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Here we report the application of a multi-disciplinary protocol for investigating thiazolidin-4-one-based compounds as new promising anti-inflammatory agents interfering with the eicosanoid biosynthesis pathways. The workflow foresaw the generation of a focused virtual library of ∼4.2 ​× ​104 molecules featuring the thiazolidin-4-one core based on the related one-pot synthetical combinatorial route. The built library was initially screened in silico against the microsomal prostaglandin E2 synthase-1 (mPGES-1) enzyme and, afterwards, 23 selected chemical items were synthesized for the subsequent biological screening, applying the one-pot multicomponent synthetic strategy. Preliminary results highlighted the moderate ability of several tested thiazolidin-4-one-based compounds in inhibiting mPGES-1. On the other hand, further computational repurposing investigations were performed on a set of synthesized compounds, highlighting the promising binding of a several items against the soluble epoxide hydrolase (sEH) enzyme, whose inhibition leads to an increase of epoxyeicosatrienoic acids (EETs) that are anti-inflammatory mediators. Three molecules (3, 9 and 21) were able to inhibit sEH featuring IC50 values in the low micromolar range. In order to further profile their anti-inflammatory properties, additional investigations of the three identified hits highlighted their ability to inhibit 5-lipoxygenase (5-LO) and thus to interfere with leukotriene biosynthesis in neutrophils, devoid of activity against cyclooxygenases (COXs) and cytotoxic effects on human monocytes. Our results, obtained by applying a multidisciplinary approach, highlight the thiazolidin-4-one-core as a valuable template for developing novel anti-inflammatory compounds able to synergistically inhibit different targets involved in the arachidonic acid cascade.

In recent years for the development of novel anticancer hybrids with two or more pharmacophores of bioactive scaffolds to produce a single molecule by blending or linking has emerged as a simple strategy by providing an effective control on malignant process with improved biological potential. In this view, Sesamol being an active scaffold with important biological activities was modified and linked with various substitutions to afford thiazolidin-4-one derivatives. Herein, we report the synthesis, characterization of around twenty one compounds and their evaluation for antioxidant and anticancer potentials. The structures of these compounds were established by IR, 1H NMR, 13C NMR, and Mass. The compounds 1–15 were evaluated for in vitro cytotoxicity against three human lung cancer cell lines (A549, MCF-7 and HeLa), respectively. In preliminary MTT [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity studies compounds 9 and 12 were found most effective. In A549 cancer cells the CTC50 (50% of cytotoxicity inhibition) were observed at 84.27 ± 2.7 & 91.98 ± 4.2 µg/ml, respectively. Moreover, in MCF-7 and HeLa cells the CTC50 values were observed at 174.3 ± 4 4.1, 69.15 ± 3.4 and 42.90 ± 3.5, 180.77 ± 4.6 µg/ml, respectively. Compounds 9 and 12 also exhibited best DNA damage activity via cell apoptosis when screened against Human breast cancer cell lines A549 and MCF-7 when compared to standard doxorubicin. In this study, Compounds 1, 9, 11 and 12 (at concentration 100 mg/kg/body wt.) were selected for in vivo anticancer activity against Dalton’s Lymphoma Ascites bearing mice. Among the tested compounds all has shown modest antitumor activity and merited anti-cancer activity due to its cytotoxic properties when compared with standard methotrexate.

To search for potent antimycobacterial lead compounds, a new series of 3-substituted phenyl-2-(2-(substituted phenyl)thiazol-4-yl) thiazolidin-4-one (5a-t) derivatives have been synthesized by the condensation of 2-substituted phenyl thiazole-4-carbaldehyde with aromatic amine followed by cyclocondensation with thioglycolic acid. The structure of the newly synthesized 2-(thiazol-4-yl)thiazolidin-4-one derivatives were characterized by the spectroscopic analysis. The synthesized compounds were screened for antimycobacterial activity against Mycobacterium tuberculosis H37Ra (MTB) (ATCC 25177) and Mycobacterium bovis BCG (BCG, ATCC 35743). Most of the 2-(thiazol-4-yl)thiazolidin-4-one derivatives showed good to excellent antimycobacterial activity against both the Mtb strains. Nine derivatives 5c, 5g, 5j, 5m, 5n, 5o, 5p, 5s, and 5t showed excellent activity against M. bovis BCG with MIC 4.43 to 24.04 μM were further evaluated for the cytotoxicity activity against HeLa A549, and HCT-116 cell lines and showed no significant cytotoxic activity at the maximum concentration evaluated. The potential antimycobacterial activities enforced that the thiazolyl-thiazolidin-4-one derivatives could lead to compounds that could treat tuberculosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A new set of derivatives bearing pyrazole-methylenehydrazono-thiazolidinone scaffold 4-23 was designed, synthesized and confirmed by different spectroscopic means and elemental analyses. In-vivo anti-inflammatory and ulcerogenic evaluation was performed for all the newly synthesized derivatives using indomethacin, celecoxib and diclofenac as standard drugs. The compounds 5, 10, 15, 17, 21, 22 appeared to be the most promising candidates producing rapid onset and long duration of anti-inflammatory activity as well as promising GIT safety profile. Furthermore, analgesic evaluation revealed that the compounds 5, 10, 15 and 22 produced potent and long acting analgesia accompanied with significant inhibition of the inflammatory cytokine TNF-α level in comparison with the standard drugs. Molecular docking study of the latter derivatives was also carried out to rationalize their binding affinities and their modes of interactions with the active site of TNF-α., (Copyright © 2021. Published by Elsevier Inc.)

This study represents the synthetic approaches of a new set of 2-(((3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazono)-5-(aryl)thiazolidin-4-one derivatives 4-22 aiming to obtain new antiproliferative candidates against human cervix carcinoma cells (Hela) of EGFR PK inhibiting potency. The cancer cells represented promising sensitivity towards the compounds 6, 7, 11, 13, 14, 16, 17 more than or equal to that against the reference drug doxorubicin. In addition, the latter compounds were tested as EGFR protein kinase inhibitors. The results revealed that compound 14 showed more significant EGFR PK inhibitory activity than the reference drug erlotinib (IC50; 0.07, 0.08 µM, respectively). Moreover, cell cycle analysis and apoptosis assay were performed for compound 14 proving its ability to cause G1/S phase arrest and apoptosis in Hela cancer cells, in addition to its activation of the caspases-7 and -3. In addition, derivative 14 increased the expression level of p53 and the ratio of Bax/Bcl-2 which confirmed its mode of action. Molecular docking study of 14 was performed to investigate its binding mode of interaction with EGFR PK in the active site with the aim of rationalizing its promising inhibitory activity. Accordingly, compound 14 might be considered as a promising scaffold anticervical cancer chemotherapeutic and deserves further optimization and in-depth biological studies., (Copyright © 2019. Published by Elsevier Inc.)

Novel seven-membered iminosugars fused thiazolidin-4-one and benzthiazinan-4-one were conveniently synthesized by the tandem Staudinger/aza-Wittig/cyclization reaction under microwave radiation. Benzoyl group (Bz) migrations were found in the synthesis of 8c and 9b using D-galactoside or D-mannoside as starting materials, respectively, which was suggested by HMBC and X-ray. The new bi/tricyclic iminosugars 3~4(a-d) and 5(b-d) were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that all compounds except 5b could effectively inhibit RT activity. Among them, compounds 3c and 4c were the best ones with the IC50 values of RT inhibitory activities of 2.11 µM and 2.73 µM, respectively. Structure-activity relationship analysis suggested that the phenyl group in the tricyclic azasugars was beneficial for their anti-HIV RT activity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Three thiazolidin-4-one derivatives were synthesized, purified and characterized by chromatographic and spectroscopic methods. In the in vitro assays, these compounds inhibited reactive oxygen species (ROS), nitrite and cytokine generation in RAW 264.7 murine macrophages and whole blood. These derivatives attenuated carrageenan-induced acute inflammation in rats. The most effective compound 4C possessed identical anti-inflammatory action at two doses (50 and 100 mg/kg). Further, the effect of compound 4C on locally induced inflammatory mediators was investigated in carrageenan-induced air pouch inflammation in rats. In this model, compound 4C inhibited the cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-6 (systemic and local). Additionally, compound 4C was able to reduce locally elevated prostaglandin-E₂ (PGE₂). Inhibition of leukocyte infiltration by compound 4C was correlated with reduced locally released myeloperoxidase (MPO). To conclude, compound 4C corrected the inflammatory condition by negative effect on cytokine (TNF-α, IL-6) network and prostaglandin-E₂ generation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)