Novel indole-based marinoquinolines as promising candidates against Toxoplasma gondii

Toxoplasma gondii, an obligate intracellular parasite, infects approximately one-third of the global population, making toxoplasmosis a significant public health concern. The current treatment - typically a combination of pyrimethamine and sulfadiazine - is limited to the acute phase of infection, and it often causes allergic reactions and severe side effects. Marinoquinolines (MQs), a class of compounds originally isolated from marine microorganisms, have exhibited promising pharmacological properties including anti-T. gondii activity in both in vitro and in vivo models. Addressing the need for more effective and safer therapies, this study investigated novel synthetic MQ derivatives for their inhibitory effects against the parasite. Seventeen MQs were synthesized with indole moieties incorporated into the marinoquinoline scaffold. All compounds were evaluated for half-maximal effective concentration (EC₅₀) against intracellular T. gondii tachyzoites (RH strain) and half-maximal cytotoxic concentration (CC₅₀) in human foreskin fibroblasts (HFFs). Selectivity indices (SICC₅₀/EC₅₀) were calculated. Two derivatives showed outstanding selectivity with SI values of 516 and 751 along with favourable in silico ADMET profiles including high gastrointestinal absorption, blood-brain barrier permeability, and no predicted toxicity. These findings support the potential of indole-based MQs as promising candidates for further preclinical development in the treatment of toxoplasmosis.