Novel 1H-1,2,3-Triazole Derivatives of Praziquantel with TRPMPZQ Modulatory Activity and Antiparasitic Effects on Larvae, Juvenile, and Adult Worms of Schistosoma mansoni.

The identification of a transient receptor potential ion channel of the melastatin subfamily activated by praziquantel (TRPMPZQ) has opened new opportunities for target-based schistosomiasis drug discovery. In this study, eight new 1H-1,2,3-triazole derivatives of praziquantel (PZQ), and their synthetic intermediates, were prepared and evaluated for their schistosomicidal activity on schistosomula, juvenile, and adult Schistosoma mansoni. Their ability to activate schistosome wild-type (WT) and mutant TRPMPZQ (Sm.TRPMPZQ), as well as a schistosome TRPM channel activated by meclonazepam (Sm.TRPMMCLZ), and TRPMPZQ from Fasciola hepatica (Fh.TRPMPZQ) and Echinococcus granulosus (Eg.TRPMPZQ), was also assessed. Initial screening of schistosomula identified six compounds significantly affecting parasite motility/morphology at 25-50 μM. Compounds 3, 4, and 5e were active against juveniles by two orthogonal methods. All compounds impaired adult worm motility, with 4 being the most potent in males (EC50: 1.3-2.3 μM) and 5e being the most potent in females (EC50: 3.1-3.9 μM). Compound 5e showed the highest selectivity indexes (75 for females and 155 for males) when compared with the HepG2 human cell line. Compounds 2, 3, 4, and 5e activated WT (EC50: 0.9-13.5 μM), and mutant Sm.TRPMPZQ showing a similar activation profile to PZQ. Like PZQ, they did not activate Fh.TRPMPZQ or Sm.TRPMMCLZ at the tested concentrations but activated Eg.TRPMPZQ with similar potencies to Sm.TRPMPZQ. Molecular modeling studies suggest that the PZQ binding site on Sm.TRPMPZQ may accommodate extended substituents on position 9 of the pyrazinoisoquinoline ring due to a conformational flexibility of the Y1517 side chain. This feature could be explored to design new PZQ analogues with improved drug metabolism and pharmacokinetic properties.