Proton-pumping-ATPase-targeted antifungal activity of cinnamaldehyde based sulfonyl tetrazoles

Azoles are generally fungistatic, and resistance to fluconazole is emerging in several fungal pathogens. We designed a series of cinnamaldehyde based sulfonyl tetrazole derivatives. To further explore the antifungal activity, in vitro studies were conducted against 60 clinical isolates and 6 standard laboratory strains of Candida. The rapid irreversible action of these compounds on fungal cells suggested a membrane-located target for their action. Results obtained indicate plasma membrane H(+)-ATPase as site of action of the synthesized compounds. Inhibition of H(+)-ATPase leads to intracellular acidification and cell death. Presence of chloro and nitro groups on the sulfonyl pendant has been demonstrated to be a key structural element of antifungal potency. SEM micrographs of treated Candida cells showed severe cell breakage and alterations in morphology.