Synthesis and Photodecomposition Studies of Photodegradable Antibiotics and Chitin Synthase Inhibitors

Abstract

The release of bioactive compounds to the biosphere, such as chitin synthase inhibitors that are causing negative effects in non-target organisms, or antibiotic agents that contribute to increasing antimicrobial resistance, has become a major problem in recent years. To try to circumvent this, the goal of this project has been to design active compounds that degrade when exposed to light. Four photodegradable scaffolds based on the core structure 1-(arylamino)-3-arylpropan-2-ol with a nitro group in different positions on the two aromatic rings were designed, and the decomposition products were investigated. The scaffolds were functionalised to give 12 target compounds that resemble commonly used chitin synthase inhibitors, and some of them displayed promising anti-lice activity (0.001-0.1 ppt). The compounds were also tested for their antimicrobial activity (6.3-50 μM), which resulted in the discovery of four active compounds. Following decomposition, all antimicrobial activity was lost and no cytotoxicity was observed, and they represent lead compounds for further development. Synthetic attempts towards several analogues of chloramphenicol were dictated by side reactions and reactivity issues, and ended up in two analogues with no antimicrobial activity. Synthesis of an analogue of the penicillin class of antibiotics was attempted and despite great efforts, problems associated with a final deprotection step was not resolved.