Design, Synthesis, and Structure–Activity Relationship of 2-(Piperazin-1-yl)quinazolin-4(3H)-one Derivatives as Active Agents against Toxoplasma gondii

A novel series of quinazolin-4(3H)-one derivatives were synthesized using a hybridization strategy that combined the quinazolin-4(3H)-one scaffold, the diarylether fragment, and the piperazine ring. The in vitro activity evaluation of these compounds against Toxoplasma gondii demonstrated that most of this series of compounds showed moderate to good effectiveness, with IC₅₀ values ranging from 5.94 to 102.2 μM. Among the synthesized derivatives, compounds 11 and 18 emerged as the most potent inhibitors, significantly reducing the replication rate of T. gondii with IC₅₀ values of 6.33 and 5.94 μM, as well as demonstrated low cytotoxicity with CC₅₀ values of 285 and 59.2 μM, respectively. The structure–activity relationship investigation indicates that the substituent at the N-3 position of the quinazolin-4(3H)-one is important for anti-T. gondii activity while the replacements at the phenyl moiety of the quinazolin-4(3H)-one and at the diarylether fragment cannot improve activity. The invasion and proliferation assay demonstrated that compound 11 could inhibit both parasite invasion and replication ability. Further investigation of the in vitro efficacy revealed irreversible action of compound 11 against T. gondii. In vivo investigations conducted within a murine model of acute infection revealed that compounds 11 and 18 exhibited a remarkable capacity to significantly diminish the parasitic load in comparison to the control group while also extending the survival duration of the subjects. These results underscore the potential of compound 11 as a candidate for further exploration in the development of antitoxoplasmosis therapies.