الفهرس 
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Abstract
The proposed benzoxazinones (268a,b) were prepared by the general condensation of 2-propenoyl chloride derivatives (266a,b) with anthranilic acid or its 5-bromo derivative in pyridine or triethylamine/toluene mixture via the benzoic acid derivatives (267a,b) (Scheme 1).Scheme 1The expected 2-acrylamido benzoates (269a-c) were obtained on treatment of benzoxazinones (268a,b) with ethanol and/or 1-butanol in presence of pyridine (Scheme 2).
Ring opening of (268a,b) with primary amines, like, benzylamine, ethanolamine and p-anisidine, in dioxane under reflux gave the corresponding benzamide derivatives (270a-f). Fusion of (268b) with ammonium acetate and/or aromatic amines, like, p-anisidine or m-chloroaniline gave the corresponding quinazolinones (271a-f) (Scheme 2).
Condensation of (268b) with active methylene compounds, like, malononitrile in presence of pyridine afforded a mixture of the acrylamide (272) and 2-(3,4-dimethoxybenzylidine)malononitrile (273), which identified authentically by condensation of 3,4-dimethoxybenzalde- hyde and malononitrile in piperidine (Scheme 2).
Furthermore, fusion of (268b) with thiosemi- carbazide without solvent at 180oC gave the triazole derivative (274) (Scheme 2), via ring opening of benzoxazinone then ring closure at the side chain hydrazide moiety. On the other hand, refluxing of (268b) with phenyl thiourea in pyridine yielded the pyrimidoquinazolinone (275) (Scheme 2), through the ring opening-ring closure, followed by addition on the α,β-unsaturated nitrile with subsequent dehydrogenation of the pyrimidine thione moiety.
With secondary amines, like piperidine, benzoxa- zinone (268a) gave a mixture of the acrylamide (276) and cyano acetamide (277), but (268b) gave only (278) (Scheme 2).Scheme 2Antitumor activity:
The Tranilast and its analogous were tested for cytotoxic activity against MCF7 (Breast Carcinoma Cell Lin), Human tumor cell lines were obtained in liquid nitrogen (-180 0C) from the American Type Culture Collection. The tumor cell lines were maintained in the National Cancer Institute, Cairo, Egypt. All tested compounds were proven to have cytotoxic activity against MCF7 (Breast Carcinoma Cell Line) at the chosen drug concentrations.
IC50: dose of the compound which reduce the survival to 50%.
The IC50 of the tested compounds are listed in (Table 1).
Compounds (270a) and (270b) are more efficient than Tranilast.
Table 1: IC50 of the Tranilast and its analogous:
Compound Number IC 50 ug/ml
269a 15.2
269b 16.95
269c 8.76
270b 9.80
270d 7.90
271a 7.7
271c 4.19
272 8.1
274 9.6
275 7.7
276 9.22
Tranilast 11.7Part II
Synthesis of novel 2-propenoyl amides, esters, heterocyclic systems and their antibacterial and antifungal screeningThis part deals with the synthesis of novel (E)-3-(2,4 dichlorophenyl)-2-cyanoacryloyl chloride (281) via the common route condensation of 2,4-dichlorobenzaldehyde with ethyl cyanoacetate in presence of piperidine to give the corresponding (E)-ethyl-3-(2,4-dichlorophenyl)-2-cyanoacr- ylate (279).Hydrolysis of (279) in alcoholic solution of sodium hydroxide (1:1mole) gave (E)-2-cyano-3-(2,4-dichlorophenyl)acrylic acid (280). Refluxing the acid (280) in thionyl chloride yielded the new 2-cyanoacryloyl chloride (281) in good yield (Scheme3).Scheme 3
The acryloylchloride (281) was treated with phenol, 4-chlorothiophenol and primary amines, like, p-anisidine, p-toluidine, p-chloroaniline and m-aminopyridine in dry benzene in the presence of TEA to give the corresponding acrylate (282),thioacrylate (283) and acrylamides (284a-d) respectively (Scheme 4).
On the other hand, reaction of acryloylchloride (281) with benzoyl hydrazine under the same conditions gave the benzoyl hydrazide derivative (285), which underwent ring closure upon heating with POCl3 to give the oxadiazole derivative (286) (Scheme 4).When the acryloyl chloride (281) was allowed to react with methyl thiourea, phenyl urea and 2-amino pyridine as 1,3-binucleophilic reagents, it gaves the pyrimidine-2-thion derivative (287), N-acryloyl-N’-phenyl urea derivative (288) and a mixture of acrylamide (289) and pyrido pyrimidine derivative (290) respectively (Scheme 4).Scheme 4
The acryloylchloride (281) was allowed to react with thiosemicarbazide to give a mixture of the thiosemi- carbazone (291) and the pyrazolone derivative (292) (Scheme 5). On the other hand, (281) was condensed with ethanolamine to give the dihydroxazole derivative (293) (Scheme 5).
2-propenoyl amide (294) was prepared by conden- sation of (281) with anthranilic acid in the presence of TEA, which gave the benzoxazinone derivative (295) upon treatment with Ac2O. (Scheme 5)
Treatment of (281) with 2-aminophenol gave the corresponding amide (296), which cyclized by influence of POCl3 to give the benzoxazole (297). (Scheme 5)Scheme 5Measurement of antimicrobial and antifungal activities using diffusion disc:
The selected samples were screened against Gram-positive; Staphylococcus aureus and Gram-negative Escherichia coli. Antifungal activity was tested against Aspergillus flavus and Candida albicans.
Table 2: Antimicrobial and antifungal results of tested compounds.Sample Escheri-chia coli
(G-) Staphyloc-occus aureus
(G+) Aspergillus flavus
(Hungus) Candida albicans
(Hungus)
Control: DMSO 0.0 0.0 0.0 0.0
Tetracycline Antibacterial agent 32 30 --- ---
Amphotericin B Antifungal agent --- --- 16 18
282 13 12 0.0 0.0
283 16 20 0.0 0.0
284a 10 13 0.0 0.0
284b 13 13 0.0 0.0
284d 10 11 0.0 0.0
285 17 15 0.0 13
287 19 18 0.0 12
292 13 15 0.0 0.0
• 0.0: no activity (inhibition zone less than 7mm)
• 7-10 weak activity
• 11-15 moderate activity
• More than 15 strong activity