Search Results (86)

Heterocyclic compounds have shown that they hold significant therapeutic activities, highlighting the importance of discovering and developing novel candidates against cancers, infections, and oxidative stress-associated disorders. In this study, we demonstrated the biological activity of our previously synthesized thiazolidinone derivatives (TZDs-1, 6, and 7). Furthermore, we synthesized and structurally characterized a new derivative (TZD-5) using IR, ¹H NMR, and ¹³C NMR spectroscopy, confirming the presence of its key functional groups, namely, carbonyl and imine. Their antioxidant activity was assessed through the DPPH assay, with TZD-5 showing the most potent effect (IC₅₀ = 24.4 µg/mL), comparable to ascorbic acid, an effect attributed to the methoxy group introduced via N-alkylation. Cytotoxicity was evaluated using the MTS assay on normal (HFF-1) and cancerous (HepG2 and A549) cell lines at two time points: 24- and 48 h exposure. Our findings highlight clear differences in cytotoxicity and selectivity among the tested thiazolidinone derivatives. TZD-1 and TZD-6 demonstrated significant, dose-dependent cytotoxic effects on both cancerous (HepG2 and A549) and normal (HFF-1) cell lines, thus limiting their therapeutic potential due to insufficient selectivity. TZD-5 exhibited moderate selectivity with higher susceptibility for HepG2 cells compared to normal cells. Notably, TZD-7 showed the most favorable cytotoxic profile, demonstrating strong selective cytotoxicity toward cancer cell lines with minimal adverse effects on normal fibroblasts. Overall, the results highlight TZD-5 and TZD-7 as promising candidates for antioxidant and selective anticancer therapies. Full article

As breast cancer remains a significant challenge for the current medical field, molecules with a 4-thiazolidinone scaffold can become promising candidates for addressing the increasing threat of cancer. This study aims to develop and evaluate the novel 4-thiazolidinone derivatives with anticancer potential. New compounds were synthesized through two different pathways, one as a two-step process and the other as a one-pot method. The second approach fits the requirements of cost-effective methodologies and allows for the reduction of synthetic steps, reagents, and reaction time. The obtained data from in vitro research showed a potent cytotoxic activity of the novel structures in micromolar concentrations against MCF-7 breast cancer cells. Further investigations into their anticancer activity revealed that the tested compounds induced apoptosis through intrinsic and extrinsic pathways, which was evidenced by their capability to reduce the mitochondrial membrane potential and induce the activation of caspases 7, 8, 9, and 10. A more detailed analysis uncovered that one of the novel compounds can affect the expression of key apoptotic proteins, tumor protein P53 (p53), cytochrome C, and Bax in treated cells. Additionally, these compounds displayed an enhanced generation of reactive oxygen species (ROS) in MCF-7 cells, which suggests that ROS-mediated mechanisms can take part in the anticancer potential of the synthesized compounds. Full article

Background: Alzheimer’s disease is a complex and multifactorial brain disorder characterized by gradual memory impairment, cognitive disturbance, and severe dementia, and, ultimately, its progression leads to patient death. This research work presents the design, synthesis, and characterization of novel imidazotriazole-based thiazolidinone derivatives (1–14), displaying promising anti-Alzheimer’s activity. Methods: These derivatives were synthesized by using 1H-imidazole-2-thiol as a starting reagent. Structural characterization was accomplished by ¹³C-NMR and ¹H-NMR, while the molecular weight was confirmed by HREI-MS. These compounds were investigated for their anti-Alzheimer’s potential under an in vitro analysis. Results: These compounds showed a significant to moderate biological potential against AChE and BChE in comparison to donepezil (IC₅₀ = 8.50 µM and 8.90 µM against AChE and BuChE), used as a reference drug. Among these compounds, analog 10 with IC₅₀ values of 6.70 µM and 7.10 µM against AChE and BuChE emerged as the lead compound of the series with promising biological efficacy against targeted enzymes. Molecular docking revealed the interactive nature of active ligands against target enzymes. These compounds were also assessed under dynamic conditions to examine the structural deviation and conformational changes in a protein complex structure. DFT calculations provided the relative stability and reactivity of the lead compounds. An ADMET analysis showed that these compounds have no toxicological profile. Conclusions: This research study paves the way for the further development and optimization of novel and selective imidazotriazole-based thiazolidinone inhibitors as potent anti-Alzheimer’s agents. Full article

Background: HIV-1 RT inhibitors were the first drugs approved to treat AIDS and remain key components of highly active antiretroviral therapy (HAART). While HAART effectively suppresses viral replication and slows disease progression, it has limitations, including long-term side effects and the emergence of drug-resistant strains, highlighting the need for new treatments. Objectives: Based on our previous experience, and insights from existing inhibitors of HIV-1 RT and RNase H, we aim to design and synthesize safer, multifunctional molecules. Methods: Using molecular docking studies, these compounds will incorporate pharmacophores targeting multiple stages of the HIV life cycle to enhance efficacy, reduce resistance, and improve pharmacokinetics. The compounds were synthesized via a one-pot three component reaction. The synthesized compounds were identified using spectroscopy and tested in vitro for activity against key HIV targets, including RNA-dependent DNA polymerase (RDDP) and RNAse H. Results: Among the synthesized compounds, several demonstrated strong inhibitory activity, with compound 11 showing IC₅₀ values comparable to the reference drug Nevirapine, and compound 4 exhibiting dual inhibition of both RT and RNase H activities. Conclusions: These findings emphasize the importance of a multidisciplinary approach, combining computational modeling with experimental validation, to identify promising leads for therapeutic development. Full article

Gastric cancer remains a significant therapeutic challenge, highlighting the need for new strategies to improve treatment efficacy. This study investigates the potential of combined therapy with the novel Thiopyrano[2,3-d]Thiazole derivative LES-6400 and the anti-HER2 antibody trastuzumab in AGS gastric cancer cells. The antitumor effects of the combined therapy were evaluated using various techniques, including the MTT assay for cell viability, [³H]-thymidine incorporation for DNA synthesis, and flow cytometry to assess apoptosis (Annexin V-FITC/PI staining), mitochondrial membrane potential (MMP), and inflammatory cytokine levels. ELISA was employed to measure the levels of IL-6, p53, and cytochrome C. The combination of LES-6400 (1 µM) and trastuzumab (10 µg/mL) demonstrated superior antitumor activity compared to monotherapy with either agent in AGS gastric cancer cells. The combination therapy enhanced apoptosis, presumably by inducing oxidative stress in the cells and disrupting mitochondrial membrane potential. Additionally, a significant increase in p53 protein levels and modulation of interleukin levels, including a marked reduction in IL-6 levels, were observed, suggesting an impact on apoptotic and inflammatory responses. These findings indicate that the combined use of LES-6400 and trastuzumab is a promising therapeutic strategy for gastric cancer, warranting further investigation into the mechanisms of action and potential clinical applications of this combined approach. Full article

Objective: To synthesize hybrid compounds of indole and oxadiazole in search of highly effective anti-diabetic therapeutic agent. Methods: With the goal of advancing diabetes research, our group designed and synthesized a library of 15 compounds based on indole-derived oxadiazole bearing varied substituted thiazolidinone via a multistep synthetic route. ¹³C-NMR, ¹H-NMR and HREI-MS were applied for the characterization of all the synthesized compounds. Their biological inhibitory activity against diabetic enzymes, i.e., α-amylase and α-glucosidase was also determined. Results: Compound 7, 9 and 15 exhibited excellent inhibition against α-amylase and α-glucosidase than the standard acarbose (IC₅₀ = 8.50 ± 0.10 µM for α-amylase and 9.30 ± 0.30 µM for α-glucosidase. To ensure the inhibitory actions of these potent analogs in molecular docking, an in silico approach was used. To determine the drug likeness of the reported analogs, an ADMET investigation was also carried out to explore the nature of the designed compounds if used as a drug. Conclusion: Fluoro-substituted analog 15 has stronger inhibition profile against both enzymes. All the potent compounds can be used as effective anti-diabetic therapeutic agents in future. Full article

Human Carbonic Anhydrases (hCA) are enzymes that contribute to cancer’s development and progression. Isoforms IX and XII have been identified as potential anticancer targets, and, more specifically, hCA IX is overexpressed in hypoxic tumor cells, where it plays an important role in reprogramming the metabolism. With the aim to find new inhibitors towards IX and XII isoforms, the hybridization of the privileged scaffolds isatin, dihydrothiazole, and benzenesulfonamide was investigated in order to explore how it may affect the activity and selectivity of the hCA isoforms. In this respect, a series of isatin thiazolidinone hybrids have been designed and synthesized and their biological activity and selectivity on hCA I, hCA II, hCA IX, and hCA XII explored. The new compounds exhibited promising inhibitory activity results on isoforms IX and XII in the nanomolar range, which has highlighted the importance of substituents in the isatin ring and in position 3 and 5 of thiazolidinone. In particular, compound 5g was the most active toward hCA IX, while 5f was the most potent inhibitor of hCA XII within the series. When both potency and selectivity were considered, compound 5f appeared as one of the most promising. Additionally, our investigations were supported by molecular docking experiments, which have highlighted the putative binding poses of the most promising compound. Full article

Presently, a major challenge is the search for new compounds that may exhibit an inhibitory effect on tumor progression. Recently, the 4-thiazolidinone (4-TZD) group has gained attention in this research field. The aim of the present study was to evaluate the anticancer effects of two new 4-TZD-based derivatives (Z)-5-[5-(2-hydroxyphenyl)- (Les- 4368) and (Z)-5-[5-(4-dimethylaminophenyl)-3-phenyl-4,5-dihydropyrazol-1-ylmethylene]-3-(3-acetoxyphenyl)-2-thioxothiazolidin-4-ones (Les-4370) on peroxisome proliferator-activated receptor gamma (PPARγ)-dependent cytotoxicity in human colorectal adenocarcinoma cells (CACO-2) and in normal human fibroblasts (BJ) in vitro. Les-4368 and Les-4370 exerted a toxic effect on both tested cell lines in high (micromolar) concentrations (10–100 µM). In addition, Les-4368 and Les-4370 applied in the BJ and CACO-2 cells in the concentration range of 10 µM to 100 µM increased the activity of caspase-3 and the production of reactive oxygen species (ROSs). The mRNA expression of PPARγ-related genes (PPARγ, AhR, PXR, and NF-κB) showed certain changes in these parameters, proving the engagement of this receptor in the induction of the biological effects of both tested 4-TZD derivatives. Moreover, the treatment of the BJ and CACO-2 cells with Les-4368, Les-4370, an antagonist (GW9662), or an agonist (rosiglitazone) of the PPARγ receptor also resulted in changes in the above-mentioned parameters. Unfortunately, the tested substances studied cell line work in a non-selective way at a relatively high concentration, which reduces their potential for clinical application. Our research is the preliminary study with the use of these compounds and requires further studies to elucidate the mechanisms of action of their anticancer potential. Full article

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. Full article

A range of hybrid molecules incorporating the ciminalum moiety in the thiazolidinone ring demonstrate significant anticancer and antimicrobial properties. Therefore, the aim of our study was to evaluate the properties and mechanism of action of two 4-thiazolidinone-based derivatives, i.e., 3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid (Les-45) and 5-[2-chloro-3-(4-nitrophenyl)-2-propenylidene]-2-(3-hydroxyphenylamino)thiazol-4(5H)-one (Les-247). In our study, we analyzed the impact of Les-45 and Les-247 on metabolic activity, caspase-3 activity, and the expression of genes and proteins related to inflammatory and antioxidant defenses and cytoskeleton rearrangement in healthy human fibroblasts (BJ) and a human lung carcinoma cell line (A549). The cells were exposed to increasing concentrations (1 nM to 100 μM) of the studied compounds for 24 h and 48 h. A decrease in the metabolic activity in the BJ and A549 cell lines was induced by both compounds at a concentration range from 10 to 100 µM. Both compounds decreased the mRNA expression of NRF2 (nuclear factor erythroid 2-related factor 2) and β-actin in the BJ cells. Interestingly, a significant decrease in the level of NF-κB gene and protein expression was detected in the BJ cell line, suggesting a direct impact of the studied compounds on the inhibition of inflammation. However, more studies are needed due to the ability of Les-45 and Les-247 to interfere with the tubulin/actin cytoskeleton, i.e., a critical system existing in eukaryotic cells. Full article

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. Full article

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 (M^pro) has been deemed a promising drug target vs. COVID-19. Indeed, M^pro 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 M^pro 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 M^pro. 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. Full article

The goal of this study was directed to synthesize a novel class of annulated compounds containing difuro[3,2-c:3′,2′-g]chromene. Friedländer condensation of o-aminoacetyl derivative 3 was performed with some active methylene ketones, namely, 1,3-cyclohexanediones, pyrazolones, 1,3-thiazolidinones and barbituric acids, furnished furochromenofuroquinolines (4,5), furochromenofuropyrazolopyridines (6–8), furochromenofurothiazolopyridines (9,10) and furochromenofuropyridopyrimidines (11, 12), respectively. Also, condensation of substrate 3 with 5-amine-3-methyl-1H-pyrazole and 6-amino-1,3-dimethyluracil, as cyclic enamines, resulted in polyfused systems 13 and 14, respectively. In vitro antimicrobial efficiency of the prepared heterocycles against microbial strains exhibited variable inhibition action, where compound 3 was the most effective against all kinds of microorganisms. A significant cytotoxic activity was seen upon the annulation of the starting compound with thiazolopyridine (9 and 10) as well as pyridopyrimidine moieties (11, 12 and 14). The spectroscopic and analytical results were used to infer the structures of the novel synthesized compounds. Full article

Carbothioamides 3a,b were generated in high yield by reacting furan imidazolyl ketone 1 with N-arylthiosemicarbazide in EtOH with a catalytic amount of conc. HCl. The reaction of carbothioamides 3a,b with hydrazonyl chlorides 4a–c in EtOH with triethylamine at reflux produced 1,3-thiazole derivatives 6a–f. In a different approach, the 1,3-thiazole derivatives 6b and 6e were produced by reacting 3a and 3b with chloroacetone to afford 8a and 8b, respectively, followed by diazotization with 4-methylbenzenediazonium chloride. The thiourea derivatives 3a and 3b then reacted with ethyl chloroacetate in ethanol with AcONa at reflux to give the thiazolidinone derivatives 10a and 10b. The produced compounds were tested for antioxidant and antibacterial properties. Using phosphomolybdate, promising thiazoles 3a and 6a showed the best antioxidant activities at 1962.48 and 2007.67 µgAAE/g dry samples, respectively. Thiazoles 3a and 8a had the highest antibacterial activity against S. aureus and E. coli with 28, 25 and 27, 28 mm, respectively. Thiazoles 3a and 6d had the best activity against C. albicans with 26 mm and 37 mm, respectively. Thiazole 6c had the highest activity against A. niger, surpassing cyclohexamide. Most compounds demonstrated lower MIC values than neomycin against E. coli, S. aureus and C. albicans. A molecular docking study examined how antimicrobial compounds interact with DNA gyrase B crystal structures. The study found that all of the compounds had good binding energy to the enzymes and reacted similarly to the native inhibitor with the target DNA gyrase B enzymes’ key amino acids. Full article

Podophyllotoxin, a cyclolignan natural product, has been the object of extensive chemomodulation to obtain better chemotherapeutic agents. Among the obtained podophyllotoxin derivatives, podophyllic aldehyde showed very interesting potency and selectivity against several tumoral cell lines, so it became our lead compound for further modifications, as described in this work, oriented toward the enlargement of the cyclolignan skeleton. Thus, modifications performed at the aldehyde function included nucleophilic addition reactions and the incorporation of the aldehyde carbon into several five-membered rings, such as thiazolidinones and benzo-fused azoles. The synthesized derivatives were evaluated against several types of cancer cells, and although some compounds were cytotoxic at the nanomolar range, most of them were less potent and less selective than the parent compound podophyllic aldehyde, with the most potent being those having the lactone ring of podophyllotoxin. In silico ADME evaluation predicted good druggability for most of them. The results indicate that the γ-lactone ring is important for potency, while the α,β-unsaturated aldehyde is necessary to induce selectivity in these cyclolignans. Full article