Exploring the Inhibition of Toxoplasma gondii α-Carbonic Anhydrase by Sulfonamides: Insights into Potential Drug Targeting

<i>Toxoplasma gondii</i>, the causative agent of toxoplasmosis, is a protozoan parasite capable of infecting a wide range of hosts, posing significant health risks, particularly to immunocompromised individuals and congenital transmission. Current therapeutic options primarily target the active tachyzoite stage but are limited by issues such as toxicity and incomplete efficacy. As a result, there is an urgent need for alternative therapies that can selectively target parasite-specific mechanisms critical for metabolic processes and host-parasite interactions. In this context, α-carbonic anhydrase (Tg_CA), an enzyme essential for <i>T. gondii</i> survival has emerged as a promising drug target. Tg_CA was successfully expressed and purified to evaluate its susceptibility to sulfonamide-based inhibitors, represented by compounds <b>1</b>-<b>24</b> and the <b>AAZ</b>-<b>HCT</b> series. These inhibitors demonstrated a broad spectrum of activity, with KI values ranging from 17.8 to 8450 nM. Several compounds exhibited moderate to high potency against Tg_CA; however, concerns regarding selectivity arose because of the inhibition of human isoforms, particularly CA I and CA II. Thus, although some inhibitors showed strong activity against Tg_CA, optimizing selectivity remains crucial for minimizing off-target effects and improving therapeutic efficacy. Further structural modifications may enhance selectivity and advance the development of effective treatments for toxoplasmosis.