Promising Antidiabetic and Antimicrobial Agents Based on Fused Pyrimidine Derivatives: Molecular Modeling and Biological Evaluation with Histopathological Effect

Diabetes is the most common metabolic disorder in both developing and non-developing countries, and a well-recognized global health problem. The WHO anticipates an increase in cases from 171 million in 2000 to 366 million by 2030. In the present study, we focus on the preparation of pyrimidine derivatives as potential antidiabetic and antimicrobial agents. Thein vivoeffect on total serum glucose concentration, cholesterol and antioxidant activity was assessed in adult male albino Wister rats and compared to the reference drug glimperide. Promising results were observed for compound 5. The histopathological study confirms that compound 5 results in significant activity with liver maintenance. The antimicrobial activities were evaluated against several bacterial strains such as Salmonella typhimurium ATCC 25566, Bacillus cereus, Escherichia coli NRRN 3008, Pseudomonas aeruginosa ATCC 10145, Staphylococcus aureus ATCC 6538and fungi such as Rhizopus oligosporus, Mucor miehei and Asperillus niger. Compounds 4 and 5 showed a good inhibition of the bacterial zone compared to the reference drug cephradine. Finally, we suggest protein targets for these drugs based on computational analysis, and infer their activities from their predicted modes of binding using molecular modeling. The molecular modeling for compounds 4 and 5 resulted in improved docking scores and hydrogen bonding. The docking studies are in good agreement with the in vitro and in vivo studies.     

Organoiron polymers containing azo dyes

The synthesis of cationic organoiron polymers with azobenzene moieties in their side chains has been accomplished via nucleophilic aromatic substitution and ring-opening metathesis polymerization (ROMP) reactions. Polyaromatic ethers and thioethers with azobenzene moieties in their side chains were functionalized with different chromophores to yield yellow-, orange- and red-colored polymers. Polynorbornenes with azobenzene-containing side chains were isolated following ROMP of their monomeric analogs. All of the organoiron polymers were soluble in polar organic solvents and underwent reversible electrochemical reduction processes. Photobleaching of the azobenzene-containing polymers was achieved in the presence of hydrogen peroxide. The metallated polymers had glass transition temperatures approximately 50 to 80°C higher than their organic analogs.     

Synthesis of iron-containing polymers with azo dyes in the backbones or side chains

The synthesis of cationic cyclopentadienyliron-containing polymers with pendent azobenzene chromophores was accomplished via metal-mediated nucleophilic aromatic substitution reactions. All of the desired polymers were isolated as vibrantly coloured materials and displayed excellent solubility in polar aprotic solvents. Cationic and neutral cyclopentadienyliron polymers incorporating azo dyes in the backbone were also prepared. Reactions of azo dyes with dichlorobenzene complexes allowed for the isolation of cationic cyclopentdienyliron (CpFe₊) complexes with azo dye chromophores. These complexes were then reacted with 1,1′-ferrocenedicarbonyl chloride to produce the trimetallic monomers with terminal chloro groups. These monomers contained two pendent CpFe₊ cations and a neutral iron moiety in the backbone. Nucleophilic substitution reactions of these monomers with oxygen and sulfur containing dinucleophiles gave rise to a new class of polymeric materials. The pendent CpFe₊ moieties could also be cleaved from the polymer backbones using photolysis to afford novel ferrocene based polymers. The UV-vis spectra of the organoiron monomers and polymers display similar wavelength maxima however incorporating azobenzene chromophores with electron-withdrawing substituent into the polymer chains resulted in bathochromic shifts of the λ_max values.     

Organoiron polynorbornenes with pendent arylazo and hetarylazo dye moieties

Organoiron polynorbornene containing arylazo or hetarylazo dye chromophores has been prepared via ring opening metathesis polymerization using Grubbs' catalyst. The obtained polymers were isolated as brightly colored materials and displayed good solubility in polar organic solvents. The colors of these polymers were affected by the nature of the incorporated azo chromophores. Thermogravimetric analysis of these materials showed that the cleavage of the cyclopentadienyliron (CpFe⁺) moieties was between 225 and 231 °C, while the degradation of the polymer backbones occurred between 400 and 450 °C. UV-vis studies in DMF showed that the organoiron polymers containing arylazo dyes exhibit wavelength maxima around 425 nm. However, the replacement of these arylazo moieties with hetarylazo dyes displayed substantial bathochromic shifts in the λ_max values (≈ 511 nm).