A Perspective on Thiazolidinone Scaffold Development as a New Therapeutic Strategy for Toxoplasmosis

Abstract

Toxoplasma gondii is one of the most successful parasites due to its ability to infect a wide variety of warm-blooded animals. It is estimated that one-third of the world's population is latently infected. The generic therapy for toxoplasmosis has been a combination of antifolates such as pyrimethamine or trimethoprim with either sulfadiazine or antibiotics such as clindamycin with a combination with leucovorin to prevent hematologic toxicity. This therapy shows limitations such as drug intolerance, low bioavailability or drug resistance by the parasite. There is a need for the development of new molecules with the capacity to block any stage of the parasite's life cycle in humans or in a different type of hosts. Heterocyclic compounds are promissory drugs due to its reported biological activity; for this reason, thiazolidinone and its derivatives are presented as a new alternative not only for its inhibitory activity against the parasite but also for its high selectivity-level with high therapeutic index. Thiazolidinones are an important scaffold known to be associated with anticancer, antibacterial, antifungal, antiviral, antioxidant, and antidiabetic activities. The molecule possesses an imidazole ring that has been described as an antiprotozoal agent with antiparasitic properties and less toxicity. Thiazolidinone derivatives have been reportedly as building blocks in organic chemistry and as scaffolds for drug discovery. Here we present a perspective of how structural modifications of the thiazolidinone core could generate new compounds with high anti-parasitic effect and less toxic results.

In vitro evaluation of new 4-thiazolidinones on invasion and growth of Toxoplasma gondii

“…We have carried out molecular docking to describe a possible binding mode of our best compounds in the parasite T. gondii . We use proteins for which some reports suggest that they may act as a target for compounds derived from the 4-thiazolidinone nucleus ( Molina et al, 2018 ; Rocha-Roa et al, 2018 ). The results for molecular dockings ( Table 2 ) suggest that compounds 1B , 2B and 3B would have a greater affinity (more negative value) for Tg CDPK1 protein than for Tg ROP18.…”

“…Molecular docking calculations were carried out to obtain the possible binding mode of the best compounds with two molecular targets from T. gondii , the Calcium-Dependent Protein Kinase 1 ( Tg CDPK1) with PDB code 4JBV and the ROP18 kinase ( Tg ROP18) with PDB code 4JRN . Previously, we suggest that these proteins may act as a target for compounds derived from the 4-thiazolidinone nucleus ( Molina et al, 2018 ; Rocha-Roa et al, 2018 ). The three-dimensional structure of the compounds was drawn and optimized using Avogadro software ( Hanwell et al, 2012 ).…”

“…Modifications on positions 2 and 5 of the 4-thiazolidinone ring have been considered as a reference point to enhance the biological activity of compounds that contain this core. Additionally, the moiety hydrazone conserved in this position of the heterocyclic ring has demonstrated to enhance the effect of the 4-thiazolidinones against T. gondii , since the molecules that have this group showed high effectiveness on the host cell invasion and replication of the parasite with low cytotoxicity, to concentrations in the micro molar scale ( Hamama et al, 2009 ; Rocha-Roa et al, 2018 ). On the other hand, the 2,5-disubstituted 1,3-thiazole nucleus could be an important pharmacological requirement, so the position N-3 in the 4-thiazolidinones would be important as an electron donor region ( D'Ascenzio et al, 2014 ; Carradori et al, 2017 ).…”