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].

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.

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].

One-pot synthesis, characterization and antiviral properties of new benzenesulfonamide-based spirothiazolidinones.

A novel series of benzenesulfonamide substituted spirothiazolidinone derivatives (3a-j) were synthesized, characterized and evaluated for their antiviral activity. The spirocyclic compounds were prepared by the condensation of 4-(aminosulfonyl)-2-methoxybenzohydrazide, appropriate cyclic ketones and 2-mercaptopropionic acid in a one-pot reaction. The structures of the new compounds were established by IR, 1H NMR, 13C NMR (APT), and elemental analysis. The new compounds were evaluated in vitro antiviral activity against influenza A/H1N1, A/H3N2 and B viruses, as well as herpes simplex virus type 1 (HSV-1), respiratory syncytial virus (RSV) and yellow fever virus (YFV). Two derivatives bearing propyl (3d) and tert-butyl (3e) substituents at position 8 of the spiro ring exhibited activity against influenza A/H1N1 virus with EC50 values in the range of 35-45 µM and no cytotoxicity at 100 µM, the highest concentration tested.

Thioproline-Based Oxidation Strategy for Direct Preparation of N-Terminal Thiazolidine-Containing Peptide Thioesters from Peptide Hydrazides.

We describe a simple and robust oxidation strategy for preparing N-terminal thiazolidine-containing peptide thioesters from peptide hydrazides. We find for the first time that l-thioproline can be used as a protective agent to prevent the nitrosation of N-terminal thiazolidine during peptide hydrazide oxidation. The thioproline-based oxidation strategy has been successfully applied to the chemical synthesis of CC chemokine ligand-2 (69aa) and omniligase-C (113aa), thereby demonstrating its utility in hydrazide-based native chemical ligation.

Discovery of Substituted 2-oxoquinolinylthiazolidin-4-one Analogues as Potential EGFRK Inhibitors in Lung Cancer Treatment.

PURPOSE: Cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer and the chemotherapeutic drugs available have high toxicity and have reported side effects hence, there is a need for the synthesis of novel drugs in the treatment of cancer. METHODS: The current research work dealt with the synthesis of a series of 3-(3-acetyl-2-oxoquinolin-1-(2H)-yl-2-(substitutedphenyl)thiazolidin-4-one (Va-j) derivatives and evaluation of their in-vitro anticancer activity. All the synthesized compounds were satisfactorily characterized by IR and NMR data. Compounds were further evaluated for their in-vitro anticancer activity against A-549 (lung cancer) cell lines. The in-vitro anticancer activity was based upon the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay method. RESULTS: The synthesized compounds exhibited satisfactory anticancer properties against the A-549 cell line. The compound (VH): showed the highest potency amongst the tested derivatives against the A-549 cell line with IC50 values of 100 µg/ml respectively and was also found to be more potent than Imatinib (150 µg/ml) which was used as a standard drug. Molecular docking studies of the titled compounds (Va-j) were carried out using AutoDock Vina/PyRx software. The synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of the EGFRK tyrosine kinase domain (PDB 1m17). CONCLUSION: Among all the synthesized analogues, the binding affinity of the compound (Vh) was found to be higher than other synthesized derivatives and a molecular dynamics simulation study explored the stability of the docked complex system.

Synthesis of Thiazolidin-4-Ones Derivatives, Evaluation of Conformation in Solution, Theoretical Isomerization Reaction Paths and Discovery of Potential Biological Targets.

Thiazolin-4-ones and their derivatives represent important heterocyclic scaffolds with various applications in medicinal chemistry. For that reason, the synthesis of two 5-substituted thiazolidin-4-one derivatives was performed. Their structure assignment was conducted by NMR experiments (2D-COSY, 2D-NOESY, 2D-HSQC and 2D-HMBC) and conformational analysis was conducted through Density Functional Theory calculations and 2D-NOESY. Conformational analysis showed that these two molecules adopt exo conformation. Their global minimum structures have two double bonds (C=N, C=C) in Z conformation and the third double (C=N) in E. Our DFT results are in agreement with the 2D-NMR measurements. Furthermore, the reaction isomerization paths were studied via DFT to check the stability of the conformers. Finally, some potential targets were found through the SwissADME platform and docking experiments were performed. Both compounds bind strongly to five macromolecules (triazoloquinazolines, mglur3, Jak3, Danio rerio HDAC6 CD2, acetylcholinesterase) and via SwissADME it was found that these two molecules obey Lipinski's Rule of Five.

Design, synthesis and evaluation of new thiazolidin-4-ones as LPA1 receptor antagonists for breast cancer therapy.

Aim: Breast cancer has been a leading cause of mortality among women worldwide in recent years. Targeting the lysophosphatidic acid (LPA)-LPA1 pathway using small molecules could improve breast cancer therapy. Materials & methods: Thiazolidin-4-ones were developed and tested on MCF-7 cancer cells, and active compounds were analyzed for their effects on apoptosis, migration angiogenesis and LPA1 protein and gene expression. Results & conclusion: Compounds TZ-4 and TZ-6 effectively reduced the migration of MCF-7 cells, and induced apoptosis. TZ-4, TZ-6, TZ-8 and TZ-14 significantly reduced the LPA1 protein, LPA1 and angiogenesis gene expression in treated MCF-7 cells. Molecular docking and molecular dynamic simulation studies reveal the ligand interactions and stability of the LPA1-ligand complex. Developed thiazolidin-4-ones showed great potential as an LPA1-targeted approach to combating breast cancer.

Breast cancer is a major cause of death for women worldwide. Using small molecules to target the lysophosphatidic acid (LPA)­LPA₁ pathway could improve breast cancer treatment. We tested a type of molecule called thiazolidin-4-ones on breast cancer cells in the lab. We looked at how these molecules affected cell death, movement, blood vessel growth and the activity of the LPA₁ gene and protein. Some of these molecules, such as TZ-4 and TZ-6, reduced the movement of cancer cells and caused them to die. They also decreased the levels of LPA₁ protein and gene activity in the cells. We used computer simulations to see how these molecules interacted with the LPA₁ protein. Our findings suggest that thiazolidin-4-ones could be a promising treatment for breast cancer by targeting LPA₁.

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 and Molecular Docking of some new Thiazolidinone and Thiadiazole Derivatives as Anticancer Agents.

New sets of functionalized thiazolidinone and thiadiazole derivatives were synthesized, and their cytotoxicity was evaluated on HepG2, MCF-7, HTC-116, and WI38 cells. The synthetic approach is based on the preparation of 4-(4-acetamidophenyl)thiosemicarbazide (4) and their thiosemicarbazones 5 a-e, which are converted to the corresponding thiazoldin-4-one compounds 6 a-e upon cyclization with ethyl bromoacetate. The thiadiazole compounds 9 and 12 were obtained by reacting 4-(4-acetamidophenyl)thiosemicarbazide with isothiocyanates and/or ethyl 2-cyano-3,3-bis(methylthio)acrylate, respectively. The thiazolidinone compounds 6 c and 6 e exhibited strong cytotoxicity against breast cancer cells, with an IC50 (6.70±0.5 µM) and IC50 (7.51±0.8 µM), respectively, very close to that of doxorubicin (IC50: 4.17±0.2 µM). In addition, the anti-cancer properties of the tested thiazolidinone and thiadiazole scaffolds were further explored by the molecular docking program (MOE)-(PDB Code-1DLS). Compounds 5 d, 5 e, 6 d, 6 e, and 7 have the best binding affinity, ranging from -8.5386 kcal.mol-1 to -8.2830 kcal.mol-1.

One-Pot Synthesis of Novel 2-Imino-5-Arylidine-Thiazolidine Analogues and Evaluation of Their Anti-Proliferative Activity against MCF7 Breast Cancer Cell Line.

An efficient surface-mediated synthetic method to facilitate access to a novel class of thiazolidines is described. The rationale behind the design of the targeted thiazolidines was to prepare stable thiazolidine analogues and evaluate their anti-proliferative activity against a breast cancer cell line (MCF7). Most of the synthesized analogues exhibited increased potency ranging from 2-15-fold higher compared to the standard reference, cisplatin. The most active thiazolidines contain a halogenated or electron withdrawing group attached to the N-phenyl ring of exocyclic 2-imino group. However, combination of the two substituents did not enhance the activity. The anti-proliferative activity was measured in terms of IC50 values using an MTT assay.

Synthesis, Biological Evaluation and Molecular Docking Studies of 5-Indolylmethylen-4-oxo-2-thioxothiazolidine Derivatives.

BACKGROUND: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains. METHODS: Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds. RESULTS: All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6-17-fold) and ketoconazole (13-52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents. CONCLUSION: Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents.

Novel 2-phenyl-3-(Pyridin-2-yl) thiazolidin-4-one derivatives as potent inhibitors for proliferation of osteosarcoma cells in vitro and in vivo.

Due to unknown pathogenesis and unidentified drug target, no drug for the treatment of osteosarcoma (OS) has been launched to the market. Herein, thiazolidinone 1a was discovered as a hit compound by phenotypic screening with an in-house patrimonial collection of structural diversity. The following SAR (Structure-Activity Relationship) study affords the final water-soluble lead compound (R)-8i as a potential inhibitor for the proliferation of OS cells by the modulation of solubility of the compounds with remarkable cellular potency (IC50 = 21.9 nM for MNNG/HOS cells) and in vivo efficacy (52.9% inhibition OS growth in mice), as well as pharmacokinetic properties. (R)-8i also significantly suppresses OS cell migration in vitro and showed to be well-tolerated. Our preliminary investigation shows that the effects of (R)-8i are not dependent on p53 and myoferlin (MYOF). These results suggest that (R)-8i might be a potential drug candidate for OS treatment.

Discovery of thiazolidin-4-one analogue as selective GSK-3ß inhibitor through structure based virtual screening.

GSK-3ß directly phosphorylate tubulin binding site of tau protein, indicating its importance in tau aggregation and, therefore, in Alzheimer's disease pathology. New GSK-3ß inhibitors were identified using a structure-based screening, ADMET analysis. These studies revealed that ZINC09036109, ZINC72371723, ZINC72371725, and ZINC01373165 approached optimal ADMET properties along with good MM-GBSA dG binding. Protein kinase assays of these compounds against eight disease-relevant kinases were performed. During disease-relevant kinase profiling, ZINC09036109 ((E)-2-((3,4-dimethylphenyl)imino)-5-(3-methoxy-4-(naphthalen-2-ylmethoxy)benzyl)thiazolidin-4-one) emerged as a selective GSK-3ß inhibitor with more than 10-fold selectivity over other disease-relevant kinases. Molecular dynamics study of ZINC09036109 molecule revealed interactions with Ile62, Phe67, Val135, Leu188, Asp200 amino acid residues of the binding site of GSK-3ß, which were highly comparable to the co-crystallized molecule and hence validating comparative better activity of this compound compared to overall screened molecules.

Structure based designing of thiazolidinone-pyrimidine derivatives as ERK2 inhibitors: Synthesis and in vitro evaluation.

Breast cancer has been associated with an overexpression of various molecular targets; accordingly, various target-specific chemotherapeutic agents have been developed. Inhibition of ERK2, a member of MAPK pathway, is an important target involved in the treatment of both oestrogen receptor-positive and triple-negative breast cancer. Thus, in continuation of our previous work on the ERK2 target, we here report novel inhibitors of this kinase. Out of three lead molecules reported in our previous study, we selected the thiazolidinone-pyrimidine scaffold for further development of small molecule inhibitors of ERK2. Analogues of the lead molecule were docked in the target kinase, followed by molecular dynamic simulations and MM-GBSA calculations. Analogues maintaining key interactions with amino acid residues in the ATP-binding domain of ERK2 were selected and duly synthesized. In vitro biochemical evaluation of these molecules against ERK2 kinase disclosed that two molecules possess significant kinase inhibitory potential with IC50 values ≤ 0.5 µM.

2-Thioxothiazolidin-4-one Analogs as Pan-PIM Kinase Inhibitors.

Proviral integration site for Moloney murine leukemia virus (PIM) kinases are proto-oncogenic kinases involved in the regulation of several cellular processes. PIM kinases are promising targets for new drug development because they play a major role in many cancer-specific pathways, such as survival, apoptosis, proliferation, cell cycle regulation, and migration. Here, 2-thioxothiazolidin-4-one derivatives were synthesized and evaluated as potent pan-PIM kinase inhibitors. Optimized compounds showed single-digit nanomolar IC50 values against all three PIM kinases with high selectivity over 14 other kinases. Compound 17 inhibited the growth of Molm-16 cell lines (EC50 = 14 nM) and modulated the expression of pBAD and p4EBP1 in a dose-dependent manner.

Novel thiazolidine derivatives as potent selective pro-apoptotic agents.

A series of 2-arylthiazolidine-4-carboxylic acid amide derivatives were synthesized and their cytotoxic activity against three cancer cell lines (PC-3, SKOV3 and MDA-MB231) was evaluated. Various structural modifications were tried including modifications of the length of the amide chain and modifications of the 2-aryl part using disubstituted phenyl and thiophene derivatives. The structure activity relationship was evaluated based on the in vitro biological evaluation against the above mentioned three cancer cell lines. The most selective compounds towards cancer cells were further evaluated against DLD-1, NCI-H520, Du145, MCF-7 and NCI-N87 cancer cells. The dodecyl amide having the 4-bromothienyl as the 2-aryl, compound 2e, exhibited the highest selectivity for cancer cells vs non-tumor cells. Mechanistic studies of the anticancer effect of compound 2e in prostate cancer PC-3 and colorectal cancer DLD-1 cells revealed that 2e could prevent the cell cycle in the G0/G1 phase by up-regulating the expression of p21 and reducing the expression of CDK2 and cyclin E. It increased the pro-apoptotic protein Bax and cleaved caspase 3, and down-regulated the expression of anti-apoptotic protein Bcl-2 to induce apoptosis. In addition, 2e also downregulated AKT, N-cadherin, and vimentin proteins expression giving indication that 2e inhibit the PI3K/AKT pathway to regulate cell cycle arrest and induce apoptosis, and can regulate the expression of epithelial-mesenchymal transition-related proteins.

Exploration of the Antimicrobial Effects of Benzothiazolylthiazolidin-4-One and In Silico Mechanistic Investigation.

BACKGROUND: Infectious diseases still affect large populations causing significant morbidity and mortality. Bacterial and fungal infections for centuries were the main factors of death and disability of millions of humans. Despite the progress in the control of infectious diseases, the appearance of resistance of microbes to existing drugs creates the need for the development of new effective antimicrobial agents. In an attempt to improve the antibacterial activity of previously synthesized compounds modifications to their structures were performed. METHODS: Nineteen thiazolidinone derivatives with 6-Cl, 4-OMe, 6-CN, 6-adamantan, 4-Me, 6-adamantan substituents at benzothiazole ring were synthesized and evaluated against panel of four bacterial strains S. aureus, L. monocytogenes, E. coli and S. typhimirium and three resistant strains MRSA, E. coli and P. aeruginosa in order to improve activity of previously evaluated 6-OCF3-benzothiazole-based thiazolidinones. The evaluation of minimum inhibitory and minimum bactericidal concentration was determined by microdilution method. As reference compounds ampicillin and streptomycin were used. RESULTS: All compounds showed antibacterial activity with MIC in range of 0.12-0.75 mg/mL and MBC at 0.25->1.00 mg/mL The most active compound among all tested appeared to be compound 18, with MIC at 0.10 mg/mL and MBC at 0.12 mg/mL against P. aeruginosa. as well as against resistant strain P. aeruginosa with MIC at 0.06 mg/mL and MBC at 0.12 mg/mL almost equipotent with streptomycin and better than ampicillin. Docking studies predicted that the inhibition of LD-carboxypeptidase is probably the possible mechanism of antibacterial activity of tested compounds. CONCLUSION: The best improvement of antibacterial activity after modifications was achieved by replacement of 6-OCF3 substituent in benzothiazole moiety by 6-Cl against S. aureus, MRSA and resistant strain of E. coli by 2.5 folds, while against L. monocytogenes and S. typhimirium from 4 to 5 folds.

Multicomponent reaction for the synthesis of new 1,3,4-thiadiazole-thiazolidine-4-one molecular hybrids as promising antidiabetic agents through α-glucosidase and α-amylase inhibition.

A simple and efficient protocol was developed to synthesize a new library of thiazolidine-4-one molecular hybrids (4a-n) via a one-pot multicomponent reaction involving 5-substituted phenyl-1,3,4-thiadiazol-2-amines, substituted benzaldehydes and 2-mercaptoacetic acid. The synthesized compounds were evaluated in vitro for their antidiabetic activities through α-glucosidase and α-amylase inhibition as well as their antioxidant and antimicrobial potentials. Compound 4e exhibited the most promising α-glucosidase and α-amylase inhibition with an IC50 value of 2.59 µM, which is ~1.5- and 14-fold superior as compared to the standard inhibitor acarbose. Structure-activity relationship (SAR) analysis revealed that the nature and position of substituents on the phenyl rings had a significant effect on the inhibitory potency.