Carbonic anhydrase (CA) inhibitors represent intriguing
tools for
treating pain. This study aims at studying the pharmacological profile
of chalcogen bioisosteres of aspirin, as inhibitors of CA isoforms
(hCA I, II, IV, VII, IX, and XII). Our results show that selenoaspirin
(5) displayed markedly superior inhibitory potency across
all tested isoforms compared to thioaspirin (7) and aspirin,
with a strong selectivity against the isoform CA IX. X-ray crystallography
confirmed that both compounds bind effectively within the active site
of hCA II, revealing unique structural characteristics compared to
those of aspirin. In a preclinical model of inflammatory pain, compound 7 exhibited a longer lasting antihyperalgesic effect than
aspirin, though with a lower potency. Conversely, compound 5 exhibited both lower potency and efficacy than aspirin in reducing
pain, which entailed both adverse effects. Nevertheless, the therapeutic
potential of chalcogen-based aspirin derivatives as novel CA inhibitors
deserves to be further explored for clinical applications.