the lowest dose of the compound that can inhibit micro-organism development.
From data in Table 10, the presence of the methyl as electron donor groups on the pyrazole rings increased the antifungal activity for compounds 74, 76, 78, and 80, but has a counter effect on the phenyl ring, e.g., in the case of compounds 80 and 81 which have M.I.C. values of 40 and 80 μg/mL, respectively. Additionally, nitro substituent as an electron-withdrawing group for compound 79 increased its effect compared with compound 77 [52]. moiety at the three-position of the pyrazole rings that considerably increases the antifungal activity [50].

Bipyrazolic Tripodal Derivatives
A series of novel bipyrazolic tripodal derivatives 74-81 was prepared in one step with good and excellent yields. Then, one equivalent of the appropriate amine derivative was added to a solution of two equivalents of the substituted hydroxymethylpyrazole in acetonitrile, and the mixture was continued under stirring at room temperature for 4-5 days. Finally, the crude material was evaporated, washed with water and CH2Cl2, and purified by silica gel column flash chromatography to give the target product 74-81 [52] The eight compounds containing bipyrazolic tripod derivatives are tested in vitro fo their efficacy against Fusarium oxysporum f. Isolated from a date palm with vascula fusariosis, F.o.a was used as the protocol described in the literature [52]. The minimum inhibition concentration (M.I.C.) is the lowest dose of the compound that can inhibi micro-organism development.
From data in Table 10, the presence of the methyl as electron donor groups on the pyrazole rings increased the antifungal activity for compounds 74, 76, 78, and 80, but ha a counter effect on the phenyl ring, e.g., in the case of compounds 80 and 81 which have M.I.C. values of 40 and 80 μg/mL, respectively. Additionally, nitro substituent as an electron-withdrawing group for compound 79 increased its effect compared with compound 77 [52]. moiety at the three-position of the pyrazole rings that considerably increases the antifungal activity [50].

Bipyrazolic Tripodal Derivatives
A series of novel bipyrazolic tripodal derivatives 74-81 was prepared in one step, with good and excellent yields. Then, one equivalent of the appropriate amine derivatives was added to a solution of two equivalents of the substituted hydroxymethylpyrazole in acetonitrile, and the mixture was continued under stirring at room temperature for 4-5 days. Finally, the crude material was evaporated, washed with water and CH2Cl2, and purified by silica gel column flash chromatography to give the target product 74-81 [52].
The eight compounds containing bipyrazolic tripod derivatives are tested in vitro for their efficacy against Fusarium oxysporum f. Isolated from a date palm with vascular fusariosis, F.o.a was used as the protocol described in the literature [52]. The minimum inhibition concentration (M.I.C.) is the lowest dose of the compound that can inhibit micro-organism development.
From data in Table 10, the presence of the methyl as electron donor groups on the pyrazole rings increased the antifungal activity for compounds 74, 76, 78, and 80, but has a counter effect on the phenyl ring, e.g., in the case of compounds 80 and 81 which have M.I.C. values of 40 and 80 μg/mL, respectively. Additionally, nitro substituent as an electron-withdrawing group for compound 79 increased its effect compared with compound 77 [52]. moiety at the three-position of the pyrazole rings that considerably increases the antifungal activity [50].

Bipyrazolic Tripodal Derivatives
A series of novel bipyrazolic tripodal derivatives 74-81 was prepared in one step, with good and excellent yields. Then, one equivalent of the appropriate amine derivatives was added to a solution of two equivalents of the substituted hydroxymethylpyrazole in acetonitrile, and the mixture was continued under stirring at room temperature for 4-5 days. Finally, the crude material was evaporated, washed with water and CH2Cl2, and purified by silica gel column flash chromatography to give the target product 74-81 [52].
The eight compounds containing bipyrazolic tripod derivatives are tested in vitro for their efficacy against Fusarium oxysporum f. Isolated from a date palm with vascular fusariosis, F.o.a was used as the protocol described in the literature [52]. The minimum inhibition concentration (M.I.C.) is the lowest dose of the compound that can inhibit micro-organism development.
From data in Table 10, the presence of the methyl as electron donor groups on the pyrazole rings increased the antifungal activity for compounds 74, 76, 78, and 80, but has a counter effect on the phenyl ring, e.g., in the case of compounds 80 and 81 which have M.I.C. values of 40 and 80 μg/mL, respectively. Additionally, nitro substituent as an electron-withdrawing group for compound 79 increased its effect compared with compound 77 [52].

Bipyrazolic Tripodal Derivatives
A series of novel bipyrazolic tripodal derivatives 74-81 was prepared in one step, with good and excellent yields. Then, one equivalent of the appropriate amine derivatives was added to a solution of two equivalents of the substituted hydroxymethylpyrazole in acetonitrile, and the mixture was continued under stirring at room temperature for 4-5 days. Finally, the crude material was evaporated, washed with water and CH 2 Cl 2 , and purified by silica gel column flash chromatography to give the target product 74-81 [52].
The eight compounds containing bipyrazolic tripod derivatives are tested in vitro for their efficacy against Fusarium oxysporum f. Isolated from a date palm with vascular fusariosis, F.o.a was used as the protocol described in the literature [52]. The minimum inhibition concentration (M.I.C.) is the lowest dose of the compound that can inhibit micro-organism development.
From data in Table 10, the presence of the methyl as electron donor groups on the pyrazole rings increased the antifungal activity for compounds 74, 76, 78, and 80, but has a counter effect on the phenyl ring, e.g., in the case of compounds 80 and 81 which have M.I.C. values of 40 and 80 µg/mL, respectively. Additionally, nitro substituent as an electron-withdrawing group for compound 79 increased its effect compared with compound 77 [52]. their efficacy against Fusarium oxysporum f. Isolated from a date palm with vascular fusariosis, F.o.a was used as the protocol described in the literature [52]. The minimum inhibition concentration (M.I.C.) is the lowest dose of the compound that can inhibit micro-organism development. From data in Table 10, the presence of the methyl as electron donor groups on the pyrazole rings increased the antifungal activity for compounds 74, 76, 78, and 80, but has a counter effect on the phenyl ring, e.g., in the case of compounds 80 and 81 which have M.I.C. values of 40 and 80 μg/mL, respectively. Additionally, nitro substituent as an electron-withdrawing group for compound 79 increased its effect compared with compound 77 [52]. their efficacy against Fusarium oxysporum f. Isolated from a date palm with vascular fusariosis, F.o.a was used as the protocol described in the literature [52]. The minimum inhibition concentration (M.I.C.) is the lowest dose of the compound that can inhibit micro-organism development. From data in Table 10, the presence of the methyl as electron donor groups on the pyrazole rings increased the antifungal activity for compounds 74, 76, 78, and 80, but has a counter effect on the phenyl ring, e.g., in the case of compounds 80 and 81 which have M.I.C. values of 40 and 80 μg/mL, respectively. Additionally, nitro substituent as an electron-withdrawing group for compound 79 increased its effect compared with compound 77 [52]. The eight compounds containing bipyrazolic tripod derivatives are tested in vitro for their efficacy against Fusarium oxysporum f. Isolated from a date palm with vascular fusariosis, F.o.a was used as the protocol described in the literature [52]. The minimum inhibition concentration (M.I.C.) is the lowest dose of the compound that can inhibit micro-organism development.
From data in Table 10, the presence of the methyl as electron donor groups on the pyrazole rings increased the antifungal activity for compounds 74, 76, 78, and 80, but has a counter effect on the phenyl ring, e.g., in the case of compounds 80 and 81 which have M.I.C. values of 40 and 80 μg/mL, respectively. Additionally, nitro substituent as an electron-withdrawing group for compound 79 increased its effect compared with compound 77 [52].
The agar diffusion technique against Fusarium oxysporum f evaluated the in vitro antifungal activities of all the new Schiff base derivative compounds, including F.o.a fungus, as described earlier [53]. In the presence of a concentration of the tested compound over the mycelium diameter of the reference culture multiplied by 100, it is found that the inhibition proportion of a molecule is proportional to the ratio of the mycelium diameter of the culture. Therefore, the minimal concentration of inhibition (M.I.C.) is the lowest dose of the compound, which inhibited the growth of the microorganism when the mixture (DMSO/EtOH + distilled water) is used as a negative control without any standard reference drug.
On the contrary, based on their M.I.C. values in Table 11, the in vitro antifungal assay 40
The agar diffusion technique against Fusarium oxysporum f evaluated the in vitro antifungal activities of all the new Schiff base derivative compounds, including F.o.a fungus, as described earlier [53]. In the presence of a concentration of the tested compound over the mycelium diameter of the reference culture multiplied by 100, it is found that the inhibition proportion of a molecule is proportional to the ratio of the mycelium diameter of the culture. Therefore, the minimal concentration of inhibition (M.I.C.) is the lowest dose of the compound, which inhibited the growth of the microorganism when the mixture (DMSO/EtOH + distilled water) is used as a negative control without any standard reference drug.
The agar diffusion technique against Fusarium oxysporum f evaluated the in vitro antifungal activities of all the new Schiff base derivative compounds, including F.o.a fungus, as described earlier [53]. In the presence of a concentration of the tested compound over the mycelium diameter of the reference culture multiplied by 100, it is found that the inhibition proportion of a molecule is proportional to the ratio of the mycelium diameter of the culture. Therefore, the minimal concentration of inhibition (M.I.C.) is the lowest dose of the compound, which inhibited the growth of the microorganism when the mixture (DMSO/EtOH + distilled water) is used as a negative control without any standard reference drug.
The agar diffusion technique against Fusarium oxysporum f evaluated the in vitro antifungal activities of all the new Schiff base derivative compounds, including F.o.a fungus, as described earlier [53]. In the presence of a concentration of the tested compound over the mycelium diameter of the reference culture multiplied by 100, it is found that the inhibition proportion of a molecule is proportional to the ratio of the mycelium diameter of the culture. Therefore, the minimal concentration of inhibition (M.I.C.) is the lowest dose of the compound, which inhibited the growth of the microorganism when the mixture (DMSO/EtOH + distilled water) is used as a negative control without any standard reference drug.
The agar diffusion technique against Fusarium oxysporum f evaluated the in vitro antifungal activities of all the new Schiff base derivative compounds, including F.o.a fungus, as described earlier [53]. In the presence of a concentration of the tested compound over the mycelium diameter of the reference culture multiplied by 100, it is found that the inhibition proportion of a molecule is proportional to the ratio of the mycelium diameter of the culture. Therefore, the minimal concentration of inhibition (M.I.C.) is the lowest dose of the compound, which inhibited the growth of the microorganism when the mixture (DMSO/EtOH + distilled water) is used as a negative control without any standard reference drug. 80 182.14
The agar diffusion technique against Fusarium oxysporum f evaluated the in vitro antifungal activities of all the new Schiff base derivative compounds, including F.o.a fungus, as described earlier [53]. In the presence of a concentration of the tested compound over the mycelium diameter of the reference culture multiplied by 100, it is found that the inhibition proportion of a molecule is proportional to the ratio of the mycelium diameter of the culture. Therefore, the minimal concentration of inhibition (M.I.C.) is the lowest dose of the compound, which inhibited the growth of the microorganism when the mixture (DMSO/EtOH + distilled water) is used as a negative control without any standard reference drug.
On the contrary, based on their M.I.C. values in Table 11, the in vitro antifungal assay findings showed that most of the screened ligands exhibited high to moderate activity against F.o.a. The maximum activity was 0.02 µg/mL, shown by compound 84, followed by compounds 87, 88, and 93 with M.I.C. values equal to 0.04 µg/mL, while compound 83 showed the most negligible M.I.C. value of 0.9 µg/mL. Other products also have numerous activities, with M.I.C.s varying from 0.08 µg/mL for compound 92 to 0.30 µg/mL for compound 86. Comparing both the structures of 83 and 84, it can be inferred that the presence at the ortho position of the phenyl ring of a strong electron-withdrawing group, such as nitro moiety (NO 2 ), is very appropriate for increasing antifungal efficiency; the presence of an electron donation group, such as methyl moiety (CH 3 ) for antifungal action, is unfavorable in the period. Unfortunately, though, the correct variables that influence the antifungal ability of these derivatives are difficult to ascertain with these early investigations. Further investigations using other models and techniques are essential for this [53].
The activities of the pyrazole compound amino acids and the agar techniques determined 94-100. The yeast of the F.o.a was isolated from a date palm touched by the vascular Fusarium prepared in a PDA medium at 37 g/L [54].
Based on Table 12, compared to blank culture, the inhibition rates of F.o.a development ranged from 0 to 480 mg/L for ester hydrochloride amino acids or their tripodal pyrazolic homologs. Inhibition activity against the growth of F.o.a. was shown by the various compounds studied, except 94 and 95. However, the rate of this inhibition changes from one molecule to another. Compound 98 has the best antifungal activity due to methyl substituents as electron donor groups in methyl alaninate (alanine ester) as the amino acid; these products' structural and electronic diversity affected their biological activities. Further developments on this subject are currently in progress in order to understand their mechanistic interactions [54].

ID
Structure MIC (mg/L) 94 tripodal pyrazolic homologs. Inhibition activity against the growth of F.o.a. was shown by the various compounds studied, except 94 and 95. However, the rate of this inhibition changes from one molecule to another. Compound 98 has the best antifungal activity due to methyl substituents as electron donor groups in methyl alaninate (alanine ester) as the amino acid; these products' structural and electronic diversity affected their biological activities. Further developments on this subject are currently in progress in order to understand their mechanistic interactions [54]. tripodal pyrazolic homologs. Inhibition activity against the growth of F.o.a. was shown by the various compounds studied, except 94 and 95. However, the rate of this inhibition changes from one molecule to another. Compound 98 has the best antifungal activity due to methyl substituents as electron donor groups in methyl alaninate (alanine ester) as the amino acid; these products' structural and electronic diversity affected their biological activities. Further developments on this subject are currently in progress in order to understand their mechanistic interactions [54]. development ranged from 0 to 480 mg/L for ester hydrochloride amino acids or their tripodal pyrazolic homologs. Inhibition activity against the growth of F.o.a. was shown by the various compounds studied, except 94 and 95. However, the rate of this inhibition changes from one molecule to another. Compound 98 has the best antifungal activity due to methyl substituents as electron donor groups in methyl alaninate (alanine ester) as the amino acid; these products' structural and electronic diversity affected their biological activities. Further developments on this subject are currently in progress in order to understand their mechanistic interactions [54]. development ranged from 0 to 480 mg/L for ester hydrochloride amino acids or their tripodal pyrazolic homologs. Inhibition activity against the growth of F.o.a. was shown by the various compounds studied, except 94 and 95. However, the rate of this inhibition changes from one molecule to another. Compound 98 has the best antifungal activity due to methyl substituents as electron donor groups in methyl alaninate (alanine ester) as the amino acid; these products' structural and electronic diversity affected their biological activities. Further developments on this subject are currently in progress in order to understand their mechanistic interactions [54]. development ranged from 0 to 480 mg/L for ester hydrochloride amino acids or their tripodal pyrazolic homologs. Inhibition activity against the growth of F.o.a. was shown by the various compounds studied, except 94 and 95. However, the rate of this inhibition changes from one molecule to another. Compound 98 has the best antifungal activity due to methyl substituents as electron donor groups in methyl alaninate (alanine ester) as the amino acid; these products' structural and electronic diversity affected their biological activities. Further developments on this subject are currently in progress in order to understand their mechanistic interactions [54].

Comparison Using Structure-Activity Relationship
To understand this structure-activity relationship and the modes of action of these new biologically active molecules, we can carry out a theoretical study with bioinformatics molecular modeling (DFT, Docking, and ADME-Tox studies) after studying the mechanism of the reaction using conceptual DFT [107,108]. As a result, we obtained various prospective targeted drugs as inhibitors for Bayoud disease ( Figure 2).
As presented in Figure 2, compounds 7, 23, 29, and 61 have the antifungal pharmacophore sites (δ − ···δ − ) in common in N1---O4, whereas other compounds have only one δ − pharmacophore site pushed by the donor effect of the substituents on the phenyl rings; this specificity interferes in the biological activity against F.o.a.

Comparison Using Structure-Activity Relationship
To understand this structure-activity relationship and the modes of action of these new biologically active molecules, we can carry out a theoretical study with bioinformatics molecular modeling (DFT, Docking, and ADME-Tox studies) after studying the mechanism of the reaction using conceptual DFT [107,108]. As a result, we obtained various prospective targeted drugs as inhibitors for Bayoud disease ( Figure 2).
As presented in Figure 2, compounds 7, 23, 29, and 61 have the antifungal pharmacophore sites (δ − ···δ − ) in common in N1---O4, whereas other compounds have only one δ − pharmacophore site pushed by the donor effect of the substituents on the phenyl rings; this specificity interferes in the biological activity against F.o.a.

Comparison Using Structure-Activity Relationship
To understand this structure-activity relationship and the modes of action of these new biologically active molecules, we can carry out a theoretical study with bioinformatics molecular modeling (DFT, Docking, and ADME-Tox studies) after studying the mechanism of the reaction using conceptual DFT [107,108]. As a result, we obtained various prospective targeted drugs as inhibitors for Bayoud disease (Figure 2). bioinformatics molecular modeling (DFT, Docking, and ADME-Tox studies) after studying the mechanism of the reaction using conceptual DFT [107,108]. As a result, we obtained various prospective targeted drugs as inhibitors for Bayoud disease ( Figure 2).
As presented in Figure 2, compounds 7, 23, 29, and 61 have the antifungal pharmacophore sites (δ − ···δ − ) in common in N1---O4, whereas other compounds have only one δ − pharmacophore site pushed by the donor effect of the substituents on the phenyl rings; this specificity interferes in the biological activity against F.o.a.  As presented in Figure 2, compounds 7, 23, 29, and 61 have the antifungal pharmacophore sites (δ − ···δ − ) in common in N 1 -O 4 , whereas other compounds have only one δ − pharmacophore site pushed by the donor effect of the substituents on the phenyl rings; this specificity interferes in the biological activity against F.o.a.

Conclusions
This review uses 100 compounds of tested small molecules divided into ten classes against Fusarium oxysporum f. sp. albedinis (F.o.a). First, compound 4 (IC 50 = 99.1 µg/mL) has the best fungus inhibition over all the pyrazole and imidazole derivatives, containing electron-donating character as para phenyl substituents. Furthermore, it is displays high toxicity in the phenyl groups on the F.o.a. Second, from βketo-enol derivatives, compounds 7, 23, 29, and 61 have the antifungal pharmacophore sites (δ − ···δ − ) in common in N1-O4, whereas other compounds have only one δ − pharmacophore site pushed by the donor effect of the substituents on the phenyl rings; this specificity interferes in the biological activity against F.o.a. Moreover, these products' structural and electronic diversity can affect their biological activities. Further developments on this subject are currently in progress to better understand their mechanistic interactions.