The novel mechanism of simocyclinone D8 (SD8) against DNA gyrase has inspired medicinal chemists for over a decade. The search for antibiotics with new mechanisms of action has never been more important with ever increasing prevalence of resistance. This project had three objectives. Firstly to contribute towards the total synthesis of SD8, by exploring chlorination reactions of dihydroxycoumarins and their corresponding starting reagents. Additionally, there was a need to establish a viable route towards the complex polyketide scaffold. Secondly, to generate a library of coumarins and screen for a low molecular weight fragment that could be taken forward as a lead compound. Thirdly, inspired by the bi-functional mode of action of SD8, the project sought to design and synthesise a coumarin-quinolone hybrid via a fragment-based approach. Herein we exploit ortho and para directing effects of phenolic OH groups to selectively chlorinate starting materials. However, we show chlorination of reagents prior to forming a coumarin is not a viable synthetic strategy. This is due to the reduced nucleophilicity imparted by the halogen on adjacent atoms. Consequently, this abrogates any ring closure reaction. We illustrate that a previously established Diels-Alder route can furnish a novel isomerised pericyclic adduct. This provides a good starting point for reaction optimisation and the onward enantioselective synthesis of the complex polyketide scaffold. Lastly, 27 different coumarin fragments were synthesised and assessed for biological activity. We illustrate that simple coumarins lack inhibition in supercoiling assays against DNA gyrase. Furthermore, when ciprofloxacin is attached to a linker there is an attenuation of activity. Strikingly, when a simple coumarin is joined to ciprofloxacin, via a linker there is a restoration of activity. We show DNA gyrase inhibition is via cleavage stabilisation. Moreover, we demonstrate activity is related to the coumarin structure and not the presence of an aromatic ring.