Novel antipyrine substituted 4-thiazolidinones: Synthesis, DNA binding and topoisomerase inhibition activities, and in-silico studies

Abstract

In this study, we report the synthesis and characterization of novel 4-thiazolidinones containing antipyrine (3a-e) derived from the starting compounds of Schiff bases (2a-e). The Schiff bases were synthesized using aldehydes of natural origin, such as citronellal, cuminaldehyde, 2-thiazolecarboxaldehyde, 5-methylfurfural, and syringaldehyde. Their FTIR spectra revealed the enol- tautomeric solid-state structures of compounds 3b and 3d. The pUC18 plasmid DNA binding specificity and capacity of the compounds to catalytically generate topoisomerase I activity were also examined using agarose gel electrophoresis. The compounds induced changes in DNA mobility and showed a topoisomerase I inhibitory effect at all doses. 4-Thiazolidinones had a higher affinity in DNA and topoisomerase I than the Schiff bases. DNA binding and topoisomerase I activities were most effective at low concentration (6 μM) for the compounds of Schiff bases 2a, d, and 4-thiazolidinones 3a, d. Furthermore, this study presents computational methods for addressing the molecules’ drug-like properties. 2a, d, and 3a, d Compounds were used as representative of the most bioactive among the newly synthesized molecules in in-silico studies. The web tools of ADMETlab, SwissADME, OSIRIS, and the BOILED-Egg method were used to conduct in-silico biological studies involving ADME prediction, BBB penetration, gastrointestinal absorption, and toxicity studies. The ADME profile of the query compounds gets within the range of applicability and is at an appropriate level. In-silico studies revealed that compounds 2a, d, and 3a, d are neither hERG blockers nor AMES toxic. However, compounds 2a and 3a have hepatotoxicity.