Ecotoxicity of Antivirals Used to Treat COVID-19 Patients: Analysis of Related Structural Features

Antiviral substances are considered emerging contaminants. Once released into the environment, they may affect organisms through complex and often still-unknown mechanisms. This study focuses on a class of antiviral substances with potential use in treating COVID-19 patients, aiming to identify specific structural characteristics that significantly contribute to their ecotoxicity. An empirical approach called quantitative structure–activity relationship (QSAR) was used for this purpose. The study examined 13 antiviral substances: atazanavir, daclatasvir, darunavir, emtricitabine, favipiravir, lopinavir, nirmatrelvir, oseltamivir, remdesivir, ribavirin, ritonavir, and sofosbuvir. The ecotoxicity of these antivirals was assessed using three tests: the Aliivibrio fischeri test, the Chlorella sp. test, and the Pseudomonas putida test. These three microorganisms represent different trophic levels in aquatic and soil ecosystems. Ecotoxicity was expressed as EC20 and EC50, and these values served as the dependent variables in the QSAR models. A large set of numerical descriptors calculated from the molecular structures of the antivirals was used as an independent variable. EC20-based QSAR models offer insight into the effects of antivirals under sub-lethal exposure conditions. The results indicated that sub-lethal exposure in Aliivibrio fischeri was associated with favorable electronic properties and compact structures that promote cellular accumulation, while long-range fragments reduced toxicity. In Chlorella sp., sub-lethal exposure was driven by optimal molecular size, chain length, and specific electronic groups enabling cell penetration and biochemical inhibition. For sub-lethal exposure in P. putida, lipophilicity and reactive group geometry enhanced toxicity, while high short-range polarity mitigated it by limiting membrane permeability. Acute toxicity patterns showed similar trade-offs: strong electronic reactivity increased potency, but steric bulk, long-range polarity, or unfavorable mass distribution frequently restricted bioavailability and reduced toxic effects. Overall, the models demonstrated that antiviral toxicity results from a balance of electronic activity, structural accessibility, and physicochemical constraints, providing a mechanistic basis for predicting the environmental risk of selected antiviral substances.