Preparation, Structural Identification, and Antibacterial Potential of Triazene Derivatives Synthesized via N-coupling Reactions

Davlye, Noissy Diosing (2024) Preparation, Structural Identification, and Antibacterial Potential of Triazene Derivatives Synthesized via N-coupling Reactions. Masters thesis, University Malaysia Sarawak.

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Abstract

Triazene poses excellent credibility in the medicinal area that has been extended back to the early 1860s. It is particularly known as a valuable linker in organic synthesis for structural modifications aimed in the development of therapeutic agents. In the present studies, three series (40a-g, 43a-i, and 45a-o) utilizing triazene as a linker were successfully synthesized through the diazotization method of p-aminoacetanilide 39 and p-anisidine 44 with a variety of amines derivatives at ortho, meta, and para positions. Alongside the formation of triazene, the reaction of 39 and 44 with meta-toluidine and meta-anisidine yielded azo structural formation instead in compounds 40f-g and 45n-o respectively. The characterization of all synthesized derivatives was done via FTIR, 1H and 13C NMR spectroscopies, along with the elemental CHN analysis which is consistent with the expected structures. Antibacterial activities of all synthesized compounds were assessed against Escherichia coli (ATC 25922) and Staphylococcus aureus (ATC 25923) by employing both Kirby-Bauer disk diffusion and turbidimetric kinetic assay. In the first series of phenyl acetamide derivatives bearing methyl and methoxy (40a-g) as well as halogen (43a-i), it was determined that the compound 43h (m-Br) exhibited remarkable antibacterial potential with 11.8 mm (S. aureus) and 12.0 mm (E. coli) inhibition outperforming standard ampicillin for E. coli (11.1 mm). The activity was believed to be attributed to the electron withdrawal properties of bromine that enhanced the hydrophobicity and electronic potential of the compounds, facilitating better penetration against the binding pocket of targeted protein in the bacteria. Meanwhile, in the second series of 4-methoxyphenyl aza derivatives (45a-o), triazene 45d (o-OCH3) demonstrated good inhibition against S. aureus and triazene 45b (o-CH3) against E. coli, with an inhibition zone of 11.4 mm and 10.5 mm respectively. The structural alteration resulting from replacing the amide group with a smaller methoxy moiety, combined with the presence of electron donating substituents may lead to a synergistic effect on bacterial activity. The results from the preliminary disk diffusion for a compound with an inhibition zone ≥ 8.8 mm prompt further analysis of its minimum inhibition concentrations (MIC) via turbidimetry assay. The findings show that 45a (H) which is the smallest molecule had the lowest MIC values (87 ppm) against S. aureus while against E. coli, compound 45i (o-Cl) gave the lowest MIC (82 ppm) outperforming the standard ampicillin (127 ppm). These may be due to the ability of the small compound molecule of 45a (H) that effectively reach the target site in S. aureus, while the lipophilic characteristics of chlorine atoms in addition to the position efficacy of 45i (o-Cl) align with lipophilic amino acid residues in E. coli. Overall, both series imply that the synthesized triazene structure of the 40a-e, 43a-i, and 45a-m had better activities than the synthesized azo structure of 40f-g and 45n-o. Keywords: Triazene, N-coupling, antibacterial, turbidimetry, Escherichia coli (ATC 25922), Staphylococcus aureus (ATC 25923)

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