Synthesis, In Silico Prediction and In Vitro Evaluation of Antimicrobial Activity, DFT Calculation and Theoretical Investigation of Novel Xanthines and Uracil Containing Imidazolone Derivatives

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.

Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors

“…As shown in Scheme 2 , the variable 5,6-diaminouracil/thiouracil derivatives 9a–e were prepared via consecutive cyclization of N -alkylurea/thiourea with ethyl cyanoacetate in the presence of sodium ethoxide, which initially gave 6-aminouracil/thiouracils 7a – e . This was readily followed by conversion via a nitrosation process using nitrous acid and then reduction of nitroso uracil/thiouracils 8 a– e via the reducing agent ammonium sulfide [ 80 , 81 ].…”

“…All starting materials and reagents were generally commercially available and purchased from Sigma-Aldrich or Lancaster Synthesis Corporation (Lancaster, UK). Compounds 4a–c and 9a–e were prepared according to the reported method [ 80 , 81 , 94 , 95 , 96 ].…”

Chemical Profile, Antioxidant and Antibacterial Activities, Mechanisms of Action of the Leaf Extract of Aloe arborescens Mill

“…The GC-MS analysis revealed the presence of phytochemicals known to induce antibacterial and antioxidant activities. For instant, the main compounds, xanthine, morpholine, octanoic and indole, possesses antimicrobial and antioxidant properties [ 28 , 29 , 30 , 31 ]. According to the literature, there are limited studies that have published the phytoconstituents of A. arborescens.…”

Microbial cytosine deaminase is a programmable anticancer prodrug mediating enzyme: antibody, and gene directed enzyme prodrug therapy

“…Unlike the human cells, microorganisms have an active CDA, catalyzing the conversion of 5-FC (non-toxic prodrug) into 5-FU (toxic anticancer drug) (Yao et al., 2005). Thus, expression of CDA in combination with uracil phosphoribosyl-transferase in tumor cells increases the cellular sensitivity to 5-FC and 5-FU ( Erbs et al., 2000 ; El-Kalyoubi et al., 2021 , ​ El-Mekawy et al., 2010 , ​ El-Sayed et al., 2010 , ​ El-Sayed et al., 2011 ).

Figure 3 Salvage pathway of cytosine and cytidine in S. typhimurium and S. cerevisiae .

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