تحضير متشعبات، أيميدازولات ودراسة تطبيقاتها البيوكيميائية والبايلوجية

Synthesis of Dendrimers, Imidazoles and Study Their Biochemical and Biological Applications

ABSTRACT

Polyamidoamine (PAMAM) dendrimer and imidazole derivatives are essential classes of organic compounds that play a significant role in medicinal chemistry. As a result, this study focuses on the synthesis and characterization of hyperbranched (PAMAM dendrimers) and new substituted imidazoles (Triimidazole and Tetraimidazole derivatives) as well as studies their properties in the biochemical and biological applications. The current research included three parts.
The first part of the thesis outlines the synthesis of PAMAM dendrimers from G1 to G3 through a divergent approach that includes two steps; a 1,4-Michael addition which yields ester-terminated dendrimers and an amidation step to generate amine-terminated dendrimers
Propane-1,3-diamine and 1,2-bis(2-aminoethoxy) ethane were chosen as various cores for the synthesis of dendrimers to produce primary and secondary amines inside the dendrimer structure (Scheme A and B).

To investigate that dendrimers were successfully prepared different spectroscopic techniques were utilized such as FTIR, (1H,13C) NMR and ESI-MS analysis. In addition to, Field Emission Scanning Electron Microscope (FE-SEM) and Energy-dispersive X-ray spectroscopy (EDX).

The second part of the thesis describes the multicomponent coupling reactions via the Debus-Radziszewski reaction to synthesized 2,4,5-triaryl imidazole derivatives ranging from 4a to 4j using 4,4′-Dimethoxybenzil, different aldehydes and ammonium acetate in the presence of glacial acetic acid as a catalyst. It also describes the synthesis of 1,2,4,5-tetraarylimidazole derivatives ranging from 5a to 5j using benzil, aromatic aldehyde, a variety of aromatic amine and ammonium acetate in the presence of sulfuric acid as a catalyst under reflux (heating conditions). The reactions in traditional heating conditions were compared with Ultrasonic irradiation and Microwave irradiation reactions as effective techniques for green synthesis, ultrasound and Microwave synthesis are being employed increasingly to accelerate organic reactions. In comparison to traditional methods, ultrasonication and microwaves have better yields, faster reaction times, higher selectivity, and fewer side effects (Scheme C).

The characterizations of synthesized imidazole derivatives compounds were mostly carried out by using melting point, FT-IR, 1HNMR, 13CNMR spectroscopy and mass spectroscopy.
The third part of the work examines the biochemical and biological applications of some newly synthesized compounds. The selected compounds were tested for their in vitro anti-urolithiasis activity, antidiabetic activity and antibacterial activity. Additionally, the in vitro hemolysis assays of selected compounds were performed for a better understanding of toxicity study.
To investigate the anti-urolithiasis potentials of the tested compounds, in vitro anti-urolithiasis inhibitory activities have been screened at various concentrations of 50, 100, 150, 200 and 250 μg/mL and various times (0, 30, 60, 180 and 360 minutes) utilizing cystone as the reference drug. The finding showed that compound G2(b) had the highest inhibiting percentage in the nucleation test, which was 91% at a concentration of 250 μg/mL after 360 minutes of the incubation period compared to the positive drug cystone, which had a percentage of 65%. Compound G2(a), on the other hand, showed the highest inhibition % in the aggregation test when incubated at 360 minutes and the concentration of 250 μg/mL, which was 69%; which was 24% higher than cystone (46%).
The antidiabetic assay at various concentrations (50, 100, 150, 200 and 250) μg/mL demonstrated moderate to good inhibitory potentials, with percentage values ranging from 48% to 90% against α-amylase and 38% to 61% against α-glucosidase. These results were encouraging. The obtained results were compared to the standard acarbose drug, which had values of 32%-65% for α-amylase and 43%-66% for α-glucosidase. Particularly, compounds 4f, 4e, 5b, and 4b were reported to be the most active, with percentage inhibition values of 90% 78%, 77% and 75%, respectively against α-amylase and compounds 4f and 4b, with percentage inhibition values of 61% and 58% against α-glucosidase at concentration 250 μg/mL.
The tested compounds were also screened for their in vitro antibacterial activity against four isolated bacteria two Gram-positive (Staphylococcus aureus, Streptococcus agalactiae) and two Gram-negative (Proteus mirabilis and Escherichia coli). The findings of the minimum inhibitory concentrations (MICs) of tested compounds at the concentrations of 100, 200, 300, 400 and 500 μg/mL showed comparable values with the standard antibiotics Azithromycin and Amoxicillin-clavulanic acid most notably 4a, 4e, 5b, and 5c with a MIC of 200 μg/mL against Staphylococcus aureus and 4e and 5b with a MIC of 300 μg/mL against Streptococcus agalactiae. The results of the antibacterial test by Agar well diffusion method demonstrated that among the screened compounds, G2(a) and G2(b) displayed excellent activity (inhibition zones) against all the bacterial strains at concentrations of their MICs as compared to reference drugs Azithromycin and Amoxicillin-Clavulanic acid.
The results of the hemolysis assay at concentrations of 100, 200, 250, 300, 400, and 500 μg/mL displayed that most screened compounds have a low effect on human red blood cells (less than 5%). Specifically, compounds G2(a), G3(a), G2(b), G3(b) and 5g were demonstrated to be significantly active with percent hemolysis ranging from (0.718% to 2.654%) compared to the standard Triton X-100, which exhibited a positive control of 97.3%. These findings reveal that some of the screened compounds were found to show potent activity, which could make them a promising drug for treatment.