Synthesis and biological evaluation of novel rhodanine-based structures with antiviral activity towards HHV-6 virus.

An increased awareness of diseases associated with Human herpesvirus 6 (HHV-6) infection or reactivation has resulted in a growing interest in the evaluation of the best treatment options available for the clinical management of HHV-6 disease. However, no compound has yet been approved exclusively for HHV-6 infection treatment. For this reason, the identification of anti-HHV6 compounds provides a valuable opportunity for developing efficient antiviral therapies. A possible target for antiviral drugs is the virus-cell fusion step. In this study, we synthetized potential fusion intermediates inhibitors based on the rhodanine structure. The obtained derivatives were tested for cytotoxicity and for antiviral activity in human cells infected with HHV6. Level of infection was monitored by viral DNA quantification at different time points up to 7 days post infection. Among the synthetized derivatives, 9e showed a significative inhibitory effect on viral replication that lasted over 7 days, probably attributable to the particular combination of hydrophilic and hydrophobic substituents to the rhodanine moiety. Our results support the use of these amphipathic fusion inhibitors for the treatment of HHV-6 infections.

The dual inhibition against the activity and expression of tyrosine phosphatase PRL-3 from a rhodanine derivative.

Increasing evidences demonstrated that PRL-3 was associated with metastatic potential in a variety of cancers including CRC, gastric cancer, ovarian cancer and so on. PRL-3 knock down inhibited the development of metastasis by reducing the size of primary tumors and inhibiting the invasion and growth of cancer cells. Therefore, PRL-3 is a promising diagnostic marker and therapeutic target in tumors. So far, only several PRL-3 inhibitors have been reported. In this study, six rhodanine derivatives were synthesized and characterized. The compounds were evaluated against tyrosine phosphatase PRL-3. Among these compounds, 5-(5-chloro-2-(trifluoromethyl)benzylidene)-2-thioxothiazolidin-4-one (4) could effectively inhibit PRL-3 with IC50 value of 15.22 µM. Fluorescent assays suggested compound 4 tightly bound to tyrosine phosphatase PRL-3 with the molar ratio of 1:1, and the binding constant of 1.74 × 106 M-1. Compound 4 entered into SW-480 cells, selectively inhibited the expression of PRL-3 and increased the phosphorylation of PRL-3 substrates, and decreased the survival rate of SW-480 cells with IC50 of 6.64 µM and induced apoptosis. The results revealed that compound 4 is a dual functional inhibitor against the activity and expression of PRL-3 and a promising anti-cancer candidate targeting PRL-3.

QM/MM analysis, synthesis and biological evaluation of epalrestat based mutual-prodrugs for diabetic neuropathy and nephropathy.

Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T1/2) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy.

New N-ribosides and N-mannosides of rhodanine derivatives with anticancer activity on leukemia cell line: Design, synthesis, DFT and molecular modelling studies.

N-ribosylation and N-mannosylation compounds have a great role in compounds activity as anticancer. The reaction of 2-thioxo-4-thiazolidinone (rhodanine) derivatives, as aglycon part, was done with ribofuranose and mannopyranose sugars (glycone part) followed by deacetylation without cleavage of the rhodanine under acidic medium. Conformational analysis has been studied using NMR methods (2D, DQF-COSY, HMQC and HMBC). All final the new deprotected nucleosides were screened against leukemia 1210, and were found to be considerably less potent (Ic50% 1.4-10.6 µM) than doxorubicin (Ic50% 0.02 µM). Compounds 10d and 10e which contain ribose moiety have better activity than those with mannose sugar. DFT calculations with B3LYP/6-31 + G (d) level were used to analyze the electronic and geometric characteristics deduced from the stable structure of the compounds. The principal quantum chemical descriptors showed a good correlation with the experimental observations. Rapid Overlay Comparison Similarity (ROCS) study was operated to explain the compounds similarity and to figure out the most important pharmacophoric features.

Green Synthesis, Biological Activity Evaluation, and Molecular Docking Studies of Aryl Alkylidene 2, 4-thiazolidinedione and Rhodanine Derivatives as Antimicrobial Agents.

AIMS AND OBJECTIVE: The magic scaffolds rhodanine and thiazolidine are very important heterocyclic compounds in drug design and discovery. Those are important heterocyclic compounds that have attracted a great deal of attention due to the fact that they exhibit a variety of bioactivities including antibacterial, antifungal, antiviral, antimalarial, and anti-inflammatory activities. These agents often exhibit selective toxicity. The goal of this study was molecular docking, green and solvent-free efficient synthesis of a new series of hetero/aromatic substituted rhodanine and thiazolidine analogues and then investigation of their antimicrobial activity. MATERIALS AND METHODS: To a mixture of TZD or rhodanine (1 mmol) in the presence of ionic liquid ChCl/urea, various aldehyde (1 mmol) was added. After completion of the reaction, obtained crude compound was collected by filtration and products were recrystallized from ethanol. The binding-free energy between all synthesized compounds with 3EEJ protein (C. glabrata enzyme) were obtained by molecular docking studies. These compounds were evaluated using microdilution method against (ATCC 6538) and (ATCC 12228) Gram-negative, (ATCC 8739) and (ATCC 9027) as Gram-positive and (ATCC 1012), (ATCC 339), C. (ATCC 1057), (ATCC 503), (ATCC 340) and (ATCC 194) as fungi. RESULTS: All of the acceptable products were determined by 1H NMR, 13C NMR, Mas and FT-IR spectroscopy. The binding-free energy between compounds 10a and 10b with 3EEJ protein were found to be -8.08 kcal/mol and -8.15 kcal/mol, respectively. These compounds having a heteroaromatic ring attached to the TZD or rhodanine core showed excellent antimicrobial activity with MIC values of 0.25-8 µg/mL (compound 10a) and 0.5-16 µg/mL (compound 10b) against the most tested fungi strains, Gram-positive and Gram-negative bacteria. CONCLUSION: A convenient and rapid method has been developed for the synthesis of rhodanine and thiazolidine-2,4-dione (TZD) derivatives as efficient antimicrobial agents using a Deep Eutectic Ionic Liquids (DEILs) choline chloride urea under solvent-free condition. Among the newly synthesized compounds, (Z)-5-((quinoxalin-3-yl) methylene) thiazolidine-2, 4-dione (10a) and (Z)- 5- ((quinoxalin-3-yl) methylene)-2-thioxothiazolidin-one (10b) exerted the promising effect and these compounds can be considered to be further probed as inhibitors of cgDHFR enzyme.

Design, synthesis, biological evaluation, and molecular modeling studies of rhodanine derivatives as pancreatic lipase inhibitors.

A series of rhodanine-3-acetic acid derivatives were synthesized via Knoevenagel condensation of rhodanine-3-acetic acid with various substituted aromatic aldehydes. The synthesized derivatives were screened in vitro for understanding the inhibitory potential towards pancreatic lipase (PL), a key enzyme responsible for the digestion of dietary fats. Derivative 8f exhibited a potential inhibitory activity towards PL (IC50 = 5.16 µM), comparable to that of the standard drug, orlistat (0.99 µM). An increase in the density of the aromatic ring resulted in potential PL inhibition. The enzyme kinetics of 8f exhibited a reversible competitive-type inhibition, similar to that of orlistat. Derivative 8f exhibited a MolDock score of -125.19 kcal/mol in docking studies, and the results were in accordance with their PL inhibitory potential. Furthermore, the reactive carbonyl group of 8f existed at a distance adjacent to Ser152 (≈3 Å) similar to that of orlistat. Molecular dynamics simulation (10 ns) of the 8f-PL complex revealed a stable binding conformation of 8f in the active site of PL (maximum root mean square displacement of ≈2.25 Å). The present study identified novel rhodanine-3-acetic acid derivatives with promising PL inhibitory potential, and further lead optimization might result in potent PL inhibitors.

Synthesis and biological evaluation of tryptophan-derived rhodanine derivatives as PTP1B inhibitors and anti-bacterial agents.

Several series of novel tryptophan-derived rhodanine derivatives were synthesized and identified as potential competitive PTP1B inhibitors and antibacterial agents. Among the compounds studied, 10b was found to have the best in vitro inhibition activity against PTP1B (IC50 = 0.36 ±â€¯0.02 µM). In addition, the compounds also showed potent inhibition against other PTPs, especially CDC25B. Molecular docking analysis demonstrated that compounds 7c and 10b could occupy both the catalytic site and the adjacent pTyr binding site simultaneously. The compounds also showed higher levels of activity against gram-positive strains, the gram-negative strain Escherichia coli 1924, and multidrug-resistant gram-positive bacterial strains. Compounds 7c, 8c, 9e, 10a, and 10c had comparable or more potent antibacterial activity than the positive controls.

Spectroscopic and In Silico DNA Binding Studies on the Interaction of Some New N-Substituted Rhodanines with Calf-thymus DNA: In Vitro Anticancer Activities.

BACKGROUND: In this era of science, cancer is a black dot on the face of humankind. Consequently, the search of promising anticancer agents continues. AIMS: Here we designed and synthesized new N-substituted rhodanines (RD1-7), evaluated their multispectroscopic interaction with calf thymus DNA, in silico and anticancer studies against MDA-MB-231cancer cell line. METHODS: By MTT assay rhodanine RD1 was found to be the most potent with IC50 value of 72.61 µM. In addition, DNA binding studies (UV-vis and fluorescence) revealed strong binding affinity of RD1-7 with DNA (Kb in the range of 1.5-7.4 × 105 M-1). Moreover, molecular docking study, experimental DNA binding and anticancer studies are all well agreed to each other. RESULTS: It was observed that H-bonding and hydrophobic attractions were responsible for stability of DNAcompound adducts. Besides, the reported rhodanines (RD1-7) were found as minor groove binders of DNA. Concisely, RD1-7 indicated promising pharmacological properties and hence, shows auspicious future for the development of novel anticancer agents. CONCLUSION: The reported rhodanines showed excellent anticancer properties. Therefore, the described rhodanines may be used as potential anticancer agents in the future.

Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-ß-lactamases.

Metallo-ß-lactamases (MBLs) enable bacterial resistance to almost all classes of ß-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.

Synthesis and biological evaluation of novel carbazole-rhodanine conjugates as topoisomerase II inhibitors.

In this study, a series of carbazole-rhodanine conjugates was synthesized and evaluated for their Topoisomerase II inhibition potency as well as cytotoxicity against a panel of four human cancer cell lines. Among these thirteen compounds, 3a, 3b, 3g, and 3h possessed Topoisomerase II inhibition potency at 20 µM. Mechanism study revealed that these compounds may function as Topo II catalytic inhibitors. It was found that the electron-withdrawing groups on the phenyl ring of compounds played an important role on enhancing both enzyme inhibition and cytotoxicity.

Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1.

Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a-d, 5f-n, and 7a-b) exhibited Zmp1 inhibition with IC50 values in the range 1.3-43.9 µM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7 µM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10 µg/ml. This work represents a step forward in targeting Zmp1 by small molecules.

A Comprehensive Review on the Biological and Pharmacological Activities of Rhodanine Based Compounds for Research and Development of Drugs.

At present, diseases resulting from various reasons have been causing deadly fears to humans and previously incogitable losses to health. Meanwhile, the patient compliance has been weakening because of drug resistance and serious drug adverse effects. There is therefore an urgent need for the development of novel structural agents. Rhodanine derivatives have exhibited wide biological activities, as well as significant industrial applications, which suggests that rhodanine heterocycle represents a key structural motif in heterocyclic chemistry and occupies a prominent position in drug discovery. Here, we review some deadly defects of clinical medicines to the therapy of diseases and important advances on rhodanine derivatives in drug researches (e.g. as anti-diabetic, anti-viral, antiinflammatory, anti-microbial, anti-tumor agents and inhibitors for Alzheimer Disease), indicating that rhodanine heterocycle could be used as a significant pharmacophore to develop novel pharmacological active molecules. It is believed that the review is of importance for new ideas in the development of and rational designs of rhodanine-based drugs.

Thiazolidinedione or Rhodanine: A Study on Synthesis and Anticancer Activity Comparison of Novel Thiazole Derivatives.

PURPOSE: A new series of thiazolyl-2,4-thiazolidinedione / rhodanine compounds T1-T23 was synthesized and tested for their anticancer activities. Hepatocellular carcinoma cell lines were chosen due to their strong drug resistance to test the new compounds. METHODS: All compounds were synthesized via Knoevenagel Condensation reaction and thiazolidinedione ester compounds (T3,T9,T15,T20) were hydrolyzed for obtaining the acidic compounds (T6,T12,T17,T23). All compounds were firstly screened for their anticancer activity against two hepatocellular carcinoma (HCC) cell lines, Huh7 and Plc/Prf/5 (Plc) cell lines by sulforhodamine B assay. Further IC50 values were calculated for three candidates (T4, T15, T21) in five different HCC (Huh7, Plc, Snu449, HepG2, Hep3B) and one breast cancer (Mcf7) cell line. RESULTS: Compounds T4, T15, T21 had very strong anticancer effects even though their 10 µM concentration in Huh7 cell line. According to IC50 values, T21 was the most effective compound with IC50 values in a range from 2 to 16 µM in 6 cancer cell lines. In terms of cytotoxicity T21 mostly affected Huh7 and interestingly it was less effective against Plc. CONCLUSIONS: Considering these results it can be suggested that compounds T4, T15 and T21 may lead to the development of more potent anticancer drugs in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis, functional evaluation and molecular modeling study.

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.

Synthesis and Bioactivity Evaluation of N-Arylsulfonylindole Analogs Bearing a Rhodanine Moiety as Antibacterial Agents.

Due to the rapidly growing bacterial resistance to antibiotics and the scarcity of novel agents under development, bacterial infections are still a pressing global problem, making new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, urgently needed. In this paper, seven series of N-arylsulfonylindole analogs 5-11 bearing rhodanine moieties were synthesized, characterized, and evaluated for antibacterial activity. According to the in vitro antimicrobial results, half of the synthesized compounds showed potent inhibition against four Gram-positive bacteria, with MIC values in the range of 0.5-8 µg/mL. For multidrug-resistant strains, compounds 6a and 6c were the most potent, with MIC values of 0.5 µg/mL, having comparable activity to gatifloxacin, moxiflocaxin and norfloxacin and being 128-fold more potent than oxacillin (MIC = 64 µg/mL) and 64-fold more active than penicillin (MIC = 32 µg/mL) against Staphylococcus aureusATCC 43300.

Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family.

The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75µM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.

Quinolidene-rhodanine conjugates: Facile synthesis and biological evaluation.

A series of rhodanine incorporated quinoline derivatives were efficiently synthesized using reusable DBU acetate as ionic liquid and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) (ATCC 25177) and Mycobacterium bovis BCG (ATCC 35743) both in active and dormant state. Compounds 3e, 3f, 3g, 3h and 3i exhibited very good antitubercular activity. The active compounds were studied for cytotoxicity against HUVEC, THP-1, macrophages, A549, PANC-1 and HeLa cell lines using modified MTT assay and were found to be noncytotoxic. Inactivity of all these compounds against Gram positive and Gram negative bacteria indicates their specificity towards the MTB. Further, the synthesized compounds have been screened for their in vitro antifungal activity. In addition, the molecular docking studies revealed the binding modes of these compounds in active site of Zmp1 enzyme, which in turn helped to establish a structural basis of inhibition of mycobacteria. The results of present study clearly indicate the identification of some novel, selective and specific inhibitors against MTB that can be explored further for potential antitubercular drug.

Synthesis and in vitro evaluation of novel rhodanine derivatives as potential cholinesterase inhibitors.

Based on a broad spectrum of biological activities of rhodanines, we synthesized aromatic amides and esters of 2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid (rhodanine-3-acetic acid) via carbodiimide- or PCl3-mediated coupling. Both esters and amides were investigated for their in vitro inhibitory potency and selectivity against acetylcholinesterase (AChE) from electric eel and butyrylcholinesterase (BChE) from equine serum using Ellman's spectrophotometric method. The derivatives exhibited mostly a moderate activity against both cholinesterases. IC50 values for AChE were in a closer concentration range of 24.05-86.85µM when compared to BChE inhibition (7.92-227.19µM). The esters caused the more efficient inhibition of AChE than amides and parent acid. The esterification and amidation of the rhodanine-3-acetic acid increased inhibition of BChE, even up to 26 times. Derivatives of 4-nitroaniline/phenol showed the activity superior to other substituents (H, Cl, CH3, OCH3, CF3). Rhodanines produced a balanced inhibition of both cholinesterases. Seven derivatives produced the more potent inhibition of AChE than rivastigmine, a clinically used drug; additional three compounds were comparable. Two amides exceeded inhibitory potency of rivastigmine towards BChE. Importantly, this is the first evidence that rhodanine-based compounds are able to inhibit BChE.

In Silico Driven Design and Synthesis of Rhodanine Derivatives as Novel Antibacterials Targeting the Enoyl Reductase InhA.

Here, we report on the design, synthesis, and biological evaluation of 4-thiazolidinone (rhodanine) derivatives targeting Mycobacterial tuberculosis (Mtb) trans-2-enoyl-acyl carrier protein reductase (InhA). Compounds having bulky aromatic substituents at position 5 and a tryptophan residue at position N-3 of the rhodanine ring were the most active against InhA, with IC50 values ranging from 2.7 to 30 µM. The experimental data showed consistent correlations with computational studies. Their antimicrobial activity was assessed against Mycobacterium marinum (Mm) (a model for Mtb), Pseudomonas aeruginosa (Pa), Legionella pneumophila (Lp), and Enterococcus faecalis (Ef) by using anti-infective, antivirulence, and antibiotic assays. Nineteen out of 34 compounds reduced Mm virulence at 10 µM. 33 exhibited promising antibiotic activity against Mm with a MIC of 0.21 µM and showed up to 89% reduction of Lp growth in an anti-infective assay at 30 µM. 32 showed high antibiotic activity against Ef, with a MIC of 0.57 µM.

[Synthesis and anti-proliferative activity of fluoroquinolone (rhodanine unsaturated ketone) amide derivatives].

To discover novel antitumor rhodanine unsaturated ketones, a series of fluoroquinolone (rhodanine α, ß-unsaturated ketone) amine derivatives (5a-5r) were designed and synthesized with fluoroquinolone amide scaffold as a carrier. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS. The in vitro anti-proliferative activity against Hep-3B, Capan-1 and HL60 cells was evaluated by MTT assay. The results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. The SAR revealed that some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing carboxyl or sulfonamide substituent were comparable to or better than comparison doxorubicin against Capan-1 cells. As such, it suggests that fluoroquinolone (rhodanine α, ß-unsaturated ketone) amines are promising leads for the development of novel antitumor fluoroquinolones or rhodanine analogues.