Synthesis and Antiparasitic Action of 2-aryl-3-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-4H-1,3-benzothiazin-4-ones

Haemonchus contortus (H. contortus) is a gastrointestinal nematode that causes significant economic losses in sheep farming. The increasing resistance to conventional anthelmintics such as albendazole, levamisole, and ivermectin highlights the urgent need for new therapeutic agents. In this context, the present work reports, for the first time, the synthesis of 1,3-benzothiazin-4-ones with ovicidal activity against H. contortus.

Compounds 5a-d were synthesized via a one-pot reaction between 1-(2-aminoethyl) pyrrolidine 1, substituted arylaldehydes 2 (4-CH3 2a, 2-NO2 2b, 4-NO2 2c, 4-OCH3 2d), and thiosalicylic acid 3. Structural characterization was confirmed by ¹H and 13C NMR spectroscopy and GC-MS analysis. Anthelmintic activity was assessed through H. contortus egg-hatching inhibition assays. All compounds exhibited measurable inhibitory effects, at least at the highest concentrations tested (40, 20, 10, 5, 2.5, and 1.25 μg·mL⁸¹).

These compounds were obtained in moderate yields (31-54%), and their structures were confirmed by GC-MS and 1D/2D NMR data. Formation of the benzothiazinone ring was supported by the characteristic H2 and C2 signals (δ 5.93-6.08 and 61.6-62.3 ppm), along with the lactam carbonyl resonance at δ 163.7-164.1 ppm.

Four novel 1,3-benzothiazin-4-ones (5a-d) were synthesized via a threecomponent one-pot reaction in moderate yields. The electronic and positional effects of the aryl substituents may influence the ovicidal activity against H. contortus, although these hypotheses require experimental validation in future mechanistic studies. All molecules displayed activity at concentrations lower than those required for the reference drug, thiabendazole (20 μg·mL⁸¹; 99.103 μM).

The results indicate that these benzothiazinone derivatives represent promising scaffolds for the development of new anthelmintic candidates. Compound 5c - 2-(2- nitrophenyl)-3-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihydro-4H-1,3-benzothiazine-4-one - exhibited the highest activity at 40 μg·mL⁸¹ (104.3 μM), inhibiting egg hatching by 39-45%.