Green Synthesis of Thiazolidine-2,4-dione Derivatives and Their Lipoxygenase Inhibition Activity With QSAR and Molecular Docking Studies

Abstract

Thiazolidinediones are five-membered, heterocyclic compounds that possess a number of pharmacological activities such as antihyperglycemic, antitumor, antiarthritic, anti-inflammatory, and antimicrobial. Conventional methods for their synthesis are often environmentally unacceptable due to the utilization of various catalysts and organic solvents. In this study, deep eutectic solvents were used in the synthesis of thiazolidinedione derivatives that acted as both solvents and catalysts. Initially, a screening of 20 choline chloride-based deep eutectic solvents for thiazolidinedione synthesis, via Knoevenagel condensation, was performed in order to find the most suitable solvent. Deep eutectic solvent, choline chloride, N-methylurea, was proven to be the best for further synthesis of 19 thiazolidinedione derivatives. Synthesized thiazolidinediones are obtained in yields from 21.49% to 90.90%. The synthesized compounds were tested for the inhibition of lipid peroxidation as well as for the inhibition of soy lipoxygenase enzyme activity. The antioxidant activity of the compounds was also determined by the ABTS and DPPH methods. Compounds showed lipoxygenase inhibition in the range from 7.7% to 76.3%. Quantitative structure–activity relationship model (R2 = 0.88; Q2loo = 0.77; F = 33.69) for the inhibition of soybean lipoxygenase was obtained with descriptors Mor29m, G2u, and MAXDP. The molecular docking confirms experimentally obtained results, finding the binding affinity and interactions with the active sites of soybean LOX-3.

L‐proline‐based DES in Knoevenagel synthesis of arylidene rhodanines, thiazolidine‐2,4‐diones, and barbituric derivatives

“…Compounds 8-11 have recently been synthesized in another DES by Loncaric et al [25]. The corresponding aldehydes were reacted with TZD in ChCl:N-methylurea (1:3) at 80 C until completion of the reaction monitored by TLC (precise times were not indicated).…”

“…It has been shown that glycerol can form a strong hydrogen bonding network in a DES, being here an H‐bond donor and L‐proline being an H bond acceptor [32, 33]. A plausible mechanism often proposed by the authors [25, 27–31] involves the activation of carbonyl group by the DES (Scheme 1). Another point to be considered is the fact that it is well established that L‐proline forms iminium ion with aldehyde to catalyze Knoevenagel condensation [34, 35] (Scheme 2).…”

“…(Z)-5-(3-hydroxy-4-methoxybenzylidene)-1,3-thiazolidin-2,4-dione(10) [25] Light yellow solid obtained after 1 h at 90 C (microwave) in 69% yield (87 mg). Mp = 256 C.1 H-NMR (DMSO-d 6 , 400 MHz): δ (ppm) 9.55 (br s, 1H, OH), 7.63 (s, 1H, =CH), 7.06 (m, 2H), 7.01 (s, 1H), 3.82 (s, 3H, OCH 3 ).…”

“…(Z)-5-(3-hydroxybenzylidene)-1,3-thiazolidin-2,4-dione(11) [25] Beige solid obtained after 22 h at 60 C in 71% yield and 30 min at 90 C (microwave) in 64% yield (70 mg). Mp = 266 C 1.…”

Electrochemical reduction of 5-benzylidene thiazolidine-2,4-diones: a greener approach to the preparation of glitazone APIs

“…14 Thiazolidine-2,4-diones are an important class of heterocycles that present a diverse range of biological activities. 15,16 These heterocycles are of particular importance in the development of novel anti-diabetic agents. Glitazones consist of a class of active pharmaceutical ingredients (APIs), with a thiazolidine-2,4dione core in their structure, which are widely used for the treatment of type 2 diabetes.…”