Designing Trifluoromethyl Pyrazolones for Selective Molluscicidal Activity Against <i>Monacha cartusiana</i>: Toward Sustainable Land Snail Control

Terrestrial gastropods are significant agricultural pests and disease carriers, posing major challenges to farm crops and various agricultural domains. Synthetic pesticides remain the primary method of pest control, but rising resistance and harmful effects on nontarget species highlight the urgent need for new, safer alternatives. Herrin, we report on the synthesis and the evaluation of a series of 5-trifluoromethyl-phenylpyrazolones against <i>Monacha cartusiana</i> (O. F. Müller, 1774) snails as potential molluscicidal agents. The newly synthesized 5-trifluoromethyl-phenyl pyrazolones derivatives <b>11-24</b> were characterized based on ¹H NMR, ¹³C-APT and ¹⁹F- NMR spectra as well as mass spectroscopy. Compounds <b>11</b>, <b>16</b>, <b>17</b> and <b>18</b> demonstrated potent anti-<i>M. cartusiana</i> activities, with <b>16</b> exhibiting the highest lethal activity (LC₅₀ = 0.58 mg/mL), surpassing the current standard, methomyl (LC₅₀ = 2.28 mg/mL). Significant increase in liver transaminase enzymes (AST and ALT), acetylcholinesterase (AChE), along with reduction in total carbohydrates and lipids, were observed after the treatment of <i>M. cartusiana</i> snails with compounds <b>11</b>, <b>16</b>, <b>17</b>, and <b>18</b> at the LC₅₀ values. Histopathological analysis of the digestive glands of treated snails revealed induced cellular damage, with the greatest structural cellular integrity loss and functional impairment observed for compound <b>16</b>. Additionally, typical CNS toxicity symptoms, including paralysis and excessive fluid secretion, suggest a dual mode of action: gastrointestinal toxicity and GABA_A-glutamate chloride ion channel (GluCl) antagonism. Homology modeling using the 3RHW (<i>Caenorhabditis elegans</i> (Maupas, 1900)) template and a GluCl ζ-subunit sequence were used to generate a 3RHW- ζ chimera for virtual screening. Additionally, induced fit docking (IFD) studies using GABA_A GluCl structures were used to generate trifluoromethylphenylpyrazole-compatible binding pockets. Docking scores derived from these models were found to support the observed molluscicidal activity. These findings identified potent 4-substituted-5-trifluoromethylphenylpyrazolones as potential useful candidates for safer, effective molluscicides.