Comment on: Target-based discovery of a broad-spectrum flukicide

Triclabendazole (TCBZ) is used as a highly potent drug against the liver flukes of the genus Fasciola.It acts by disrupting microtubule formation and interfering with energy metabolism.Its targeted and specific action against these parasites makes it an excellent candidate for treating fascioliasis.However, emerging reports indicate a growing resistance to TCBZ among Fasciola populations.In contrast, praziquantel (PZQ) is ineffective against Fasciola due to a single amino acid alteration in the target protein, a transient receptor potential ion channel of the melastatin family (TRPM PZQ ) within these species [1,2].A recent study by Marchant and colleagues [3] has identified a new broad-spectrum drug, a benzamidoquinazolinone analog (BZQ), which successfully activates TRPM PZQ ion channels across various parasitic flukes, including F. hepatica, a species resistant to PZQ.The discovery of BZQ represents a significant breakthrough as it serves as a potent, broad-spectrum activator of TRPM PZQ ion channels in parasitic flukes.Notably, BZQ was shown to be effective against both S. mansoni and F. hepatica in ex vivo studies, inducing rapid paralysis and causing tegumental damage similar to the effects of PZQ on schistosomes.Additionally, BZQ demonstrated efficacy comparable to PZQ in reducing worm burden in a mouse model of schistosomiasis.The development of BZQ could pave the way for a new, effective treatment for trematode infections that have been resistant to current therapies, including TCBZ. Target-based discovery of a broad-spectrum flukicideQuinazolinones are known for their diverse biological activities, including antibacterial, antifungal, and anticancer properties.The authors identified that one of their 22 compounds (an N-benzamidoquinazolinone) is a potent agonist for SmTRPM PZQ (EC 50 = 1.15 M) and FhTRPM PZQ (EC 50 = 3.0 M), highlighting its effectiveness against both these targets.To further optimize the activity of the N-benzamidoquinazolinone scaffold, a structure-activity relationship (SAR) analysis was conducted.A series of PZQ analogs were synthesized to explore SAR, revealing stringent requirements for efficacy at TRPM PZQ .Among these, compound 20 emerged as the most potent agonist, with an EC 50 of 0.09 M for SmTRPM PZQ .Electrophysiological recordings confirmed that BZQ is a more potent activator of both SmTRPM PZQ and FhTRPM PZQ compared to compound 1, with EC 50 values of 0.11 M and 0.27 M, respectively.BZQ induced single-channel activity in both TRPM PZQ variants, demonstrating its ability to activate the channels effectively.Notably, BZQ caused rapid contraction and paralysis in S. mansoni.At the same time, it effectively induced muscle contraction and surface damage in F. hepatica, unlike PZQ, which showed no effect on the liver fluke.BZQ exhibited high potency against various Fasciola species, with IC 50 values of 1.12 M for immature and 2.72 M for adult F. hepatica in motility assays, indicating its potential as a more effective