Mechanism-DrivenDesign of Isothiazolinone Alternatives

The extensive application of isothiazolinones has led to widespread pollution and poses a threat to ecological health, creating a need for the development of green alternatives. With the objective of devising chemical design strategies, we initially explored the structure–activity relationship (SAR) and structure–toxicity relationship (STR) of isothiazolinones. By comparing the antimicrobial activities of commercial isothiazolinone analogues, chlorine substitutions were identified as key determinants of pathogen growth inhibition potency. The variability of reproductive endocrine-disrupting toxicity was primarily driven by the length of the alkyl carbon chain, based on interactions with molecular initiating events and disturbances in sex hormones. Inspired by the SAR and STR guidelines, two new isothiazolinones (i.e., Target 1 and Target 2) were designed and synthesized. Compared to the commercial analogue dichloro-octylisothiazolinone, Target 1, which has a shorter alkyl chain and the same chlorine count, demonstrated slightly stronger antimicrobial activity, significantly lower endocrine-disrupting toxicity, and longer environmental persistence. Meanwhile, Target 2, containing ether bonds within a shorter alkyl chain and the same chlorine count, exhibited weaker antimicrobial activity, significantly lower endocrine-disrupting toxicity, and slightly longer environmental persistence. Overall, this study proposes a mechanism-driven design strategy for isothiazolinone alternatives that successfully reduces endocrine toxicity while maintaining antimicrobial activity.