There are a number of derivatives of quinolines and chalcones including several natural as well as semi-synthetics molecules. of note, there are some studies suggesting that these two nuclei of quinoline and chalcones can be linked with suitable linkers and that this enhances tremendously the activity of these compounds. Thiol site-specific PEGylation is intensely being utilized to modify macromolecules, biomolecules, and surfaces. Protein PEGylation is able to address the fundamental issues of site-specific conjugation and high-efficiency conjugation. Based on their selective chemical reactivity, reactive thiol and PEG reagents provide the best opportunity for efficient and site-specific PEGylation. However, to use a thiol reactive PEG reagent, it is necessary to recombinantly engineer a new moiety for further evalution. To prepare the new molecular hybrids, the quinoline nucleus, one of the privileged scaffolds, was coupled with various chalcone derivatives accommodate thiol reactive site via an appropriate PEG linker to produce a total of five PEGylated molecular hybrids The synthesized compounds displayed novel antibacterial activity.