الفهرس 
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Abstract
The current work illustrates the versatile role of β- aroylpropionic acid with different nitrogen nucleophiles to synthesize novel various pyridazin-3(2H)-one derivatives as well as some condensed acyclic compounds from simple readily obtainable materials.
The work can be divided into two main parts:-
I. Chemistry:
Synthesis of pyridazin-3(2H)-one derivatives.
II. Biological evaluation:
a. Study of the antifungal activity, the insecticidal activity of the synthesized compounds
b. Formulations of the most active synthesized pyridazin- 3-(2H)-one derivatives in the form of Emulsifiable Concentrate (EC) formulation.
Part I
I. Chemistry:
Synthesis of pyridazin-3(2H)-one derivatives:
Strategy of the synthesis of β-aroylpropionic acid derivative 3 was started from the preparation of chalcone 1 by Claisen-Schmidt reaction followed by refluxing chalcone 1 with aqueous solution of KCN in ethanol. Afterwards, the cyano group was hydrolyzed by 70% H2SO4 to afford the privilege β-aroylpropionic acid derivative 3 [cf. scheme I].
Scheme I
Structurally, compound 3 has the doubly electrophilic centers, which encourage us to a robust approach for the synthesis of diverse novel nitrogen heterocyclic compounds especially pyridazinone moiety by using doubly nucleophilic centers. Refluxing β-aroylpropionic acid 3 with hydrazine hydrate in ethanolic solution afforded 6-([1,1’-biphenyl]-4-yl)- 4-(3,4-dimethoxyphenyl)-4,5-dihydropyridazin-3(2H)-one 4.
Also, compound 4 was emanated from cyclization of β- aroylpropionic acid 3 using freshly distilled acetic anhydride to give 2(5H)-furanone derivative 5, followed by refluxing the later with hydrazine hydrate in ethanol, On the other hand, refluxing 2(5H)-furanone derivative 5 with ammonium acetate in absolute ethanol afforded pyrrolone derivative 6. Similarly, 2-phenyl-4,5-dihydropyridazin-3(2H)-one derivative 7 was commenced from reaction of β-aroylpropionic acid 3 with phenyl hydrazine in ethanolic solution.
Refluxing β-aroylpropionic acid 3 with 2,4-dinitrophenyl hydrazine (DNP) awarded the opening hydrazone derivative 8. Meanwhile, the closed pyridazinone derivative 9 was obtained under fusion. Synthesis of 1,2-oxazin-6-one derivative 11 was
afforded by refluxing compound 3 with hydroxylamine hydrochloride in pyridine [cf. scheme II].
Scheme II
Treatment of β-aroylpropionic acid 3 with thiosemicarbazide and/or semicarbazide hydrochloride in absolute ethanol furnished thiosemicarbazone and semicarbazone derivatives 12 and 14, respectively. Afterwards, cyclization of compound 12 by refluxing in glacial acetic acid gave 3-([1,1’-biphenyl]-4-yl)-5-(3,4-dimethoxyphenyl)-6-oxo- 5,6-dihydropyridazine-1(4H)-carbothioamide 13 as the sole product. On the other hand, under the same conditions,
compound 14 in glacial acetic acid gave 4,5-dihydropyridazin- 3(2H)-one 4.
Meanwhile, fusion of compound 3 with semicarbazide hydrochloride for 2h at 140ºC afforded 6-oxopyridazine-1(6H)- carboxamide 16. Furthermore, refluxing compound 3 with cyanoacetohydrazide in boiling ethanol gave afford 3-(3-([1,1’- biphenyl]-4-yl)-5-(3,4-dimethoxyphenyl)-6-oxo-5,6- dihydropyridazin-1(4H)-yl)-3-oxopropanenitrile N-cyanoacetyl dihydropyridazinone derivative 17 [cf. scheme III].
Scheme III
Unsaturation of dihydropyridazinone ring 4 by using bromine in glacial acetic acid afforded the pyridazinone derivative 18. N-alkylation of compound 18 with ethyl chloroacetate in dry acetonitrile in the presence of anhydrous K2CO3 gave ethyl N-acetate derivative 19. On the other hand, 3-chloropyridazine derivative 20 was obtained via reaction of compound 18 with POCl3. Ultimately, Hydrazinolysis of 3-
chloropyridazine derivative 20 with hydrazine monohydrate in dioxane as a solvent afforded 3-hydrazinylpyridazine 21 [cf. scheme IV].
Scheme IV
II. Biological evaluation:
Part II
a. Study of the antifungal activity, the insecticidal activity of the synthesized compounds:
Antifungal activity
In our study we aim to synthesize different new heterocyclic compounds bearing the pyridazin-3(2H)-one derivatives. Most of the new synthesized pyridazin-3(2H)-one derivatives were evaluated as antifungal agents on Fusarium solani, Alternaria solani and Fusarium semitectum fungi. This is due to the fact that these fungi cause many dangerous harms for higher plants as well as stored fruits, Pyridazine and pyridazonone derivatives are characterized by their fungicidal activity.
a. Fungicidal activity of some synthesized compounds against (Fusarium solani) pathogenic fungus:
from the data we concluded that the synthesized DNP- hydrazone derivative 8 showed remarkable antifungal activity (IC50 = 223.62 μg/ml) comparable to the standard fungicide which have IC50 (217.25 μg/ml), while N-thioamide dihydropyridazinone derivative 13 has the least potent fungicidal activity where its IC50 was (1084.34 μg/ml). The other tested compounds were arranged according to their fungicidal activity as follow β-aroylpropionc acid 3, N- cyanoacetyl dihydropyridazinone derivative 17 and thiosemicarbazone derivative 12 where their IC50 were (289.28,
384.18 and 542.78 μg/ml).
The homologous response was in the order Azoxystrobin
standard fungicide > 8 > 17 > 3 > 12 > 13 as it explicit from
their toxicity line′s slopes of 2.319, 2.091, 2.033, 2.023, 1.844
and 1.438 respectively.
b. Fungicidal activity of some synthesized compounds against (Alternaria solani) pathogenic fungus:
from these results we concluded that the response of (Alternaria solani) differ from that of (Fusarium solani) where, DNP-hydrazone derivative 8 was the more effective compound against tested fungus than other compounds including the standard fungicide azoxystrobin, and its IC50 was (240.08 μg/ml).
Studying toxicity line′s slopes revealed that symmetric responses were in configuration 13 > 17 > 3 > 8 > azoxystrobin
>12 where the slope values were (3.898, 2.465, 2.424, 2.177,
2.062 and 1.845) on sequence.
c. Fungicidal activity of some synthesized compounds against (Fusarium semitectum) pathogenic fungus:
This fungus exhibited different responsiveness towards tested compounds where the most fungicidal potency showed with β-aroylpropionic acid 3 where its IC50 was (239.25 μg/ml) while N-thioamide dihydropyridazinone derivative 13 possessed the least fungicidal activity and its IC50 was (605.01 μg/ml). Also, compounds 8 and 17 revealed fungicidal activity close to each other where their IC50 were (289.28, and 288.59 μg/ml respectively) while, standard fungicide recorded IC50 value (291.06 μg/ml).
On concerning symmetric response of treated fungus towards tested compounds we showed that it was arranged as 13 > 3 > 8 > standard fungicide (azoxystrobin) > 17 > 12 as
shown from their toxicity line′s slopes 3.722, 2.563, 2.023,
2.16 1.999, and 1.900, respectively.
Insecticidal activity
The insecticidal activity of the synthesized pyridazine and pyridazinone derivatives against 4th instar larvae of cotton leaf worm (spodoptera littoralis) evaluated according to the following sequence using leaf dipping technique.
a. Insecticidal activity of 4-subsitituted pyridazinone derivatives and pyridaben as registered standard against 4th instar larvae of cotton leaf worm (spodoptera littoralis):
The obtained results showed that 6-oxopyridazine-1(6H)- carboxamide derivative 16 has the highest insecticidal activity among the tested pyridazinone derivatives where its LC50 was (472.29 μg/ml) followed by (pyridaben) reference insecticide where its LC50 was (721.04 μg/ml) and then 1,2-oxazin-6-one derivative 11 with LC50 (775.44 μg/ml). On the other hand, the insecticidal potency of other tested substituted pyridazinone found to be in the following order 3-chloropyridazine derivative 20, 3-hydrazinylpyridazine derivative 21, pyridazinone derivative 18 and ethyl N-acetate derivative 19 where their LC50 were (827.59, 898.47, 994.52 and 1224.04 μg/ml) respectively.
The rest of the tested pyrdazinone derivatives could be arranged according to homogeneity of treated larvae to be 21 > 18 > 11 > 20 > 19 where the slopes of their toxicity lines were 2.153, 2.059, 1.994, 1.985, and 1.950 respectively.
b. Insecticidal activity of dihydropyridazinone derivatives and pyridaben as registered standard against 4th instar larvae of cotton leaf worm (spodoptera littoralis):
The obtained result revealed that closed pyridazinone derivative 9 which has LC50 (401.85 μg/ml) was the most potent compound against tested pest followed by N-thioamide
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dihydropyridazinone derivative 13 with LC50 (600.94 μg/ml) while LC50 of standard reference insecticide was (721.04 μg/ml).
Closed pyridazinone derivative 9 and this homogeneity and response decrease in the order 15 > 7 > 13 > (pyridaben) reference insecticide > 17 > 4 as it clear from the slopes of their toxicity lines which were (2.372, 2.175, 2.118, 1.991, 1.935,
1.926, and 1.893) respectively.
c. Insecticidal activity of butanoic acid derivatives and pyridaben reference insecticide against 4th instar larvae of cotton leaf worm (spodoptera littoralis):
The obtained result revealed that opening hydrazone derivative 8 which had LC50 (459.16 μg/ml) was the most potent derivative followed by semicarbazone derivatives 14 and thiosemicarbazone derivative 12 and finally (pyridaben) where their LC50 were (488.35, 521.17 and 721.04 μg/ml) respectively.
d. Insecticidal activity of some synthesized derivatives and pyridaben as reference insecticide against 4th instar larvae of cotton leaf worm (spodoptera littoralis):
The obtained result revealed that reference standard insecticide (pyridaben) was more potent than other synthesized derivatives where its LC50 was (721.04 μg/ml) followed by 4- ([1,1’-Biphenyl]-4-yl)-2-(3,4-dimethoxyphenyl)-4- oxobutanenitrile 2 and its LC50 was (896.62 μg/ml) while furanone derivative 5 recorded the least potent compound where its LC50 was (1440.87 μg/ml), and the other two compounds β-aroylpropionic acid derivative 3 and finally pyrrolone derivative 6 where their LC50 were (1096.90, and
1198.51 μg/ml) on consequence.
b. Formulations of the most active synthesized pyridazin-3-(2H)-one derivatives in the form of Emulsifiable Concentrate (EC) formulation:
Formulations of the most active synthesized pyridazin- 3-(2H)-one derivatives in the form of Emulsifiable Concentrate (EC) formulation:-
The aforementioned biological activity results motivated us to subject dinitrophenyl butanoic acid derivative 8 and dinitrophenyl pyridazinone derivative 9 to formulation in the form of emulsifiable concentrate (EC) to be as follow dinitrophenyl butanoic acid derivative 8 (A10% EC) while dinitrophenyl pyriadazinone 9 (B10% EC).
a. Physical properities
The physicochemical properties of the formulated derivatives as emulsifiable concentrates (EC) formulation were studied and compared with Helbstar 20% EC formulation, and the result a proved the stability of the prepared formulations under different storage conditions.
b. Biological activity
Insecticidal activity of the newly prepared emulsifiable concentrate (EC) formulation (A 10% EC and B 10% EC) in comparison with reference registered formulation (Helbstar 20% EC):
The results showed that (B10% EC) formulation was more potent than (Helbstar 20% EC) where it recorded LC50 value (134.30 μg/ml) while (Helbstar 20% EC) recorded the higher LC50 value among the three tested formulation to be (417.78 μg/ml). On the other hand, (A 10% EC) formulation recorded moderate value of LC50 between the other two formulation to be (175.42 μg/ml).
x
Slope of toxicity lines decreased in order 2.338 > 2.241 >
1.577 and this sequence declared that, the homologous response variation of the treated cotton leaf worm (spodoptera littoralis) strain to tested formulation be in order (B10% EC) > (A 10% EC) > (Helbstar 20% EC).