In Vitro Anti-Toxoplasma gondii Activity Evaluation of a New Series of Quinazolin-4(3H)-one Derivatives

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Toxoplasmosis poses a significant threat to human health, causing severe eye and brain diseases, particularly in immunocompromised individuals and pregnant women.
• Current treatments for toxoplasmosis have limitations, including multiple side effects and prolonged dosing periods, necessitating the development of more effective and less toxic alternatives.

Purpose of the Study:

• To synthesize and evaluate a series of 2-(piperazin-1-yl)quinazolin-4(3H)-one derivatives for their in vitro activity against Toxoplasma gondii tachyzoites.
• To identify novel compounds with high efficacy and low toxicity for the treatment of toxoplasmosis.

Main Methods:

• Synthesis of 26 novel 2-(piperazin-1-yl)quinazolin-4(3H)-one derivatives.
• In vitro anti-Toxoplasma gondii activity screening using cell phenotype assays.
• Structure-activity relationship (SAR) analysis to guide compound optimization.
• Molecular docking studies to predict binding interactions with the target enzyme TgCDPK1.

Main Results:

• Two compounds, 8w and 8x, demonstrated significant efficacy against T. gondii tachyzoites, with IC50 values of 4 μM and 3 μM, respectively.
• The presence of a diaryl ether moiety in the piperazine side chain was associated with potent anti-parasitic activity.
• SAR studies indicated that hydrophobic aryl groups on the side chain are favorable for enhanced activity.
• Molecular docking revealed high affinity of compounds 8w and 8x to TgCDPK1, primarily through interactions within the ATP-binding cleft's hydrophobic pocket.

Conclusions:

• The synthesized 2-(piperazin-1-yl)quinazolin-4(3H)-one derivatives, particularly 8w and 8x, represent promising leads for the development of new anti-toxoplasmosis agents.
• These compounds exhibit potent in vitro activity and favorable interactions with the TgCDPK1 target, suggesting a viable therapeutic strategy.
• Further investigation into the mechanism of action and in vivo efficacy is warranted to advance these compounds towards clinical application.