Benzoxaboroles Are Inhibitors of the η-Class Carbonic Anhydrase From Plasmodium falciparum

Malaria remains a major global health burden, compounded by increasing resistance to current therapies. Plasmodium falciparum carbonic anhydrase (PfaCA), a η-class metalloenzyme essential for the parasite metabolism and survival, has recently emerged as a promising antimalarial target. In this study, benzoxaborole 4 and its 6-substituted triazolyl derivatives (5-18) were evaluated for PfaCA inhibition and in vitro antiplasmodial activity against the P. falciparum 3D7 strain. Compounds 13 and 14 emerged as the most potent inhibitors (K_I = 0.45 and 0.43 µM, respectively) of the enzyme, coupled with notable antiplasmodial activity (IC₅₀ = 34 and 47 µM). Among the tested compounds, the ethyl ester 7 demonstrated the strongest antiplasmodial activity (IC₅₀ = 2.5 µM). Molecular docking studies further supported the favorable binding of active derivatives within the PfaCA active site. These findings highlight the potential of benzoxaborole-based scaffolds as a new chemotype for antimalarial drug development.