Microwave-Assisted Synthesis of Coumarin-Azo Derivatives, In silico and In vitro Evaluation for Potential Antibacterial Agent

Nur Arif, Mortadza (2023) Microwave-Assisted Synthesis of Coumarin-Azo Derivatives, In silico and In vitro Evaluation for Potential Antibacterial Agent. PhD thesis, Universiti Malaysia Sarawak.

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Abstract

The overuse and lack of regulation of antibiotics has resulted in the emergence of antibiotic�resistant bacteria or superbugs. This cause a decline in the effectiveness of current antibiotics that are critical in modern medicine. Hence, the search of new and effective drugs in medicinal chemistry is in demand to combat the health crisis. Natural products serve as an excellent scaffold for the development of new and innovative synthetic drugs with exceptional pharmaceutical properties. Coumarin 1 is a natural compound with medicinal values that has excellent antibacterial effects by binding to the B subunit of DNA gyrase in bacterial cells. Chemical modification of the coumarin moiety with other active moieties and pharmacophores could be a promising strategy for developing new potential antibiotics. A series of halogenated coumarin-azo derivatives 27a-g were successfully synthesized via diazo coupling reaction, whereas halogenated coumarin-azo derivatives bearing active group (i.e., ester, nitrile, and carboxylic) 30a-g, 31a-g, 32a-g via diazo coupling, Knoevenagel condensation and hydrolysis. The synthesis of coumarin-triazene bearing alkoxy long chain 37a-c were obtained through multiple steps reaction such as etherification, hydrolysis, Knoevenagel and diazo coupling reaction. All the synthesized compounds were analyzed using Carbon, Hydrogen, Nitrogen and Sulfur (CHNS) elemental analyzer and characterized using Fourier Transform Infrared (FTIR), 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy. The physiochemical and pharmacokinetic properties of the synthesized compounds were evaluated, where coumarin derivatives 27a-g, 30a-g, 31a-g, and 32a-g satisfied all the parameters of Lipinski’s rule of 5 (Molecular weight < 500 g/mol, Lipophilicity < 5, Hydrogen bond donor < 5; Hydrogen bond acceptor < 10, Topology polar surface area < 140 Å, and Rotatable bond < 10) except for 37a-c. Molecular docking interaction with bacterial DNA gyrase protein were screened using AutoDock Vina and showed that halogenated coumarin-azo 31c, 32b and 32c scored excellent binding affinity of -8.1 kcal/mol against Escherichia coli, whereas 31c and 31e scored -9.0 kcal/mol against Staphylococcus aureus which are better compared to references compound clorobiocin (-6.7 and -7.0 kcal/mol, respectively). The incorporation of azobenzene and halogens increased the compounds' lipophilicity for better binding and interaction with enzymes' hydrophobic active sites. The binding affinity of coumarin-triazene 37a with additional aromatic groups and aliphatic chains (C10) was comparable (-6.7 and -6.1 kcal/mol) to the clorobiocin, likely due to the formation of additional hydrophobic interactions with the receptor. The antibacterial screening via agar well diffusion however, showed poor inhibition against E. coli and S. aureus. The in vitro bioassay suggests that the compounds have a limited ability to permeate the bacterial cell membrane and interact with the targeted enzyme.

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