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 <b>2a-c</b> as a key intermediate. The corresponding xanthine <b>3-5</b> and imidazolone derivatives <b>6-13</b> were obtained via reaction of oxazolone derivative <b>2a-c</b> with 5,6-diaminouracils <b>1a-e</b> under various conditions. Xanthine compounds <b>3-5</b> were obtained by cyclocondensation of 5,6-diaminouracils <b>1a-c</b> with different oxazolones in glacial acetic acid. Moreover, 5,6-diaminouracils <b>1a-e</b> were reacted with oxazolones <b>2a-c</b> in presence of drops of acetic acid under fused condition yielding the imidazolone derivatives <b>6-13</b>. Furthermore, Schiff base of compounds <b>14-16</b> were obtained by condensing 5,6-diaminouracils <b>1a,b,e</b> 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 <b>3</b>, <b>6</b>, <b>13</b> and <b>16</b> displayed the highest activity against <i>Escherichia coli</i> as revealed from the IC₅₀ values (1.8-1.9 µg/mL). The compound <b>16</b> displayed a significant antifungal activity against <i>Candia albicans</i> (0.82 µg/mL), <i>Aspergillus flavus</i> (1.2 µg/mL) comparing to authentic antibiotics. From the TEM microgram, the compounds <b>3</b>, <b>12</b>, <b>13</b> and <b>16</b> 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 <b>12</b> 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.