Synthesis, Molecular Docking Analysis and Evaluation of Antibacterial and Antioxidant Activities of Quinoline Analogs

Abstract

Quinoline scaffold has been used to synthesize antibacterial, antimalarial and anticancer drugs. It is easily amenable to introduce various bioisosteres on the scaffold and for developing different bioactive molecules. Thus this project was designed to synthesize novel quinoline analogs and evaluate their antibacterial and antioxidant activities. In this dissertation, 26 quinoline analogs and 2 Schiff bases were synthesized. The structures of the synthesized compound were established using spectroscopic techniques. The drug-likeness properties of eighteen of the synthesized compounds were evaluated and results showed that all the eighteen synthesized compounds satisfy Lipinski’s rule of five with zero violations. All of the synthesized compounds were also screened for their antibacterial activities using paper disc diffusion against three Gram positive and three Gram negative bacteria strains. Ciprofloxacin and DMSO was used as a positive and negative control, respectively. Compound 225 (19.3 ± 3.1 mm), 227 (20.7 ± 1.5 mm) and 228 (19.7± 1.5 mm) were among those that showed comparable antibacterial mean inhibition zone compared to ciprofloxacin (22.0 ± 1.0 mm). The in silico molecular docking study of the synthesized compounds were evaluated against DNA gyrase for Gram negative and topoisomerase IV for Gram positive bacterial strains. Compounds 199, 219, 225, 227, 228 and 230 displayed good docking scores and were in a good agreement with the in vitro antibacterial analyses. The radical scavenging activities of the compounds were evaluated using 1,1-diphenyl-2-picryl hydrazyl (DPPH) method. The findings of this assay indicated that some of them possess strong to moderate antioxidant properties compared to ascorbic acid. Two of them, compound 227 (IC50 = 1.25 μg/mL) and 235 ((IC50 = 1.755 μg/mL) were stronger than ascorbic acid in radical scavenging activities presumably due to the presence of easily transferable electron with in the molecules. The molecular docking values of the two compound against human peroxidoxin 5 were also significant. The in silico anticancer properties of the compounds were evaluated by docking against human topoisomerase IIα, most of them showed stronger binding energy than the reference drug (Voreloxin). Thus, compounds 211, 213, 216, 217, 224, 225, 226 and 228 might have better anticancer activities. Among the scaffolds developed in this study, various bioisosteres can be attached on quinoline-stilbenes and [2,3'- biquinoline]-4-carboxylic acid scaffold to improve their bioactivities. Therefore, these scaffolds may serve as leads to develop effective drug candidates if further research is being conducted on them.