Identification of Quinoline Tethered Thiadiazole/Thiazole Derivatives as Potent Tyrosinase Inhibitors With Promising Anti‐ <i>Toxoplasma gondii</i> Agents: Design, Synthesis, and Computational Analysis

Abstract

ABSTRACT Toxoplasmosis, caused by the protozoan parasite Toxoplasma gondii , remains a serious global health concern, largely because current treatments with sulfonamides and pyrimethamine are toxic and increasingly ineffective due to rising drug resistance. In response, this study describes the design, synthesis, and laboratory evaluation of novel hybrid molecules that merge a quinoline backbone with either thiadiazole (compounds 8a – e ) or thiazole (compounds 12a – d ) bioactive groups to develop safer and more effective therapies. Cytotoxicity tests on mouse (L929) and human (Hs27) fibroblast cell lines revealed distinct safety profiles: the thiadiazole hybrids ( 8a – e ) were significantly toxic to host cells, whereas the thiazole‐based versions ( 12a – d ) were much safer, with several showing no toxicity even at 250 µg/mL. When tested against T. gondii , the quinoline‐thiazole hybrids proved the most effective. Notably, 12b and 12c achieved IC 50 values of 0.40 and 0.52 µg/mL, respectively, better than the reference drug pyrimethamine (IC 50 = 0.74 µg/mL). Compound 12c emerged as the top candidate, with an excellent selectivity index (SI) of 71.0 in human Hs27 cells. Further mechanistic work showed that 12c strongly inhibits tyrosinase, a potential parasitic target. Kinetic studies revealed a mixed‐type inhibition mechanism, with an IC 50 of approximately 5 µM, 10 times more potent than kojic acid (48 µM), a standard inhibitor. Molecular docking and dynamics simulations confirmed stable binding between 12c and tyrosinase. Together, these findings underscore the therapeutic promise of the quinoline‐thiazole scaffold, particularly compound 12c , as a lead for developing targeted, low‐toxicity anti‐toxoplasmosis drugs. The results are expected to expand the existing toolkit of small molecules targeting the parasite and reinforce the importance of molecular hybridization in drug development. Additional research is needed to clarify how these compounds work and to assess their effectiveness in living organisms in order to fully unlock their potential as anti‐parasitic drugs.