Trypanothione reductase inhibitors: a comprehensive review of in silico insights, bioactivity, and structure-activity relationships.

Neglected tropical diseases resulting from infection by kinetoplastid parasites constitute a significant global health challenge on account of issues related to toxicity, drug resistance, and availability of therapeutic agents. Among the potential molecular targets identified, trypanothione reductase, a parasite-specific enzyme involved in maintaining redox balance, has emerged as an attractive target for antiparasitic drug discovery. This paper presents recent progress in designing trypanothione reductase inhibitors through scaffold-based strategies and includes several scaffolds, including nitrogenous heterocycles, sulfur-selenium-based scaffolds, chalcones, quinones, multi-heterocyclic fusions, organometallics, and peptidomimetic derivatives. The inhibitors act in several ways, including competitive, and mixed inhibition, binding to the active site, blocking the dimer interface, generating redox imbalance, and inducing ROS-mediated parasite death. Structure-activity relationship research has revealed that cationic centers, hydrophobic moieties, optimum linkers, bulky aromatic rings, and redox-active groups are critical factors for improved potency and selectivity. Although tremendous progress has been made, challenges such as selectivity, pharmacokinetics, and the transfer from enzyme inhibition to cellular efficacy remain difficult. This review provides vital insights into the rational design and development of novel, selective, trypanothione reductase-targeted inhibitors.