Abstract
Novel xanthine and imidazolone derivatives were synthesized based on oxazolone derivatives 2a-c as a key intermediate. The corresponding xanthine 3-5 and imidazolone derivatives 6-13 were obtained via reaction of oxazolone derivative 2a-c with 5,6-diaminouracils 1a-e under various conditions. Xanthine compounds 3-5 were obtained by cyclocondensation of 5,6-diaminouracils 1a-c with different oxazolones in glacial acetic acid. Moreover, 5,6-diaminouracils 1a-e were reacted with oxazolones 2a-c in presence of drops of acetic acid under fused condition yielding the imidazolone derivatives 6-13. Furthermore, Schiff base of compounds 14-16 were obtained by condensing 5,6-diaminouracils 1a,b,e with 4-dimethylaminobenzaldehyde in acetic acid. The structural identity of the resulting compounds was resolved by IR, 1H-, 13C-NMR and Mass spectral analyses. The novel synthesized compounds were screened for their antifungal and antibacterial activities. Compounds 3, 6, 13 and 16 displayed the highest activity against Escherichia coli as revealed from the IC50 values (1.8–1.9 µg/mL). The compound 16 displayed a significant antifungal activity against Candia albicans (0.82 µg/mL), Aspergillus flavus (1.2 µg/mL) comparing to authentic antibiotics. From the TEM microgram, the compounds 3, 12, 13 and 16 exhibited a strong deformation to the cellular entities, by interfering with the cell membrane components, causing cytosol leakage, cellular shrinkage and irregularity to the cell shape. In addition, docking study for the most promising antimicrobial tested compounds depicted high binding affinity against acyl carrier protein domain from a fungal type I polyketide synthase (ACP), and Baumannii penicillin- binding protein (PBP). Moreover, compound 12 showed high drug- likeness, and excellent pharmacokinetics, which needs to be in focus for further antimicrobial drug development. The most promising antimicrobial compounds underwent theoretical investigation using DFT calculation.
Highlights
IntroductionFunctionalized imidazolones were recognized by their strong therapeutic effect, especially as a powerful CNS depressant, anticonvulsant, sedative and hypnotic, fungicidal, antibacterial, antihistamine, anti-inflammatory, MAO inhibitory, antihypertensive, antiparkinsonian and anthelmintic activities [4,5,6,7,8,9,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]
We reported the synthesis of novel purine derivatives and the assessment of their antibacterial and antifungal activities. 5,6-Diaminouracils 1a-e, the key starting material for the obtained compounds, were synthesized by the reaction between ethyl cyanoacetate and different urea derivatives followed by nitrosation and reduction by conventional methods [25,38,39]
The antimicrobial efficacy of the synthesized uracil derivatives was evaluated by disc diffusion assay for the antibiotic resistant bacteria; E. coli, Pseudomonas sp., Salmonella sp., Staphylococcus aureus and Bacillus sp., in addition to pathogenic fungi
Summary
Functionalized imidazolones were recognized by their strong therapeutic effect, especially as a powerful CNS depressant, anticonvulsant, sedative and hypnotic, fungicidal, antibacterial, antihistamine, anti-inflammatory, MAO inhibitory, antihypertensive, antiparkinsonian and anthelmintic activities [4,5,6,7,8,9,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25] Uracils and their derivatives are one of the most essential structural motifs for drug design [26]. Uracil derivatives were recognized as potent anticancer inhibitors by inhibiting histone deacetylase [37] Based on this fact, new antimicrobial drugs will be needed to overcome these problems. Chemical structures of Fluconazole, Bacmethrin, and Prismsol, as authentic drugs, and the current synthesized compounds “imidazolopyrimidine-2,4-diones, 5- (imidazole-1-yl) uracils and Schiff base of uracils
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