الفهرس 
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Abstract
Chemical Part In this part, we aimed to synthesize of the new carboximidamides and 1,2,4-oxadiazoles linked with different heterocylic rings as the following: I- Synthesis of the new carboximidamides and 1,2,4-oxadiazoles linked with benzoxazole ring: Reaction of (1,3-benzoxazol-2-ylthio)acetic acid (3) with aryl amidoximes namely; benzamidoxime (1a), 4-chlorobenzamidoxime (1b), 4-methoxybenzamid-oxime (1c), 3,4-dimethoxybenzamidoxime (1d), 3,4,5-trimethoxybenzamidoxime (1e), 3,4-methylenedioxybenzamidoxime (1f), 4-nitrobenzamidoxime (1g), 1-naphthylamidoxime (1h) and 2-naphthylamidoxime (1i) in dry acetonitrile at room temperature using an excess of N,N’-carbonyldiimidazole CDI (1.1 mol) as coupling reagent gave the corresponding; N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]-benzenecarboximidamide (4), N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]-4-chloro-benzenecarboximidamide (5), N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]-4-methoxy-benzenecarboximidamide (6), N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]-3,4-dimethoxybenzenecarboximidamide (7), N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]-3,4,5-trimethoxybenzenecarboximidamide (8), N’-[2-(1,3-benzoxazol-2-ylthio)-acetoxy]-1,3-benzodioxole-5-carboximidamide (9), N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]-4-nitrobenzenecarboximidamide (10), N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]naphthalene-1-carboximidamide (11) and N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]naphthalene-2-carboximidamide (12), respectively, Scheme i.
Summary
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Scheme i
Summary
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Continuous Scheme i Studying and optimizing the reaction condition using different solvents for cyclization of carboximidamide 4 via elimination of H2O, in order to increase the yield of 2-{[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]thio}-1,3-benzoxazole (13), Scheme ii. Thus, using acetonitrile under reflux, gave the target product in low yield (30 %) (Method A, Scheme ii); Using DMSO/NaOH under stirring at room temperature as reported procedure by Biernacki et al. in 2020 gave 45 % yield (Method B, Scheme ii); while using dimethylformamide DMF under heating at 80-90 ºC, gave the highest yield of the target product 13 (83 %), (Method C, Scheme ii). Scheme ii
Summary
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Therefore, by using the optimized condition; reaction of (1,3-benzoxazol-2-ylthio)acetic acid (3) with aryl amidoximes 1a-i in dimethylformamide DMF and using an excess of N,N’-carbonyldiimidazole CDI (1.1 mol) as coupling reagent at room temperature gave unisolated N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]arylcarboximidamide 4-12, respectively (mentioned by TLC, see Scheme i), which followed by heating at 80-90 ºC for 16-30 hrs to give the corresponding; 2-{[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]thio}-1,3-benzoxazole (13), 2-({[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzoxazole (14), 2-({[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzoxazole (15), 2-({[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benz-oxazole (16), 2-({[3-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzoxazole (17), (2-({[3-1,3-benzodioxol-5-yl)-1,2,4-oxadiazol-5-yl]methyl}-thio)-1,3-benzoxazole (18), 2-({[3-(4-nitrophenyl)-1,2,4-oxadiazol-5-yl]methyl}-thio)-1,3-benzoxazole (19), 2-({[3-(1-naphthyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzoxazole) (20) and 2-({[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzoxazole (21), respectively, Scheme iii.
Summary
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Scheme iii
Summary
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Continuous Scheme iii II- Synthesis of the new carboximidamides and 1,2,4-oxadiazoles linked with benzothiazole ring: Reaction of acetic acid derivative 23 with aryl amidoximes 1a-i in dry acetonitrile at room temperature using CDI as coupling reagent gave the corresponding; N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]benzenecarboximidamide (24), N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]-4-chlorobenzenecarboximdamide (25), N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]-4-methoxybenzenecarboximidamide (26), N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]-3,4-dimethoxybenzenecarboximidamide (27), N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]-3,4,5-trimethoxybenzenecarboximid-amide (28), N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]-1,3-benzodioxole-5-carboximidamide (29), N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]-4-nitrobenzene-carboximidamide (30), N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]naphthalene-1-carboximidamide (31) and N’-[2-
Summary
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(1,3-benzothiazol-2-ylthio)acetoxy]naphthalene-2-carboximidamide (32), respectively, Scheme iv. Scheme iv
Summary
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Continuous Scheme iv Reaction of (1,3-benzothiazol-2-ylthio)acetic acid (23) with aryl amidoximes 1a-i in DMF and using an excess equivalent mole (1.1 mol) of CDI as coupling reagent at room temperature gave the unisolated; N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]arylcarboximidamide 24-32, respectively (mentioned by TLC, see Scheme 12). Thus, 2-{[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]thio}-1,3-benzo-thiazole (33), 2-({[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzothiazole(34), 2-({[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzothiazole (35), 2-({[3-(3,4-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-methyl}thio)-1,3-benzothiazole (36), 2-({[3-(3,4,5-trimethoxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzothiazole (37), 2-({[3-(1,3-benzodioxol-5-yl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzothiazole (38), 2-({[3-(4-nitrophenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzothiazole (39), 2-({[3-(1-naphthyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzothiazole (40), and 2-({[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1,3-benzothiazole (41), were produced, when the
Summary
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temperature of the reaction mixture was raised to 80-90 ºC for 16-30 hrs, respectively, Scheme v. Scheme v
Summary
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Continuous Scheme v The new starting material alkyl amidoxime; 2-(1,3-benzothiazol-2-ylthio)-N’-hydroxyethanimidamide (43) was prepared via the reaction of 2-(1,3-benzothiazol-2-ylthio)acetonitrile (42) with hydroxylamine hydrochloride in the presence of TEA in distilled water, Equation i. Eq. i Reaction of acetic acid derivatives namely; (1,3-benzoxzol-2-ylthio)acetic acid (3) and/or (1,3-benzothiazol-2-ylthio)acetic acid (23) with alkyl amidoxime 43 in dry acetonitrile at room temperature using an excess equivalent mole (1.1 mol) of
Summary
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CDI as coupling reagent, gave the corresponding carboximidamides; 2-(1,3-benzothiazol-2-ylthio)-N’-[2-(1,3-benzoxazol-2-ylthio)acetoxy]ethanimidamide (44) and 2-(1,3-benzothiazol-2-ylthio)-N’-[2-(1,3-benzothiazol-2-ylthio)acetoxy]-ethanimidamide (45), respectively; Scheme vi. Scheme vi III- Synthesis of the new 1,2,4-oxadiazoles linked with benzimidazole ring: Reaction of acetic acid derivative 47 with aryl amidoximes 1a-c and/or 1f-i in DMF at 80-90 ºC, using CDI as coupling reagent gave the corresponding 1,2,4-oxadiazoles; 2-{[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]thio}-1H-benzimidazole (48), 2-({[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1H-benzimidazole (49), 2-({[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1H-benzimid-azole (50) 2-({[3-(1,3-benzodioxol-5-yl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1H-benzimidazole (51), 2-({[3-(4-nitrophenyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1H-benzimidazole (52), 2-({[3-(1-naphthyl)-1,2,4-oxadiazol-5-yl]methyl}thio)-1H-benzimidazole (53) and 2-({[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]methyl}-thio)-1H-benzimidazole (54), respectively (Scheme vii).
Summary
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Scheme vii
Summary
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Attempts for preparation and isolation of N’-[2-(1H-benzimidazol-2-ylthio)acetoxy]arylcarboximidamide I from the reaction of acetic acid derivative 47 with arylamidoxime 1b,c,i in acetonitrile at room temperature, using CDI as coupling reagent were failed, while their reactions gave the unexpected 6-amino-6-aryl-5,6-dihydro[1,6,2,4]oxathiadiazocino[4,5-a]benzimidazol-3(2H)-one 55-57, respectively, Method A, Scheme viii. On the other hand, a mixture of 6-aryl-1,6,2,4-oxathiadiazocino[4,5-a]benzimidazoles 55-57 and 2-{[(3-aryl-1,2,4-oxadiazol-5-yl)methyl]thio}-1H-benzimidazoles 49, 50 & 54 was separated from the reaction of acetic acid derivative 47 with aryl amidoxime 1b,c,i under reflux, Method B, Scheme viii. The postulated reaction mechanism for the formation of unexpected products 55-57 was assumed to proceed through the formation of the intermediate I, which undergoes intramolecular cyclization via nucleophilic addition of lone pair’s nitrogen at carbon Schiff base bond, (Scheme viii). Scheme viii
Summary
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IV- Design for the synthesis of new carboximidamides and 1,2,4-oxadiazoles linked with isatin ring: Herein, we designed and aimed to synthesize a series of carboximidamide and 1,2,4-oxadiazole derivatives linked with N-alkyl isatin, using 4-aminobenzoic acid as linker. The starting materials; 4-((2-oxoindolin-3-ylidene)amino)benzoic acid (58) and 4-((1-methyl-2-oxoindolin-3-ylidene)amino)benzoic acid (59) were prepared via the reaction of isatin and/or N-methyl isatin with p-aminobenzoic acid, respectively, using acetic acid as solvent, Scheme ix. Scheme ix Thus, reaction of benzoic acid derivative 58 with aryl amidoximes 1b,c,g,i in acetonitrile and using an excess of CDI (1.1 mol) as coupling reagent at room temperature gave the corresponding; 4-chloro-N’-[(4-{[2-oxo-1,2-dihydro-3H-indol-3-ylidene]amino}benzoyl)oxy]benzenecarboximidamide (60), 4-methoxy-N’-[(4-{[2-oxo-1,2-dihydro-3H-indol-3-ylidene]amino}benzoyl)oxy]benzenecarboximidamide (61), 4-nitro-N’-[(4-{[2-oxo-1,2-dihydro-3H-indol-3-ylidene]amino}benzoyl)oxy]-benzenecarboximidamide (62), N’-[(4-{[2-oxo-1,2-dihydro -3H-indol -3-ylidene]-amino}benzoyl)oxy]-naphthalene-2-carboximidamide (63), respectively, Scheme 18. In the same manner, reaction of benzoic acid derivative 59 with aryl amidoximes 1b,c,f gave the corresponding; 4-chloro-N’-[(4-{[1-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]amino}benzoyl)oxy]benzenecarboximidamide (64), 4-methoxy-N’-[(4-{[1-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]amino}-benzoyl)oxy]benzene-
Summary
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carboximidamide (65), N’-[(4-{[1-methyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-amino}benzoyl)oxy]-1,3-benzodioxole-5-carboximidamide (66), respectively, Scheme x. Scheme x
Summary
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Attempt for cyclization of carboximidamide 63 via elimination of water molecule, using acetonitrile under reflux was failed, while its treatment with solid sodium hydroxide in dimethyl sulfoxide (DSMO) at room temperature was succeed to synthesize the target product: 3-({4-[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]phenyl}imino)-1,3-dihydro-2H-indol-2-one (67), Equation ii. Eq. ii While, reaction of N-ethyl isatin with 4-aminobenzoic acid in acetic acid gave the unexpected 4-acetamidobenzoic acid (68), instead of 4-{[1-ethyl-2-oxo-1,2-dihydro-3H-indol-3-ylidene]amino}benzoic acid (69), Scheme xi. Scheme xi Thus, treatment of compound 68 with aryl amidoximes 1b,i and/or 3-nitrobenzamidoxime (1j) in dry acetonitrile at room temperature using an excess of CDI (1.1 mol) as coupling reagent gave the corresponding; N-{4-[({[amino(4-
Summary
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chlorophenyl)methylene]amino}oxy)carbonyl]phenyl}acetamide (70), N-{4-[({[amino(2-naphthyl)methylene]amino}oxy)carbonyl]phenyl}acetamide (71) and N-{4-[({[amino(3-nitrophenyl)methylene]amino}oxy)carbonyl]phenyl}acetamide (72), respectively (Scheme xii). Scheme xii Also, treatment of benzoic acid derivative 68 with amidoxime 1b in acetonitrile in the presence of CDI as coupling reagent under reflux gave N-{4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]phenyl}acetamide (73), Equation iii. Eq. iii
Summary
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Theoretical part Here, in this part we theoretically studied the reaction sequence of (1,3-benzothiazol-2-ylthio)acetic acid (23) with benzamidoxime (1a) in the presence of N,N’-carbonyldiimidazole CDI as catalyst to form carboximidamide and 1,2,4-oxadiazole derivative using the semi-empirical AM1 method. The theoretical studies proved that the cyclization step of carboximidamide 24 is extremely difficult and this was found to be with accordance with the experimental procedures. Biological activity and Molecular docking studies: The in vitro antimicrobial activity of newly synthesized carboximidamides and 1,2,4-oxadiazoles was evaluated against Gram-positive bacteria such as: Bacillus Subtilis (ATCC 6633) and Staphylococcus aureus (ATCC 6538) strains; Gram-negative bacteria such as Escherichia coli (ATCC 8739) and Klebsiella pneumonia (ATCC 13883) as well as fungi such as: Candida albicans (ATCC 10221) and Aspergillus niger strains compared to the standard antibiotic (Gentamycin) using Agar diffusion method. Also, the minimal inhibitory concentration (MIC) for some selected most potent compounds was detected. Most of them were found to be more active against Gram-positive bacteria (B. Subtilis and S. aureus) as well as Gram-negative bacteria (K. pneumonia); while they are less active against Gram-negative bacteria (E. coli) as well as fungi (C. albicans and A. niger). The results revealed that compounds `4, 14, 17, 30, 33 and 34 are the most potent and elicited remarkable antibacterial activity against the Gram-positive (B. Subtilis and S. aureus) and the Gram negative bacteria (E. coli and K. pneumonia) compared to gentamycin as a reference drug. The molecular docking results of 4 and 33 suggested that they may act as potent inhibitors of E. Coli DNA gyrase and E. Coli DNA topoisomerase IV.