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.

Effect of Thiazolidin-4-one Against Lipopolysaccharide-Induced Oxidative Damage, and Alterations in Adenine Nucleotide Hydrolysis and Acetylcholinesterase Activity in Cultured Astrocytes.

Astrocytes play multiple important roles in brain physiology. However, depending on the stimuli, astrocytes may exacerbate inflammatory reactions, contributing to the development and progression of neurological diseases. Therefore, therapies targeting astrocytes represent a promising area for the development of new brain drugs. Thiazolidinones are heterocyclic compounds that have a sulfur and nitrogen atom and a carbonyl group in the ring and represent a class of compounds of great scientific interest due to their pharmacological properties. The aim of this study was to investigate the effect of 3-(3-(diethylamino)propyl)-2-(4-(methylthio)phenyl)thiazolidin-4-one (DS27) on cell proliferation and morphology, oxidative stress parameters, activity of the enzymes ectonucleotidases and acetylcholinesterase (AChE) and interleukin 6 (IL-6) levels in primary astrocyte cultures treated with lipopolysaccharide (LPS), to model neuroinflammation. The astrocyte culture was exposed to LPS (10 µg/ml) for 3 h and subsequently treated with compound DS27 for 24 and 48 h (concentrations ranging to 10-100 µM). LPS induced an increase in astrocyte proliferation, AChE activity, IL-6 levels, oxidative damage, ATP and ADP and a reduction in AMP hydrolysis in rat primary astrocyte cultures. DS27 treatment was effective in reversing these alterations induced by LPS. Our findings demonstrated that DS27 is able to modulate cholinergic and purinergic signaling, redox status, and the levels of pro-inflammatory cytokines in LPS-induced astrocyte damage. These glioprotective effects of DS27 may be very important for improving neuroinflammation, which is associated with many brain diseases.

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.

Design, Synthesis, Molecular docking, and biological evaluation of novel 2,3-diaryl-1,3-thiazolidine-4-one derivatives as potential anti-inflammatory and cytotoxic agents.

A new series of 2,3-diaryl-1,3thiazolidin-4-one derivatives was designed, synthesized, and evaluated for their cytotoxicity and COXs inhibitory activities. Among these derivatives, compounds 4 k and 4j exhibited the highest inhibitory activities against COX-2 at IC50 values of 0.05 and 0.06 µM, respectively. Compounds 4a, 4b, 4e, 4 g, 4j, 4 k, 5b, and 6b, which exhibited the highest inhibition% against COX-2, were evaluated for their anti-inflammatory activity in rats. Results showed 41.08-82.00 % inhibition of paw edema thickness by the test compounds compared to celecoxib (inhibition% = 89.51 %). In addition, compounds 4b, 4j, 4 k, and 6b exhibited better GIT safety profiles compared to celecoxib and indomethacin. The four compounds were also evaluated for their antioxidant activity. The results revealed the highest antioxidant activity for 4j (IC50 = 45.27 µM) comparable to torolox (IC50 = 62.03 µM). The antiproliferative activity of the new compounds was evaluated against HePG-2, HCT-116, MCF-7, and PC-3 cancer cell lines. The results showed the highest cytotoxicity for compounds 4b, 4j, 4 k, and 6b (IC50 = 2.31-27.19 µM), with 4j being the most potent. Mechanistic studies revealed the ability of 4j and 4 k by inducing marked apoptosis and cell cycle arrest at the G1 phase in HePG-2 cancer cells. These biological results may also suggest a role for COX-2 inhibition in the antiproliferative activity of these compounds. The results of the molecular docking study for 4 k and 4j into the active site of COX-2 revealed good fitting and correlation with the results of the in vitro COX­2 inhibition assay.

Design and synthesis of some novel hybrid molecules based on 4-thiazolidinone bearing pyridine-pyrazole scaffolds: molecular docking and molecular dynamics simulations of its major constituent onto DNA gyrase inhibition.

Due to multidrug resistance, microbial infections have become significant on a global level. As infections caused by several resistant bacteria and fungi severely harm mankind, scientists have developed new antibiotics to combat these infections. In order to develop novel antimicrobial agents, a series of 4-thiazolidinone-based 5-arylidene hybrids (5a-o) have been designed and synthesized to evaluate their antibacterial and antifungal activities. For the determination of the structure of a novel synthesized hybrid, various spectral techniques, e.g., IR, 1H NMR, 13C NMR, and Mass spectroscopy, were used. Two bacterial gram-negative (Escherichia coli and Pseudomonas aeruginosa), two gram-positive strains (Staphylococcus aureus and Streptococcus pyogenes), and one fungal strain (Candida albicans) were used to evaluate antimicrobial activity. Compounds 5c, 5g, and 5i were effective due to their MIC values of 62.5 µg/mL against tested bacterial strains (S. pyogenes (5c), P. aeruginosa (5g), and E. coli (5i), respectively.) and 250 µg/mL against C. albicans fungal strains, respectively. Additionally, molecular docking and 100 ns molecular dynamic simulations were carried out to investigate the stability of molecular contacts and to establish how the newly synthesized inhibitors fit together in the most stable conformations.

Novel N-methylsulfonyl-indole derivatives: biological activity and COX-2/5-LOX inhibitory effect with improved gastro protective profile and reduced cardio vascular risks.

Three novel series of N-methylsulfonylindole derivatives 3a&b, 4a-e, and 5a-e were synthesised. Different biological activities of the synthesised compounds were studied. Antimicrobial activity showed that, compounds 4b, 4e and 5d had selective antibacterial activity against the Gram-negative bacteria, Salmonella enterica and/or E. coli. The anti-oxidant activity of the synthesised compounds was evaluated by DPPH radical scavenging activity. In vitro anti-inflammatory activity was estimated. Compounds 4d, 4e, 5b, and 5d showed the highest anti-inflammatory activity. The COX-1, COX-2 and 5-LOX inhibitory activities were measured using enzyme immune assay (EIA) kits. Due to the dual COX-2/5-LOX inhibitory activity of compound 5d, its cardiovascular profile was determined by measuring cardiac biomarkers (LDH, CK-MB, and Tn-I). Besides, the histopathological study of the heart muscle and stomach were examined for the most active COX-2 inhibitors 4e and 5d. Finally, a molecular modelling study and pharmacokinetic properties were obtained using different computational methods.

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.

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.

Coumarin derivatives with potential anticancer and antibacterial activity: Design, synthesis, VEGFR-2 and DNA gyrase inhibition, and in silico studies.

A series of coumarin derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Compound 3e exhibited significant antiproliferative activity and was further evaluated at five doses at the National Cancer Institute. It effectively inhibited vascular endothelial growth factor receptor-2 (VEGFR-2) with an IC50 value of 0.082 ± 0.004 µM compared with sorafenib. While compound 3e significantly downregulated total VEGFR-2 and its phosphorylation, it markedly reduced the HUVEC's migratory potential, resulting in a significant disruption in wound healing. Furthermore, compound 3e caused a 22.51-fold increment in total apoptotic level in leukemia cell line HL-60(TB) and a 6.91-fold increase in the caspase-3 level. Compound 3e also caused cell cycle arrest, mostly at the G1/S phase. Antibacterial activity was evaluated against Gram-positive and Gram-negative bacterial strains. Compound 3b was the most active derivative, with the same minimum inhibitory concentration and minimum bactericidal concentration value of 128 µg/mL against K. pneumonia and high stability in mammalian plasma. Moreover, compounds 3b and 3f inhibited Gram-negative DNA gyrase with IC50 = 0.73 ± 0.05 and 1.13 ± 0.07 µM, respectively, compared to novobiocin with an IC50 value of 0.17 ± 0.02 µM. The binding affinity and pattern of derivative 3e toward the VEGFR-2 active site and compounds 3a-c and 3f in the DNA gyrase active site were evaluated using molecular modeling. Overall, ADME studies of the synthesized coumarin derivatives displayed promising pharmacokinetic properties.

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.

Novel Azine Linked Hybrids of 2-Indolinone and Thiazolodinone Scaffolds as CDK2 Inhibitors with Potential Anticancer Activity: In Silico Design, Synthesis, Biological, Molecular Dynamics and Binding Free Energy Studies.

Molecular hybrid of 2-indolinone-thiazolidinone is a well known scaffold for variable biological activities including anticancer activity. Accordingly, in the current work aided with structure-based molecular modeling studies, a library of novel twenty-six hybrids, 4(a-z), was designed and synthesized. Docking studies in the active site of CDK2, one of the key checkpoints enzymes, revealed that the binding scores of the designed molecules are comparable to the reference enzyme's inhibitors Sunitinib, Nintedanib, and Semaxanib. Variable antiproliferative activities are shown for these molecules against human liver (HepG2), breast (MCF7), and colon (HCT-29) cell lines considering Doxrubacin as a refrence drug. Compared to cytotoxic activities on the normal fibroblasts (WI-38), the tested molecules had better selectivity against the cancerous cells, expressed by their selectivity index (SI), than Doxrubacin and compound 4i was the safest compound. CDK2 inhibitory results of compounds 4f, 4g, 4h, and 4w showed IC50 at 59.43, 143.6, 27.42, and 61.63 nM respectively, while that of Sunitinib was 23.8 nM. To clarify the obtained biological activities of these molecules, broad docking and molecular dynamic simulations studies were undertaken and confirmed the consistency between the computational and the in vitro CDK2 inhibitory activities. Furthermore, in silico ADME/Tox profiles were done for the most active molecules using SwissADME and pkCSM-pharmacokinetics web-based methods predicted good pharmacokinetics, bioavailability, and toxicity profiles for the tested compounds.

Mandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations.

A series of new spirothiazolidinone derivatives with a mandelic acid moiety were synthesized and subsequently tested in growth inhibition assays against Mycobacterium tuberculosis strain H37Rv. Compound 16 displayed the highest inhibition value of 98% at lower than 6.25 µg/mL concentration. A single crystal X-ray analysis was conducted on this compound to confirm the structure and determine its absolute configuration. Afterwards, reverse docking and molecular dynamics simulations of this specific stereoisomer were performed against a selection of 10 putative targets of M. tuberculosis to suggest possible mechanisms of action. Our results suggest HadAB, Pks13, DprE1, FadD32 and InhA as possible target proteins for the observed antimycobacterial activity of compound 16.

Iron-catalyzed intermolecular cross-dehydrogenative C(sp3)-H/C(sp)-H coupling of pyrimidine bearing 4-thiazolidinones with terminal alkynes.

A novel, simple and efficient protocol for the Fe-catalyzed, intermolecular cross-dehydrogenative coupling of pyrimidine bearing 4-thiazolidinones systems and terminal alkynes was established. This methodology offers a high yielding, straightforward, and one-pot approach towards the synthesis of alkynylated 4-thiazolidinones without prior activation of C(sp3)-H and C(sp)-H. The results of control experiments indicated that this conversion might proceed via a radical process.

Design, synthesis, and preliminary pharmacological evaluation of novel thiazolidinone derivatives as potential benzodiazepine agonists.

Thiazolidinones are well-known heterocycles that demonstrate promising biological effects such as anticonvulsant activity. Hybridization of these chemicals with scaffold, which has necessary pharmacophores for binding to the benzodiazepine receptors, can prompt a novel structure possessing extensive anticonvulsant effects. In this study, novel derivatives of thiazolidinone as new benzodiazepine agonists were designed, synthesized, and biologically evaluated. Compound 5h, 4-chloro-2-(2-fluorophenoxy)-N-(4-oxo-2-(p-tolyl)thiazolidin-3-yl)benzamide, exhibited considerable anticonvulsant activity, proper sedative-hypnotic effect, no memory impairment, and no muscle relaxant effect. The pharmacological effects of the designed compounds were antagonized by flumazenil, which confirmed the benzodiazepine receptors' involvement in their biological effects. Based on in silico calculations of ADME properties of our novel compounds, they could be active oral agents potentially. In this study, we designed novel structures by the hybridization of thiazolidinone moiety with scaffold which has necessary pharmacophores for binding to the benzodiazepine receptors. The results are very promising for developing new lead compounds as benzodiazepine agonists possess anticonvulsant effects.

Novel Hydrazono-2-Iminothiazolidin-4-Ones Based on a Monoterpenic Skeleton as Potential Antitumor Agents: Synthesis, DFT Studies, in†Vitro Cytotoxicity, Apoptosis Inducing Properties and Molecular Docking.

A series of novel 2-iminothiazolidin-4-one analogs have been synthesized from limonaketone, and structurally characterized by HR-MS, 1 H-NMR and 13 C-NMR spectroscopy techniques, and the structure of compound 4 was elucidated by XRD. The newly synthesized products were biologically evaluated in vitro for their cytotoxic activity against human cancer cell lines HT-1080, A549, and MCF-7. Thiazolidinones 9 and 10 were the most active compounds in HT-1080 cell lines (IC50 =15.85±1.75 and 16.13±1.55 µM, respectively). The apoptosis induction of the derivatives 9 and 10 were studied using annexin V staining, caspase-3/7 activity and cell cycle analysis. Compound 10 showed the highest ability of apoptosis induction and caspase-3/7 activation associated with S-phase growth arrest in HT-1080. Meanwhile, compound 9 has a moderate apoptotic effect and G0/G1-phase arrest in the after-mentioned cell. The molecular docking suggested that compounds 9 and 10 formed stable ligand-caspase-3 complexes. Besides, the presence of phenyl moiety in ligand 10 is responsible for the enhancement of the caspase-3 activation by the apparition of two additional hydrogen bonds with Cys163 and Gln161amino acids.

Potential Fluorinated Anti-MRSA Thiazolidinone Derivatives with Antibacterial, Antitubercular Activity and Molecular Docking Studies.

MRSA infection is one of the alarming diseases in the current scenario. Identifying newer molecules to treat MRSA infection is of urgent need. In the present study, we have designed fluorinated thiazolidinone derivatives with various aryl/heteroaryl units at 5th position of the thiazolidinone core as promising anti-MRSA agents. All the compounds were screened for antibacterial activity against four bacterial strains. Among the tested compounds, the halogenated compounds with simple arylidene ring, (5Z)-5-[(3-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4b), (5Z)-5-[(4-chloro-2-fluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4c), (5Z)-5-[(3-fluoro-4-methylphenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4f) and (5Z)-5-[(3,5-difluorophenyl)methylidene]-2-[(1,3-thiazol-2-yl)amino]-1,3-thiazol-4(5H)-one (4g) showed excellent activity with MIC 3.125-6.25 µg/mL against S. aureus and P. aeruginosa organism. Furthermore, these potent compounds were screened against MRSA strains, ESKAPE panel organism, and H37Rv mycobacterium strain. Compounds 4c (MIC 0.39 µg/mL), and 4f (MIC 0.39 and 0.79 µg/mL) displayed promising activity against MRSA strains (ATCC and clinical isolates, respectively). The most potent compounds, 4c and 4f eradicated the growth of bacterial colonies in a time-kill assay indicated that these are bactericidal in nature. The preliminary toxicity study of the potent molecules revealed that these compounds are non-hemolytic in nature as they did not induce lysis in human RBCs. In addition, the molecular docking and dynamics studies of compounds 4b, 4c, 4f and 4g were carried out on MurB protein of S. aureus (PDB code: 1HSK). Docking results demonstrated remarkable hydrogen bonding interaction with key amino acids ARG310, ASN83, GLY79 and π-π interactions with TYR149 which confirm the mode of action of the molecules.

Synthesis and Molecular Docking of New Bis-Thiazolidinone-Based Chalcone Analogs as Effective Inhibitors of Acetylcholinesterase and Butyrylcholinesterase.

This work reports the convenient strategy for the synthesis of bis-thiazolidinone based chalcone analogs (1-20) from readily available thiosemicarbazide hydrochloride, ammonium thiocyanate and benzaldehyde. All the newly afforded bis-thiazolidinone based chalcone analogs (1-20) were screened in vitro for their acetylcholinesterase and butyrylcholinesterase inhibition profile. It was noteworthy, that all the synthetic analogs (except analogs 10, 12 and 14, which are found to be inactive) showed moderate to good inhibitory potentials on screening against acetylcholinesterase having range of inhibitory with IC50 values from 0.070±0.050 to 7.60±0.10 µM, and similarly for butyrylcholinesterase with range IC50 values from 0.10±0.050 µM to 10.70±0.20 µM, respectively as compared to standard Donepezil inhibitor (IC50 =2.16±0.12 µM), (IC50 =4.5±0.11 µM).Among the series, the analogs with hydroxy group showed superior inhibitory potentials against acetylcholinesterase and butyrylcholinesterase enzymes. Therefore, analog 20 (IC50 =0.070±0.050 µM), (IC50 =0.10±0.050 µM) bearing trihydroxy substitutions on ortho-, meta- and para-position of both rings A and B was found to be the most active inhibitor of acetylcholinesterase and butyrylcholinesterase enzymes among the current synthesized series (1-23). Analog 19 (IC50 =0.15±0.050 µM), (IC50 =0.20±0.050 µM) bearing dihydroxy substitutions on ortho- and meta-position of both ring A and ring B was identified as the second most potent inhibitor against both these enzymes. Interestingly, the compound (16) (IC50 =1.50±0.10 µM against AChE) has a better selectivity index (2.60) than standard Donepezil drug (2.083) for AChE over BuChE. The different types of spectroscopic techniques such as HR-EI-MS, 1 H- and 13 C- NMR were used to confirm the structure of all the newly synthetics analogs. To find structure-activity relationship, molecular docking studies were carried out to understand the binding mode of active inhibitors with active site of enzymes and results supported the experimental data.

4-Thiazolidinone-Bearing Hybrid Molecules in Anticancer Drug Design.

Oncological diseases have currently reached an epidemic scale, especially in industrialized countries. Such a situation has prompted complex studies in medicinal chemistry focused on the research and development of novel effective anticancer drugs. In this review, the data concerning new 4-thiazolidinone-bearing hybrid molecules with potential anticancer activity reported during the period from the years 2017-2022 are summarized. The main emphasis is on the application of molecular hybridization methodologies and strategies in the design of small molecules as anticancer agents. Based on the analyzed data, it was observed that the main directions in this field are the hybridization of scaffolds, the hybrid-pharmacophore approach, and the analogue-based drug design of 4-thiazolidinone cores with early approved drugs, natural compounds, and privileged heterocyclic scaffolds. The mentioned design approaches are effective tools/sources for the generation of hit/lead compounds with anticancer activity and will be relevant to future studies.

Discovery of 5-Methylthiazole-Thiazolidinone Conjugates as Potential Anti-Inflammatory Agents: Molecular Target Identification and In Silico Studies.

A series of previously synthesized 5-benzyliden-2-(5-methylthiazole-2-ylimino)thiazoli- din-4-one were evaluated for their anti-inflammatory activity on the basis of PASS predictive outcomes. The predictive compounds were found to demonstrate moderate to good anti-inflammatory activity, and some of them displayed better activity than indomethacin used as the reference drug. Structure-activity relationships revealed that the activity of compounds depends not only on the nature of the substituent but also on its position in the benzene ring. The most active compounds were selected to investigate their possible mechanism of action. COX and LOX activity were determined and found that the title compounds were active only to COX-1 enzymes with an inhibitory effect superior to the reference drug naproxen. As for LOX inhibitory activity, the derivatives failed to show remarkable LOX inhibition. Therefore, COX-1 has been identified as the main molecular target for the anti-inflammatory activity of our compounds. The docking study against COX-1 active site revealed that the residue Arg 120 was found to be responsible for activity. In summary, the 5-thiazol-based thiazolidinone derivatives have been identified as a novel class of selective COX-1 inhibitors.

New Biologically Hybrid Pharmacophore Thiazolidinone-Based Indole Derivatives: Synthesis, In Vitro Αlpha-Amylase and Αlpha-Glucosidase Along with Molecular Docking Investigations.

Amylase and glucosidase enzymes are the primary harmful source in the development of the chronic condition known as diabetes mellitus. The main function of these enzymes is to break the macromolecules into simple sugar units which are directly involved in the solubility of blood, hence increasing blood glucose levels. To overcome this effect, there is a need for a potent and effective inhibitor that inhibits the conversion of macromolecules of sugar into its smaller units. In this regard, we synthesized thiazolidinone-based indole derivatives (1−20). The synthesized derivatives were evaluated for α-amylase and α-glucosidase inhibitory activity. Different substituted derivatives were found with moderate to good potentials having IC50 values ranging, for α-amylase, from 1.50 ± 0.05 to 29.60 ± 0.40 µM and, for α-glucosidase, from IC50 = 2.40 ± 0.10 to 31.50 ± 0.50 µM. Among the varied substituted compounds, the most active analogs four (1.80 ± 0.70 and 2.70 ± 0.70), five (1.50 ± 0.05 and 2.40 ± 0.10, respectively) of the series showed few folds better inhibitory activity than standard drug acarbose (IC50 = 10.20 ± 0.10 and 11.70 ± 0.10 µM, respectively). Moreover, structure−activity relationship (SAR) was established and binding interactions were analyzed for ligands and proteins (α-amylase and α-glucosidase) through a molecular docking study.