2,4‐Thiazolidinedione (TZD) is a privileged and highly utilised scaffold for the development of pharmaceutically active compounds. This sulfur‐containing heterocycle is a versatile pharmacophore that confers a diverse range of pharmacological activities. TZD has been shown to exhibit biological action towards a vast range of targets interesting to medicinal chemists. In this review, we attempt to provide insight into both the historical conventional and the use of novel methodologies to synthesise the TZD core framework. Further to this, synthetic procedures utilised to substitute the TZD molecule at the activated methylene C₅ and N₃ position are reviewed. Finally, research into developing clinical agents, which act as modulators of peroxisome proliferator‐activated receptors gamma (PPARγ), protein tyrosine phosphatase 1B (PTP1B) and aldose reductase 2 (ALR2), are discussed. These are the three most targeted receptors for the treatment of diabetes mellitus (DM).

Herein, we present a synthetic compound library comprising of 13 structurally diverse heterocyclic monosquarate-amide derivatives. The compounds featured in this library were designed as potential bioisosteric replacements carboxylic acid moiety's. A good selection of the compounds presented exhibit unique molecular architecture and have shown promising results following in silico evaluation of 'druglike properties' using Swiss ADME. The research presented in this work focuses on the preparation of derivatives of 3,4-dihydroxycyclobut-3-ene-1,2-dione, a known carboxylic acid bioisostere.

Histone deacetylase 8 (HDAC8) is a clinically validated target in neuroblastoma, where isoform selective inhibition offers a strategy to suppress tumour growth while limiting off‐target toxicity. Hydroxamic acids remain the dominant zinc‐binding group (ZBG) in HDAC inhibitors but are also associated with metabolic instability, suboptimal pharmacokinetics and nonspecific metal chelation. In this study, we report the biological evaluation of a focussed library of 51 squaric acid derivatives as alternative, non‐hydroxamic HDAC inhibitors. While a subset of these compounds has been described previously in a synthetic context, their HDAC inhibitory activity and selectivity have not been reported to date. The compounds organised into four structural subfamilies were screened against HDAC8 with moderate isoform selectivity. Structure activity relationships, supported by molecular docking and in silico techniques, highlight the influence of substitution pattern, electronic properties and molecular rigidity on HDAC8 inhibition. Collectively, these findings establish squaric acid derivatives as a viable non‐hydroxamic acid scaffold for the development of selective HDAC inhibitors.

The title compound, 3-(diphenylamino)-4-ethoxycyclobut-3-ene-1,2-dione (6), was prepared by reaction of diphenylamine (2) with diethyl squarate (DES; 5) as part of our ongoing studies on monosquarate-amides. Following purification and recrystallisation, the product was isolated as a green crystalline solid. Its structure was established by spectroscopic methods, including FTIR, ¹H NMR, ¹³C NMR and HRMS, and was unambiguously confirmed by single-crystal X-ray diffraction. This work provides access to a previously unreported diphenylamino-substituted squaric acid derivative.

The title compound 3-(diphenylamino)-4-ethoxycyclobut-3-ene-1,2-dione (6), was prepared by reaction of diphenylamine (2) with diethyl squarate (DES; 5) as part of our ongoing studies on monosquarate-amides. Following purification and recrystallisation, the product was isolated as a green crystalline solid. Its structure was established by spectroscopic methods including: FTIR, ¹H NMR, ¹³C NMR and HRMS and was unambiguously confirmed by single crystal X-ray diffraction. This work provides access to a previously unreported diphenylamino substituted squaric acid derivative.

Monosquarate-amides contain four-non protonated carbon environments that can be challenging to observe by routine ¹³C NMR spectroscopy. Using 3-((4-Bromobenzyl)(methyl)amino)-4-ethoxycyclobut-3-ene-1,2-dione as a representative example, the effects of scan number, acquisition temperature and relaxation delay were investigated systematically. Increased signal averaging improved sensitivity, while elevated temperatures simplified partially resolved resonances. Longer relaxation delays afforded only modest additional benefit. Single-crystal X-ray diffraction confirmed the molecular structure and revealed a shortened N-C(squarate) bond and near-planar nitrogen geometry.