Synthetic Approaches and Biological Evaluation of Some New Sulfonate Ester-Containing Imidazolone Derivatives

Oxazolone derivative 2 was utilised as a key intermediate for the synthesis of some new imidazolone derivatives. Reaction of 2 with p-aminoacetophenone in the presence of acetic acid containing catalytic amount of freshly fused sodium acetate gives the corresponding imidazolone derivative 3 which on reaction with diethyl oxalate in the presence of granulated sodium metal afforded the corresponding imidazolone derivative 4. Condensation of compound 3 with some aromatic aldehydes afforded the corresponding cinnamoylphenyl derivatives 5a-c, respectively. Besides, compounds 5a-c reacted with hydrazine hydrate in boiling ethanol and yield the corresponding 4-arylidene-1(p-(5-aryl-2pyrazolin-3-y1) phenyl)-2-phenyl-2-imidazolin-5-ones 6a-c, respectively. Moreover, refluxing of compounds 5a-c with both ethylcyanoacetate and/or malononitrile in ethanol and ammonium acetate afforded 7a-c and 8a-c, respectively. Claisen reaction of 3 with ethylacetate gives the corresponding imidazolone derivative 9 which on reaction with thiourea in ethanol afforded the corresponding thienopyrimidine derivative 10. On the other hand, reaction of oxazolone 2 with both ethyl p-aminobenzoate and anthranilic acid in glacial acetic acid and freshly fused sodium acetate has been also studied. Structures of the newly synthesized compounds were established by elemental analysis and spectral data. Representative compounds of the synthesized products were tested and evaluated as antifungal and antimicrobial agents. Most of compounds exhibited good activities, where 3, 5b, 5c, 6a, 7b, 7c, 8a, 9, 11, 13 and 14 exhibited good activities against Bacillus Thuringenesis and Klebseilla Pneumonia, while compounds 3, 4, 6a, 6b, 6c, 7c, 8a, 8c, 11, 12 and 16 exhibited good activities against Trichoderma Herzianum and Trichoderma Virdi.


Introduction
Substituted oxazolone and imidazolone derivatives have become of great importance due to their wide range of biological activity. Previous studies have been reported that, it exhibit good anticonvulsant, bactericidal, fungicidal and insecticidal activities. Besides, they were shown a wide range of pharmaceutical properties [1][2][3][4][5]. On the other hand, it has been stated that, compounds containing aromatic sulfonate or sulfonamide moieties possess high acaricidal as well as insecticidal activity [6][7].

Results and Discussion
The present investigation aims to synthesize a series of products bearing both aryl sulfonate, oxazolone and imidazolone moieties in the same molecule hoping that these new products might show high biocidal activity. Thus, The In the present study, oxazolone 2 reacts with p-aminoacetophenone in glacial acetic acid and fused sodium acetate giving (Z)-4-((1-(4-acetylphenyl)-5-oxo-2-phenyl -1H-imidazol-4(5H)-ylidene)methyl)phenyl4-methylbenzen e sulfonate 3. Structure of 3 was confirmed by both analytical and spectral data. The IR spectrum exhibited absorption bands at 1715 and 1679 cm -1 characteristic for (-COCH 3 ) and (CON) groups, respectively. 1 H-NMR spectrum exhibited singlet signal at δ 2.6 characteristic for COCH 3 protons. Moreover, the mass spectrum measurement gave an evi-Some New Sulfonate Ester-Containing Imidazolone Derivatives dence for the proposed structure, which showed the molecular ion peak at m/e 536 (M + ) (Scheme 2). Treatment of compound 3 with diethyl oxalate in the presence of granulated sodium metal produced the corresponding imidazolone derivative 4. In addition, compound 3 undergoes condensation with some aromatic aldehydes namely, benzaldehyde; p-anisaldehyde and p-tolualdehyde to give the corresponding cinnamoylphenyl derivatives 5 a-c , respectively (scheme 2). Chemical structures of compounds 5 a-c were established on both elemental and spectral evidences. So, the IR spectrum in general showed stretching frequencies at 1675 and 1645 cm -1 attributable to the CON and C=O (Chalcone) groups. 1 H-NMR spectra of compound 5 b showed multiple signals at about δ 8. 2-8.3 corresponding to olefinic CH=CH protons and singlet signal at δ 4.4 for the OCH 3 protons. Besides, compound 5 c revealed multiple signals at about δ 8. 2-8.3 corresponding to olefinic CH=CH protons and singlet signal at δ 2.1 for the -CH 3 protons. Moreover, structures 5 a-c were confirmed by the mass spectral measurements which showed the molecular ion peaks at m/e 624 (M + ), m/e 654 (M + ) and m/e 638 (M + ), respectively.
Besides, compounds 5 a-c reacted with hydrazine hydrate in boiling ethanol to give the corresponding 4-arylidene-1-(p-(5-aryl-2-pyrazolin-3-y1)phenyl)-2-phenyl-2-imidazolin-5-ones 6 a-c , respectively. Structures 6 a-c were established on both elemental and spectral evidences. So, 1 H-NMR spectrum in general showed revealed doublet signals at δ 3.1 corresponding for CH 2 protons of pyrazole. The IR spectra of these compounds showed characteristic absorption bands at 3200-3260 cm -1 attributable to (-NH) group. In addition, structures 6 a-c were confirmed by the mass spectrophotometric measurements which showed the molecular ion peaks at m/e 638 (M + ), m/e 668 (M + ) and m/e 652 (M + ), respectively. Moreover, refluxing of compounds 5 a-c with both ethylcyanoacetate and/or malononitrile in ethanol and excess of ammonium acetate afforded 7 a-c and 8 a-c , respectively (scheme 3).
On the other hand, treatment of imidazolone 3 with ethylacetate in the presence of sodium metal gives the corresponding 1,3-diketone derivative 9 which reacted with thiourea in ethanol giving the thiopyrimidine derivative 10. The structure of compound 10 was elucidated on the basis of both analytical and spectral data. The IR spectrum of compound 10 displayed absorption band at 1370 cm -1 due to (C=S) group. In addition, the mass spectrum gives a molecular ion peak at m/e 621 (M + +2) (scheme 4).
On the other hand, refluxing of oxazolone 2 with anthranilic acid in glacial acetic acid and fused sodium acetate gives the benzoxazinone derivative 17 instead of compound 17 ' (scheme 8). The structure of compound 17 was elucidated on the basis of both analytical and spectral data. The IR spectrum showed absorption bands at 3470, 1760 and 1595 cm -1 due to amidic (NH), carbonyl of lactone and (C=C) groups. 1 H-NMR spectrum revealed singlet signals at δ 4.9 characteristic for CH=C protons. Moreover, the mass spectrum showed the molecular ion peak at m/e 538 (M + ). Formation of compound 17 could proceed via the plausible mechanism (scheme 9).

Antimicrobial Activity
All the compounds were subjected to biological screening and they showed promising antibacterial and antifungal activity which were comparable to the activity of known standard drugs. The results are summarized in Table ( 1,2). The results for antibacterial activities depicted in Table 1 revealed that, most compounds exhibited good activities against the reference chemotherapeutics, where 3, 5b, 5c, 6a, 7b, 7c, 8a, 9, 11, 13 and 14 exhibited good activities against Bacillus Thuringenesis and compounds 3, 5a, 5c, 6a, 7b, 8a, 10, 13, 14, 15 and 16 exhibited good activities against Klebseilla Pneumonia. On the other hand, the results for antifungal activities depicted in Table 2 revealed that, compounds 3, 4, 6a, 6b, 6c, 7c, 8a, 8c, 11, 12 and 16 exhibited good activities against the Trichoderma Herzianum and Trichoderma Virdi. Therefore, the obtained results indicated that, the antimicrobial activity is dependent on the attached groups with oxazolone and imidazolone derivatives. A comparison of antibacterial and antifungal activities of compounds with their structures revealed that, the compounds that bearing aryl sulfonate, oxazolone and imidazolone moieties in the same molecule exhibited significant activity against Bacillus Thuringenesis, Klebseilla Pneumonia, Trichoderma Herzianum and Trichoderma Virdi.

Conclusions
A series of novel substituted imidazolone derivatives were synthesized by the reaction of oxazolone derivative 2 with some primary aromatic amines namely, p-aminoacetophenone, ethyl p-aminobenzoate and anthranilic acid. All the compounds were subjected to biological screening. Most of compounds exhibited good activities, where 3, 5 b , 5 c , 6 a , 7 b , 7 c , 8 a , 9, 11, 13 and 14 exhibited good activities against Bacillus Thuringenesis and Klebseilla Pneumonia, while compounds 3, 4, 6 a , 6 b , 6 c , 7 c , 8 a , 8 c , 11, 12 and 16 exhibited good activities against Trichoderma Herzianum and Trichoderma Virdi. This proves the high therapeutic value of these compounds and encourages further study to explore their biological potential.