Identification of environmentally biodegradable scaffolds for the benign design of quinolones and related substances

Many micropollutants, such as pharmaceuticals and other chemicals, are present globally in the aquatic environment. During effluent treatment and in the environment, transformations result in new chemicals of often unknown structure, fate, and toxicity. The design of chemicals, that can be fully mineralized or broken down into non-hazardous fragments, is considered a green chem-istry approach avoiding such problems from the very beginning (benign by design). N -heterocycles are central lead scaffolds for many important chemicals and pharmaceuticals such as quinolines, isoquinolines, quinolones, fluoroquinolones, naphthyridones, and quinazolinones. Understanding their environmental biodegradability is mandatory for the design of greener de-rivatives. While the biodegradability of simple quinolines has already been reported in the litera-ture, information on more complex azaarenes and other N-heterocycles is rather scarce.The goal of this study was to investigate the ready biodegradability of several N-heterocycles to identify biodegradable lead scaffolds. LC-HRMS studies were performed to identify possible metabolites. Out of the 84 tested substances, only 14 were readily biodegradable in either the closed bottle test (OECD 301D) or the manometric respiratory test (OECD 301F). Hydroxylation at the C2 position increased the biodegradation level of the quinolines generally and tolerated even fluorine in the molecule. Moreover, 4-oxo-1,4-dihydroquinoline-3-carboxylic acid has been tested as readily biodegradable. It is an important bioactive lead scaffold with many different ap-plications, i.e., in antibiotics. All other quinolones containing the beta-keto-carboxylic acid moiety were persistent, including their bioisosteres. The identified biodegradable scaffolds can be used to design new environmentally biodegradable molecules following green fragment-based design.

Automated summary

Many micropollutants, including pharmaceuticals and other chemicals, are found worldwide in aquatic environments. Transformations during effluent treatment and in the environment can lead to the formation of new chemicals with unknown structure, fate, and toxicity. Designing chemicals that can be fully mineralized or broken down into non-hazardous fragments is considered a green chemistry approach to prevent these issues from the beginning. This study focused on investigating the biodegradability of various N-heterocycles to identify environmentally friendly lead scaffolds, and found that only a small portion of the tested substances were readily biodegradable.