A blending-based therapeutic strategy using diaryl dichalcogenides and ivermectin against gastrointestinal nematodes of small ruminants

Abstract

Gastrointestinal nematode (GIN) infections have a significant impact on small ruminants worldwide. The widespread multidrug resistance in nematodes has led to the investigation of novel compounds. The present study aimed to investigate the in vitro effect of recently synthesized diaryl dichalcogenides: diacetal ditelluride (LQ07), diacetal diselenide (LQ62), and diacetyl diselenide (LQ68), individually and in combination with ivermectin (IVM) against GIN, predominantly Haemonchus contortus (78 %). The compounds were tested through the egg hatch (EHT) and the larval migration inhibition test (LMIT). Cell death and viability assays were employed to investigate the mode of action of the compounds on treated infective third-stage free-living larvae (L3) with propidium iodide (PI). A concentration-dependent ovicidal and larvicidal effect was observed for all tested compounds. The egg hatch inhibitory effect was more potent for LQ68 and IVM, with an inhibitory concentration of 50 % (IC₅₀) of 0.47 mmol L⁻¹ and 0.44 mmol L⁻¹, respectively. LQ62 exhibited the most potent larvicidal activity (IC₅₀ of 0.90 mmol L⁻¹). Mechanistic experiments revealed no significant alterations in the levels of reactive oxygen and nitric oxide species. Even though PI demonstrated distinct patterns of transcuticular diffusion and identified the most susceptible tissues for each compound. Variations in the compounds’ activity depended on the developmental stage of the parasites. Blending IVM with organochalcogen compounds (OCs) showed an additive effect of up to 34 %, contributing to developing novel blending-based therapeutic strategies. A distinctive mechanism of action of the OCs can also be an advantage in controlling multidrug-resistant parasites of ruminants.