5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry

Abstract

The presented review is an attempt to summarize a huge volume of data on 5-ene-4-thiazolidinones being a widely studied class of small molecules used in modern organic and medicinal chemistry. The manuscript covers approaches to the synthesis of 5-ene-4-thiazolidinone derivatives: modification of the C5 position of the basic core; synthesis of the target compounds in the one-pot or multistage reactions or transformation of other related heterocycles. The most prominent pharmacological profiles of 5-ene derivatives of different 4-thiazolidinone subtypes belonging to hit-, lead-compounds, drug-candidates and drugs as well as the most studied targets have been discussed. Currently target compounds (especially 5-en-rhodanines) are assigned as frequent hitters or pan-assay interference compounds (PAINS) within high-throughput screening campaigns. Nevertheless, the crucial impact of the presence/nature of C5 substituent (namely 5-ene) on the pharmacological effects of 5-ene-4-thiazolidinones was confirmed by the numerous listed findings from the original articles. The main directions for active 5-ene-4-thiazolidinones optimization have been shown: i) complication of the fragment in the C5 position; ii) introduction of the substituents in the N3 position (especially fragments with carboxylic group or its derivatives); iii) annealing in complex heterocyclic systems; iv) combination with other pharmacologically attractive fragments within hybrid pharmacophore approach. Moreover, the utilization of 5-ene-4-thiazolidinones in the synthesis of complex compounds with potent pharmacological application is described. The chemical transformations cover mainly the reactions which involve the exocyclic double bond in C5 position of the main core and correspond to the abovementioned direction of the 5-ene-4-thiazolidinone modification.

Rhodanine‐Furan Bis‐Heterocyclic Frameworks Synthesis via Green One‐Pot Sequential Six‐Component Reactions: A Synthetic and Computational Study

“…The 1 H NMR spectrum of 7 c showed two singlets for the methyl groups of the tert-butyl and isopropyl amine (δH = , which are related to the diastereotopic hydrogens of CH 2 CO 2 H and the SCH, respectively, two singlets for two methoxy groups (δH = 3.77 and 3.84 ppm, 6H), a multiplet for methine proton of isopropyl amine (δH = 5.19-5.26 ppm, 1H) and a singlet for NH (δH = 6.94 ppm). The 13 C NMR spectrum of compound 7 c exhibited the presence of two amide carbonyls and two ester carbonyls between 162 and 176 ppm and the most prominent peaks include the peak of C=S in 202 ppm accompanied by 15 distinct resonances in agreement with the desired product. Also, due to the confirmed conformational rotation of amide bonds which caused to two rotamers, duplicate peaks with same coupling constants were observed in some 1 H and 13 C NMR spectra.…”

“…The synthesized products were characterized using of IR, 1 H NMR, 13 C NMR and mass spectral analysis data. For instance, the peak at m/z: 541 for compound 7 c represents the molecular ion, which is consistent with the 1:1:1:1:2 adduct of isopropylamine, carbon disulfide, maleic anhydride, DMAD and tert-butyl isocyanide.…”

“…Furthermore, functionalized furans represent synthetic scaffolds which are abundant in biologically active molecules, for example, calicogorgins, α‐clausenan accompanied by furan fatty acids . Also, rhodanines, also known as 2‐thioxo‐1,3‐thiazolidin‐4‐one are potential targets in many different areas of medicinal chemistry and pharmacological industries for the preparation of anti‐diabetics, antimicrobial, antitubercular agents and herbicides . Hence, according to an old proverb, “In unity there is a strength” the combination of these pharmacophores (furans and rhodanines) in the one structure could be an ideal candidate for the development of new pharmacologically active scaffolds through the union of two MCRs approach.…”

“…[9] Also, rhodanines, also known as 2-thioxo-1,3-thiazolidin-4-one are potential targets in many different areas of medicinal chemistry [10] and pharmacological industries for the preparation of antidiabetics, [11] antimicrobial, [12] antitubercular agents and herbicides. [13] Hence, according to an old proverb, "In unity there is a strength" the combination of these pharmacophores (furans and rhodanines) in the one structure could be an ideal candidate for the development of new pharmacologically active scaffolds through the union of two MCRs approach. In Figure 1, several pharmaceutically and drug-like molecules based on rhodanine-furan bis-heterocyclic frameworks were shown that successfully used in the treatment of Alzheimer's disease, [14] Diabetes mellitus, [15] as inhibitors of RNA polymerase with antibacterial activity.…”

Thiopyrano[2,3-d]Thiazoles as New Efficient Scaffolds in Medicinal Chemistry

“…This is argued by a variety of inherent biological activity, low selectivity and the ability of 5-ylidene-4-thiazolidinones to be Michael acceptors. Despite this, rigorous selection based on SAR analysis and proved selectivity leave such compounds a «right to life» in medicinal chemistry [12][13][14]. Moreover, the objects of our review (thiopyranothiazoles) can be considered as mentioned Michael acceptors properties (Figure 1) [15][16][17].…”