In silico DFT and molecular modeling of novel pyrazine-bearing thiazolidinone hybrids derivatives: elucidating in vitro anti-cancer and urease inhibitors.

In the present work, one of the leading health issues i.e. cancer was targeted by synthesizing and biologically investigating the potential of pyrazine-based thiazolidinone derivatives (1-13). The basic structure of the synthesized compounds was determined using a variety of spectroscopic techniques, including 1H NMR, 13C NMR, and HREI-MS. These scaffolds were studied for their biological profiles as anti-cancer as well as anti-urease agents. The biological effectiveness of these compounds was compared using the reference tetrandrine (IC50 = 4.50 ± 0.20 µM) and thiourea (IC50 = 5.10 ± 0.10 µM), respectively. Among novel compounds, scaffold 3, 6, 7 and 10 demonstrated an excellent potency with highest inhibitory potential (IC50 = 1.70 ± 0.10 and 1.30 ± 0.20 µM), (IC50 = 4.20 ± 0.10 and 5.10 ± 0.30 µM), (IC50 = 2.10 ± 0.10 and 3.20 ± 0.20 µM) and (IC50 = 2.70 ± 0.20 and 4.20 ± 0.20 µM), respectively, out of which scaffold 3 emerged as the leading compound due to the presence of highly reactive -CF3 moiety which interacts via hydrogen bonding. Molecular docking investigations of the potent compounds was also carried out which revealed the binding interactions of ligands with the active sites of enzyme. Moreover, the electronic properties, nucleophilic and electrophilic sited of the lead compounds were also studied under density functional theory (DFT).

The Proapoptotic Action of Pyrrolidinedione-Thiazolidinone Hybrids towards Human Breast Carcinoma Cells Does Not Depend on Their Genotype.

The development of new, effective agents for the treatment of breast cancer remains a high-priority task in oncology. A strategy of treatment for this pathology depends significantly on the genotype and phenotype of human breast cancer cells. We aimed to investigate the antitumor activity of new pyrrolidinedione-thiazolidinone hybrid molecules Les-6287, Les-6294, and Les-6328 towards different types of human breast cancer cells of MDA-MB-231, MCF-7, T-47D, and HCC1954 lines and murine breast cancer 4T1 cells by using the MTT, clonogenic and [3H]-Thymidine incorporation assays, flow cytometry, ELISA, and qPCR. The studied hybrids possessed toxicity towards the mentioned tumor cells, with the IC50 ranging from 1.37 to 21.85 µM. Simultaneously, these derivatives showed low toxicity towards the pseudonormal human breast epithelial cells of the MCF-10A line (IC50 > 93.01 µM). Les-6287 at 1 µM fully inhibited the formation of colonies of the MCF-7, MDA-MB-231, and HCC1954 cells, while Les-6294 and Les-6328 did that at 2.5 and 5 µM, respectively. Les-6287 suppressed DNA biosynthesis in the MCF-7, MDA-MB-231, and HCC1954 cells. At the same time, such an effect on the MCF-10A cells was significantly lower. Les-6287 induces apoptosis using extrinsic and intrinsic pathways via a decrease in the mitochondrial membrane potential, increasing the activity of caspases 3/7, 8, 9, and 10 in all immunohistochemically different human breast cancer cells. Les-6287 decreased the concentration of the metastasis- and invasion-related proteins MMP-2, MMP-9, and ICAM-1. It did not induce autophagy in treated cells. In conclusion, the results of our study suggest that the synthesized hybrid pyrrolidinedione-thiazolidinones might be promising agents for treating breast tumors of different types.

Catalyzed syntheses of novel series of spiro thiazolidinone derivatives with nano Fe2O3: spectroscopic, X-ray, Hirshfeld surface, DFT, biological and docking evaluations.

Twelve spiro thiazolidinone compounds (A-L) were synthesized via either conventional thermal or ultrasonication techniques using Fe2O3 nanoparticles. The modification of the traditional procedure by using Fe2O3 nanoparticles led to enhancement of the yield of the desired candidates to 78-93% in approximately half reaction time compared with 58-79% without catalyst. The products were fully characterized using different analytical and spectroscopic techniques. The structure of the two derivatives 4-phenyl-1-thia-4-azaspirodecan-3-one (A) and 4-(p-tolyl)-1-thia-4-azaspirodecan-3-one (B) were also determined using single crystal X-ray diffraction and Hirshfeld surface analysis. The two compounds (A and B) were crystallized in the orthorhombic system with Pbca and P212121 space groups, respectively. In addition, the crystal packing of compounds revealed the formation of supramolecular array with a net of intermolecular hydrogen bonding interactions. The energy optimized geometries of some selected derivatives were performed by density functional theory (DFT/B3LYP). The reactivity descriptors were also calculated and correlated with their biological properties. All the reported compounds were screened for antimicrobial inhibitions. The two derivatives, F and J, exhibited the highest levels of bacterial inhibition with an inhibition zone of 10-17 mm. Also, the two derivatives, F and J, displayed the most potent fungal inhibition with an inhibition zone of 15-23 mm. Molecular docking investigations of some selected derivatives were performed using a B-DNA (PDB: 1BNA) as a macromolecular target. Structure and activity relationship of the reported compounds were correlated with the data of antimicrobial activities and the computed reactivity parameters.

Thiazolidinone-linked-1,2,3-triazoles with (R)-Carvone as new potential anticancer agents.

Aim: This study explores the cytotoxic and apoptotic effects of novel thiazolidinone-1,2,3-triazole hybrids on HT-1080, A-549, and MDA-MB-231 cancer cell lines.Methods & results: The synthesized compounds underwent comprehensive characterization (NMR and HRMS) to confirm their structures and purity. Subsequent anticancer activity screening across diverse cancer cell lines revealed promising antitumor potential notably, compounds 6f and 6g. Mechanistic investigations unveiled that compound 6f triggers apoptosis through the caspase-3/7 pathway. In terms of in silico studies, the compound 6f was identified as a potent inhibitor of caspase-3 and caspase-7.Conclusion: The present study underscores the therapeutic potential of thiazolidinone-1,2,3-triazole hybrids against certain cancer cells. These findings highlight a promising avenue for the development of cancer treatment strategies utilizing these (R)-Carvone-based derivatives.

[Box: see text].

Identification of novel benzothiazole-thiadiazole-based thiazolidinone derivative: in vitro and in silico approaches to develop promising anti-Alzheimer's agents.

Aim: The present study describes benzothiazole derived thiazolidinone based thiadiazole derivatives (1-16) as anti-Alzheimer agents.Materials & methods: Synthesis of benzothiazole derived thiazolidinone based thiadiazole derivatives was achieved using the benzothiazole bearing 2-amine moiety. These synthesized compounds were confirmed via spectroscopic techniques (1H NMR, 13C NMR and HREI-MS). These compounds were biologically evaluated for their anti-Alzheimer potential. Binding interactions with proteins and drug likeness of the analogs were explored through molecular docking and ADMET analysis, respectively. In the novel series, compound-3 emerged as the most potent inhibitor when compared with other derivatives of the series.Conclusion: The present study provides potent anti-Alzheimer's agents that can be further optimized to discover novel anti-Alzheimer's drugs.

[Box: see text].

Role of 4-Thiazolidinone-Pyrazoline/Indoline Hybrids Les-4369 and Les-3467 in BJ and A549 Cell Lines.

Cancer is one of the most important problems of modern societies. Recently, studies have reported the anticancer properties of rosiglitazone related to its ability to bind peroxisome proliferator receptor γ (PPARγ), which has various effects on cancer and can inhibit cell proliferation. In this study, we investigated the effect of new 4-thiazolidinone (4-TZD) hybrids Les-4369 and Les-3467 and their effect on reactive oxygen species (ROS) production, metabolic activity, lactate dehydrogenase (LDH) release, caspase-3 activity, and gene and protein expression in human foreskin fibroblast (BJ) cells and lung adenocarcinoma (A549) cells. The ROS production and caspase-3 activity were mainly increased in the micromolar concentrations of the studied compounds in both cell lines. Les-3467 and Les-4369 increased the mRNA expression of PPARG, P53 (tumor protein P53), and ATM (ATM serine/threonine kinase) in the BJ cells, while the mRNA expression of these genes (except PPARG) was mainly decreased in the A549 cells treated with both of the tested compounds. Our results indicate a decrease in the protein expression of AhR, PPARγ, and PARP-1 in the BJ cells exposed to 1 µM Les-3467 and Les-4369. In the A549 cells, the protein expression of AhR, PPARγ, and PARP-1 increased in the treatment with 1 µM Les-3467 and Les-4369. We have also shown the PPARγ modulatory properties of Les-3467 and Les-4369. However, both compounds prove weak anticancer properties evidenced by their action at high concentrations and non-selective effects against BJ and A549 cells.

New Thiazolidine-4-One Derivatives as SARS-CoV-2 Main Protease Inhibitors.

It has been more than four years since the first report of SARS-CoV-2, and humankind has experienced a pandemic with an unprecedented impact. Moreover, the new variants have made the situation even worse. Among viral enzymes, the SARS-CoV-2 main protease (Mpro) has been deemed a promising drug target vs. COVID-19. Indeed, Mpro is a pivotal enzyme for viral replication, and it is highly conserved within coronaviruses. It showed a high extent of conservation of the protease residues essential to the enzymatic activity, emphasizing its potential as a drug target to develop wide-spectrum antiviral agents effective not only vs. SARS-CoV-2 variants but also against other coronaviruses. Even though the FDA-approved drug nirmatrelvir, a Mpro inhibitor, has boosted the antiviral therapy for the treatment of COVID-19, the drug shows several drawbacks that hinder its clinical application. Herein, we report the synthesis of new thiazolidine-4-one derivatives endowed with inhibitory potencies in the micromolar range against SARS-CoV-2 Mpro. In silico studies shed light on the key structural requirements responsible for binding to highly conserved enzymatic residues, showing that the thiazolidinone core acts as a mimetic of the Gln amino acid of the natural substrate and the central role of the nitro-substituted aromatic portion in establishing π-π stacking interactions with the catalytic His-41 residue.

Probing benzenesulfonamide-thiazolidinone hybrids as multitarget directed ligands for efficient control of type 2 diabetes mellitus through targeting the enzymes: α-glucosidase and carbonic anhydrase II.

Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 µM), comparable with that of the positive control (acarbose; IC50 = 0.420 µM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.

Synthesis of novel (R)-carvone-tagged thiazolidinone as anticancer leads: characterization, in vitro antiproliferative evaluation and in silico studies.

This work describes the successful synthesis of a series of three novel thiazolidinone-carvone-O-alkyl hybrids through a two-step approach involving heterocyclization and O-alkylation reactions. Comprehensive structural characterization of the obtained products was achieved using NMR and HRMS spectroscopic techniques. This study assessed in vitro antiproliferative activity of synthesized thiazolidinone-carvone-O-alkyl hybrids (5a-c) against various human cancer cell lines, viz. HT-1080 (fibrosarcoma), A-549 (lung cancer), MCF-7 (breast cancer) and MDA-MB-231 (breast cancer). MTT assay revealed promising results for compounds 5b and 5c, demonstrating good antiproliferative activity against A-549 and MCF-7 cell lines comparable to the positive control, Doxorubicin. Compound 5a, harbouring an O-acetoxy group, displayed limited anticancer activity against MCF-7 and MDA-MB-231 cells, with IC50 values of 69.33 ± 0.42 µM and >100 µM, respectively. Docking results confirmed that the compounds 5a-c binds at the active site of p21 with docking scores -2.0, -4.8, and -7.0 kcal/mol, respectively. Compound 5a-c also showed good binding potential against Bcl2 protein with docking score of -4.9, -6.0, -5.5 kcal/mol, respectively. Furthermore, binding energy analysis and dynamics simulation studies of compounds towards p21 and Bcl2 yielded promising results. In PAK4 assay, compound 5c showed comparable potency (IC50 6.76 µM) with the standard control UC2288 (IC50 6.40 µM), while in BCL-2 TR-FRET assay, 5c exhibited good inhibition (IC50 1.78 µM) as compared to Venetoclax (IC50 0.016 µM). In conclusion, compounds 5a-c could be used as a structural framework for the discovery of novel therapeutics to combat different types of cancer.Communicated by Ramaswamy H. Sarma.

Antioxidant and Antimicrobial Potential of 1,8-Naphthyridine Based Scaffolds: Design, Synthesis and in Silico Simulation Studies within Topoisomerase II.

A series of spiro ß-Lactams (4 a-c, 7 a-c) and thiazolidinones (5 a-c, 8 a-c) possessing 1,8-naphthyridine moiety were synthesized in this study. The structure of the newly synthesized compounds has been confirmed by IR, 1H-NMR, 13C NMR, mass spectra, and elemental analysis. The synthesized compounds were tested in vitro for their antibacterial and antifungal activity against various strains. The antimicrobial data showed that most of the compounds displayed good efficacy against both bacteria and fungi. The structure-activity relationship (SAR) studies suggested that the presence of electron-withdrawing chloro (3 b, 4 b, and 5 b) and nitro groups (7 b, 8 b) at the para position of the phenyl ring improved the antimicrobial activity of the compounds. The free radical scavenging assay showed that all the synthesized compounds exhibited significant antioxidant activity on DPPH. Compounds 8 b (IC50=17.68±0.76 µg/mL) and 4 c (IC50=18.53±0.52 µg/mL) showed the highest antioxidant activity compared to ascorbic acid (IC50=15.16±0.43 µg/mL). Molecular docking studies were also conducted to support the antimicrobial and SAR results.

Design, synthesis, biological evaluations and in silico studies of N-substituted 2,4-thiazolidinedione derivatives as potential a-glucosidase inhibitors.

Diabetes mellitus is considered as one of the principal global health urgencies of the twenty first century. In the present investigation, novel N-substituted 2,4-thiazolidinedione derivatives were designed, synthesized, and characterized by spectral techniques. All the newly synthesized N-substituted 2,4-thiazolidinedione derivatives were tested for in vitro α-glucosidase inhibitory activities and compounds A-12 and A-14 were found to be the most potent which were further subjected to in-vivo disaccharide loading test. The most potent compound was also found to be non-toxic in cytotoxicity studies. Further, docking studies were carried out to investigate the binding mode and key interactions with amino acid residues of α-glucosidase. Molecular dynamic simulations studies for the compounds acarbose, A2, A12, and A14 were done with α-glucosidase protein. Further, ΔG was calculated for acarbose, A2, A12, and A14. In silico studies and absorption, distribution, metabolism, excretion (ADME) prediction studies were also executed to establish the 'druggable' pharmacokinetic profiles. Here, we have developed novel N-substituted TZD analogues with different alkyl groups as α-glucosidase inhibitors.Communicated by Ramaswamy H. Sarma.

Identification of Indazole-Based Thiadiazole-Bearing Thiazolidinone Hybrid Derivatives: Theoretical and Computational Approaches to Develop Promising Anti-Alzheimer's Candidates.

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties (1-17) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC50 values ranging from 0.86 ± 0.33 µM to 26.73 ± 0.84 µM (AChE) and 0.89 ± 0.12 µM to 27.08 ± 0.19 µM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC50 = 1.26 ± 0.18 µM for AChE) and (1.35 ± 0.37 µM for BuChE), respectively. Specifically, the derivatives 1-17, 1, 9, and 14 were found to be significantly active, with IC50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 µM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 µM (against BuChE), respectively.The structure-activity relationship (SAR) studies revealed that derivatives bearing para-CF3, ortho-OH, and para-F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta-Cl, -NO2, and para-chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1H-NMR, 13C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data.

Synthesis and Antiproliferative Potential of Thiazole and 4-Thiazolidinone Containing Motifs as Dual Inhibitors of EGFR and BRAFV600E.

Thiazole and thiazolidinone recur in a wide range of biologically active compounds that reach different targets within the context of tumors and represent a promising starting point to access potential candidates for treating metastatic cancer. Therefore, searching for new lead compounds that show the highest anticancer potency with the fewest adverse effects is a major drug-discovery challenge. Because the thiazole ring is present in dasatinib, which is currently used in anticancer therapy, it is important to highlight the ring. In this study, cycloalkylidenehydrazinecarbothioamides (cyclopentyl, cyclohexyl, cyclooctyl, dihydronapthalenylidene, flurine-9-ylidene, and indolinonyl) reacted with 2-bromoacetophenone and diethylacetylenedicarboxylate to yield thiazole and 4-thiazolidinone derivatives. The structure of the products was confirmed by using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and single-crystal X-ray analyses. The antiproliferative activity of the newly synthesized compounds was evaluated. The most effective inhibitory compounds were further tested in vitro against both epidermal growth factor receptor (EGFR) and B-Raf proto-oncogene, serine/threonine kinase (BRAFV600E) targets. Additionally, molecular docking analysis examined how these molecules bind to the active sites of EGFR and BRAFV600E.

Proton tautomerism and stereoisomerism in 5-[(dimethylamino)methylidene]-4-[3/4-(trifluoromethylphenyl)amino]-1,3-thiazol-2(5H)-ones: synthesis, crystal structure and spectroscopic studies.

5-[(Dimethylamino)methylidene]-4-{[3-(trifluoromethyl)phenyl]amino}-1,3-thiazol-2(5H)-one and the [4-(trifluoromethyl)phenyl]amino derivative, both C13H12F3N3OS, with the trifluoromethyl group substituted at the arene ring at the meta and para positions, were synthesized to study the structural changes associated with proton tautomerism of the amidine system. The studied compounds were found to be in the amine tautomeric form in both the solid and the liquid (dimethyl sulfoxide solutions) phase. In both isomers, the [(trifluoromethyl)phenyl]amino residue assumes a synperiplanar conformation with respect to the thiazolone system, while the 5-[(dimethylamino)methylidene] residue adopts the Z configuration. Density functional theory (DFT) calculations correctly predicted that the synperiplanar arrangement is favoured in both isomers. In the crystal, the whole independent molecule of the para compound is disordered over two alternative positions, with occupancy factors of 0.926 (3) and 0.074 (3).

Pyrrole-thiazolidinone hybrids as a new structural class of broad-spectrum anti-infectives.

A series of pyrrole-thiazolidinone hybrids was designed, synthesized and evaluated for activities against ESKAP bacteria panel and mycobacterial pathogens. From the series, compound 9d showed prominent activity against S. aureus (MIC = 0.5 µg/mL) and compound 9k showed the most promising activity against M. tuberculosis H37Rv (MIC = 0.5 µg/mL). Potent derivatives were found to be non-toxic when tested against Vero cells. Compound 9d upon evaluation in vitro against several MRSA and VRSA strains produced activity comparable or better than standard drugs. In the anti-biofilm assay, 9d reduced S. aureus biofilm by >11% at 10x MIC. The dual inhibitory effect exhibited by pyrrole-thiazolidinone hybrids confirms their potential as new class of promising anti-infective agents.

A novel synthesized prodrug of gemcitabine based on oxygen-free radical sensitivity inhibited the growth of lung cancer cells.

In the present study, we introduced the H 2O 2-sensitive thiazolidinone moiety at the 4th amino group of gemcitabine (GEM) to synthesize a new target compound named GEM-ZZQ, and then we confirmed its chemical structure by nuclear magnetic resonance spectroscopy. We further confirmed that GEM-ZZQ had a good chemical stability in different pH solutions in vitro and that it could be activated by H 2O 2 to release GEM. Pharmacodynamic studies revealed that the growth inhibition of human normal epithelial cells was weaker by GEM-ZZQ than by GEM treatment and that the inhibition of various lung cancer cell lines by GEM-ZZQ was similar to that of GEM. For the lung cancer cell lines that are resistant to the epidermal growth factor receptor (EGFR)-targeting inhibitor osimertinib, GEM-ZZQ showed less growth inhibition than GEM; however, GEM-ZZQ in combination with cisplatin showed better synergistic effects than GEM in the low-dose groups. In summary, we provided a new anti-cancer compound GEM-ZZQ for treating lung cancer by modifying the GEM structure.

In Vitro Genotoxic and Antigenotoxic Effects of Ten Novel Synthesized 4-Thiazolidinone Derivatives.

Heterocyclic compounds are found in a variety of drug molecules, and bioactive natural products. 4-Thiazolidinones (4-TZDs), which represent an important class of heterocyclic compounds, are of great interest today with their diverse bioactivities. In this study, ten novel 4-TZD derivatives (C1-C10) were synthesized, characterized by spectroscopic techniques, and their genotoxic, and antigenotoxic properties were investigated in vitro using the Ames Salmonella/microsome mutagenicity assay in the concentration range of 0.2-1.0 mM/plate. The results revealed that none of the compounds were mutagenic on the three different Salmonella typhimurium strains up to the highest concentration tested. Furthermore, in our study, C1, C4, C6, and C9 showed significant, ranging from moderate to strong, antigenotoxic effects against mutagen-induced DNA damage at relatively higher doses. Among these, C4 had the best potential to inhibit the number of revertant colonies induced by 9-aminoacridine (9-AA), with a maximum inhibition rate of 47.9 % for 1.0 mM/plate. As a result, preliminary knowledge about the safety of the use of ten novel synthesized 4-TZD compounds likely to exhibit many bioactivities was obtained in this study. In addition, the significant in vitro antimutagenic activity of some derivatives increases the importance of studies for the development of new pharmacological agents for cancer prevention.

Discovery and optimization of 2,3-diaryl-1,3-thiazolidin-4-one-based derivatives as potent and selective cytotoxic agents with anti-inflammatory activity.

Several studies have indicated the potential therapeutic outcomes of combining selective COX-2 inhibitors with tubulin-targeting anticancer agents. In the current study, a novel series of thiazolidin-4-one-based derivatives (7a-q) was designed by merging the pharmacophoric features of some COXs inhibitors and tubulin polymerization inhibitors. Compounds 7a-q were synthesized and evaluated for their cytotoxic activity against MCF7, HT29, and A2780 cancer cell lines (IC50 = 0.02-17.02 µM). The cytotoxicity of 7a-q was also assessed against normal MRC5 cells (IC50 = 0.47-13.46 µM). Compounds 7c, 7i, and 7j, the most active in the MTT assay, significantly reduced the number of HT29 colonies compared to the control. Compounds 7c, 7i, and 7j also induced significant decreases in the tumor volumes and masses in Ehrlich solid carcinoma-bearing mice compared to the control. The three compounds also exhibited significant anti-HT29 migration activity in the wound-healing assay. They have also induced cell cycle arrest in HT29 cells at the S and G2/M phases. In addition, they induced significant increases in both early and late apoptotic events in HT29 cells compared to the control, where 7j showed the highest effect. On the other hand, compound 7j (1 µM) displayed weak inhibitory activity against tubulin polymerization compared to colchicine (3 µM). On the other hand, compounds 7a-q inhibited the activity of COX-2 (IC50 = 0.42-29.11 µM) compared to celecoxib (IC50 = 0.86 µM). In addition, 7c, 7i, and 7j showed moderate inhibition of inflammation in rats compared to indomethacin, with better GIT safety profiles. Molecular docking analysis revealed that 7c, 7i, and 7j have higher binding free energies towards COX-2 than COX-1. These above results suggested that 7j could serve as a potential anticancer drug candidate.

Pyrrolidinedione-thiazolidinone hybrid molecules with potent cytotoxic effect in squamous cell carcinoma SCC-15 cells.

The hybrid heterocyclic molecules are perspective materials in the development of anticancer drugs. Here, the pyrrolidinedione-thiazolidinone hybrid molecules were designed as potent anticancer agents. This study aimed to investigate the cytotoxic effect of three derivatives 1-(4-hydroxyphenyl)-, 1-(4-chlorophenyl)- and 1-(4-bromophenyl)-3-[5-[2-chloro-3-(4-nitrophenyl)prop-2-enylidene]-4-oxo-2-thioxothiazolidine-3-yl]pyrrolidine-2,5-diones (Les-6287, Les-6294, and Les-6328, respectively), their effect on the production of the reactive oxygen species (ROS), apoptosis induction, and expression of genes - PPARγ, AHR, and NRFL2 - whose products are important in metabolism in human tongue squamous cell carcinoma cells of SCC-15 line. The results of resazurin reduction and lactate dehydrogenase (LDH) release assays proved the toxicity of the tested derivatives for the SCC-15 cells. Les-6287, Les-6294, and Les-6328 inhibited the viability of SCC-15 cells with the half-maximal effective concentration (EC50) in the range of 10.18-32.75 µM at 24 and 48 h treatment. These derivatives reduced the metabolism of SCC-15 cells with the half-maximal inhibitory concentration (IC50) of 6.72-39.85 µM at 24 and 48 h treatment. Les-6287, Les-6294, and Les-6328 reduced the metabolism of normal human keratinocytes of HaCaT line murine fibroblasts of Balb/c 3T3 line to a lesser extent. The compounds used in a range from 50 to 100 µM concentrations decreased ROS production in the SCC-15 cells. The derivatives Les-6287 and Les-6328 decreased the level of expression of mRNA of PPARγ, AHR, and NRFL2 genes in these cells at PPARγ siRNA knockdown and without it. Thus, the anticancer effect of studied hybrid pyrrolidinedione-thiazolidinones in the SCC-15 carcinoma cells is accompanied by a reduction of their metabolic activity and ROS level, and increase in caspase 3 activity. However, these changes are not the result of direct interaction of Les-6287, Les-6294, and Les-6328 with the PPARγ molecule.

Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights.

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications.