Synthesis and Multidisciplinary Preclinical Investigations of Ferrocenyl, Ruthenocenyl, and Benzyl Derivatives of Thiabendazole as New Drug Candidates against Soil-Transmitted Helminth Infections

An estimated 1.5 billion people worldwide are infected with at least one parasitic nematode species classified as soil-transmitted helminths (STHs). The recommended control strategy is to reduce morbidity using a single oral dose of the benzimidazole drugs, albendazole and mebendazole. The extensive use of benzimidazoles over the last decades has increased the risk of emerging drug resistance. Additional drawbacks, such as insufficient drug efficacy, particularly against hookworm and whipworm infections, highlight the urgent need for new and improved treatment options. In this work, we present the synthesis, characterization, and biological evaluation of four novel (organometallic and benzyl) derivatives (<b>1</b>-<b>4</b>) of the broad-spectrum anthelmintic thiabendazole. The <i>in vitro</i> evaluation of the derivatives on different life stages of five nematode species and <i>Schistosoma mansoni</i> demonstrated that the activity profile of thiabendazole could be extended. The highest activity <i>in vitro</i> was observed with benzyl derivative <b>2</b> against adult <i>Trichuris muris</i> (80% activity at 100 μM, after 72 h) compared to the parent compound thiabendazole (15% activity). Both ferrocenyl (<b>1</b> and <b>3</b>) and ruthenocenyl (<b>4</b>) derivatives demonstrated notable efficacy against adult <i>S. mansoni</i> at 50 μM. No toxicity was seen using the hepatocyte-derived carcinoma cell line HUH7 and the human neuroblastoma cell line SH-SY5Y. <i>In vivo</i> studies in the <i>Heligmosomoides polygyrus</i> mouse model revealed worm burden reductions of 61-78% following single oral doses of 100-200 mg/kg. Future derivatization efforts could focus on two separate targets: one aimed at enhancing STH activity and a second series pursuing the antischistosomal activity.