Can a Small Change in the Heterocyclic Substituent Significantly Impact the Physicochemical and Biological Properties of (Z)-2-(5-Benzylidene-4-oxo-2-thioxothiazolidin-3-yl)acetic Acid Derivatives?

Rhodanine-3-acetic acid derivatives are attractive compounds with versatile effects. What is very important is that compounds of this type have many biological properties. They are tested, among others, as fluorescent probes for bioimaging and aldose reductase inhibitors. Rhodanine-3-acetic acid derivatives also have antibacterial, antifungal and anticancer activity. The presented work demonstrates that a slight change in the five-membered heterocyclic substituent significantly affects the properties of the compounds under consideration. Three rhodanine-3-acetic acid derivatives (A-1-A-3) were obtained in the Knoevenagel condensation reaction with good yields, ranging from 54% to 71%. High thermal stability of the tested compounds was also demonstrated above 240 °C. The absorption and emission maxima in polar and non-polar solvents were determined. Then, the possibility of using the considered derivatives for fluorescence bioimaging was checked. Compounds A-1 and A-2 were successfully used as fluorescent dyes of fixed cells of mammalian origin. In addition, biological activity tests against bacteria and fungi were carried out. Our results showed that A-1 and A-2 showed the most excellent antimicrobial activity among the newly synthesized compounds, especially against Gram-positive bacteria.

Arylidene and amino spacer-linked rhodanine-quinoline hybrids as upgraded antimicrobial agents.

Antibiotic resistance associated with various microorganisms such as Gram-positive, Gram-negative, fungal strains, and multidrug-resistant tuberculosis increases the risk of healthcare survival. Preliminary therapeutics becoming ineffective that might lead to noteworthy mortality presents a crucial challenge for the scientific community. Hence, there is an urgent need to develop hybrid compounds as antimicrobial agents by combining two or more bioactive heterocyclic moieties into a single molecular framework with fewer side effects and a unique mode of action. This review highlights the recent advances (2013-2023) in the pharmacology of rhodanine-linked quinoline hybrids as more effective antimicrobial agents. In the drug development process, linker hybrids acquire the top position due to their excellent π-stacking and Van der Waals interaction with the DNA active sites of pathogens. A molecular hybridization strategy has been optimized, indicating that combining these two bioactive moieties with an arylidene and an amino spacer linker increases the antimicrobial potential and reduces drug resistance. Moreover, the structure-activity relationship study is discussed to express the role of various functional groups in improving and decrementing antimicrobial activities for rational drug design. Also, a linker approach may accelerate the development of dynamic antimicrobial agents through molecular hybridization.

New Hybrid Tetrahydropyrrolo[3,2,1-ij]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation.

Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa. For the synthesis of new hybrid derivatives of pyrrolo[3,2,1-ij]quinoline-2-one, we used a convenient structural modification of the tetrahydroquinoline fragment by varying the substituents in positions 2, 4, and 6. In addition, the design of target molecules was achieved by alkylating the amino group of the rhodanine fragment with propargyl bromide or by replacing the rhodanine fragment with 2-thioxoimidazolidin-4-one. The in vitro testing showed that eight derivatives are capable of inhibiting both coagulation factors, two compounds are selective inhibitors of factor Xa, and two compounds are selective inhibitors of factor XIa. Overall, these data indicate the potential anticoagulant activity of these molecules through the inhibition of the coagulation factors Xa and XIa.

Rhodanine Derivatives as Anticancer Agents: QSAR and Molecular Docking Studies.

BACKGROUND: Rhodanine derivatives have a proven wide range of biological activities. OBJECTIVE: The aim of this study was to evaluate the cytotoxic effect of a series of rhodanine derivatives and investigate the quantitative structure-activity relationships, as well as binding modes to tyrosine kinase. METHODS: Cytotoxic effect on cell proliferation (CaCo-2, HeLa, MDCK-1, Hut-78, K562) in vitro was evaluated by the MTT viability assay. QSAR analysis was performed with Dragon descriptors using QSARINS software. Molecular docking was performed on the tyrosin kinase (c-Src) (PDB ID: 3G6H) using iGEMDOCK. RESULTS: Compounds with the best inhibiting activity toward all cell lines were the ones possessing only one group in the C2 of the phenyl ring. QSAR study on the cytotoxic activity against Human T cell lymphoma achieved the model that satisfies the fitting and internal cross-validation criteria (R2 = 0.75; Q2 LOO = 0.64). Descriptors included in the model (MATS2e, MATs7e, RDF060p) revealed the importance of the presence of atoms with higher polarizability in the outer region of molecules. The findings of the molecular docking study performed on the c-Src are in accordance with the results of the QSAR study. The key interactions with binding site residues were achieved through oxygen atoms from phenoxy and rhodanine groups and rhodanine sulphur atoms. CONCLUSION: Rhodanine derivatives could be developed as novel tyrosine kinase inhibitors in the treatment of leukemia.

Novel rhodanine based inhibitors of aldose reductase of non-acidic nature with p-hydroxybenzylidene functional group.

Aldose reductase, the first enzyme of the polyol pathway represents a key drug target in therapy of diabetic complications. In this study a series of six novel rhodanine based inhibitors of aldose reductase was designed, synthesized, and tested for their ability to inhibit aldose reductase and for selectivity relative to structurally related aldehyde reductase. Aldose reductase inhibitory activities of the compounds were characterized by the IC50 values ranging from 2000 nM to 20 nM. The values of selectivity factors relative to aldehyde reductase were decreasing in the same array from 24 to 5. In silico docking into the inhibitor binding site of aldose reductase revealed a specific binding pattern of the compounds comprising interaction of the deprotonated 4-hydroxybenzylidene group with the anion-binding sub-pocket of aldose reductase, creating a strong H-bond and charge interactions. Predicted pH-distribution profiles of the novel compounds into octanol, supported by experimentally determined distribution ratios, favour drug uptake at the physiological pH, as a result of the presence of the low-acidic phenolic group, instead of the more acidic carboxymethyl functional group.

Rhodanine derivatives: An insight into the synthetic and medicinal perspectives as antimicrobial and antiviral agents.

Rhodanine or 2-Thioxothiazolidin-4-one is a privileged heterocyclic compound offering a wide opportunity for structural modification, lead development, and modification. It is one of the highly decorated scaffolds in the drug discovery process. Rhodanine derivatives possess a plethora of biological activities due to their ability to interact with a diverse range of protein targets, which provide tremendous opportunities to discover new drugs with different modes of action. The most common strategy for developing novel rhodanine derivatives is the introduction of structurally diverse substituents at the C-5 or N-3, or both positions. Since the inception of Epralestat into the market in 1992, the exploration of rhodanine-3-acetic acids has led to the development of novel leads against different biological targets such as MRSA, HHV-6, Mycobacterial tuberculosis, dengue, etc. In the current pandemic era, some rhodanine compounds have been explored against SARS-CoV-2. In recent years, rhodanine and its derivatives have witnessed significant progress in developing new drug leads as potential antimicrobial and antiviral agents. Different synthetic methodologies and recent developments in the medicinal chemistry of rhodanine derivatives, including biological activities, their mechanistic aspects, structure-activity relationships, and in silico findings, have been compiled in the present review. This article will benefit the scientific community and offer perspectives on how these scaffolds as privileged structures might be exploited in the future for rational design and discovery of rhodanine-based bio-active molecules.

Correlation of hepatic copper levels, rhodanine scores and histological diagnosis in archived canine liver samples.

The liver is the main storage site for copper. Excess copper accumulation, however, is a risk factor for the development of chronic hepatitis in dogs. Mass spectrometry or rhodanine staining are frequently used methods to assess copper levels in the liver. The association was studied between analytic hepatic copper levels and rhodanine scores in archived canine formalin-fixed-paraffinembedded liver sections from 2014 to 2021 with various diagnoses. Thirty-six (N = 36) liver samples with analytic interpretation of toxic (n = 12), high normal (n = 17), and normal (n = 7) copper levels were selected for the study. Rhodanine staining for each of these samples was graded (scale: 1 to 5), and the association was determined between actual liver copper levels and rhodanine scores and histological diagnoses (chronic hepatitis or other diagnoses). The analytic copper level and rhodanine scores were significantly higher (P < 0.05) in samples designated as toxic compared to normal. There was a significant association between hepatic copper levels and rhodanine scores (P < 0.05). Rhodanine score, but not the actual liver copper levels were significantly (P < 0.05) associated with chronic hepatitis versus other diagnoses. Rhodanine scores of ≥ 1.89 were statistically significant predictors of chronic hepatitis. It was concluded from this study that actual liver copper levels are positively associated with rhodanine scores and rhodanine scores can be a useful predictor of chronic hepatitis.

Le foie est le principal site de stockage du cuivre. Cependant, une accumulation excessive de cuivre est un facteur de risque pour le développement d'une hépatite chronique chez le chien. La spectrométrie de masse ou la coloration à la rhodanine sont des méthodes fréquemment utilisées pour évaluer les niveaux de cuivre dans le foie. L'association entre les niveaux analytiques de cuivre hépatique et les scores de rhodanine a été étudiée dans des sections de foie de chien archivées fixées au formol et incluses dans de la paraffine de 2014 à 2021 avec divers diagnostics. Trente-six (N = 36) échantillons de foie avec interprétation analytique des niveaux de cuivre toxiques (n = 12), normaux élevés (n = 17) et normaux (n = 7) ont été sélectionnés pour l'étude. La coloration à la rhodanine de chacun de ces échantillons a été évaluée (échelle : 1 à 5) et l'association a été déterminée entre les niveaux réels de cuivre dans le foie et les scores de rhodanine et les diagnostics histologiques (hépatite chronique ou autres diagnostics). Les niveaux analytiques de cuivre et les scores de rhodanine étaient significativement plus élevés (P < 0,05) dans les échantillons désignés comme toxiques par rapport à la normale. Il y avait une association significative entre les niveaux de cuivre hépatique et les scores de rhodamine (P < 0,05). Le score de rhodanine, mais pas les niveaux réels de cuivre dans le foie, était significativement (P < 0,05) associé à l'hépatite chronique par rapport à d'autres diagnostics. Les scores de rhodanine ≥ 1,89 étaient des prédicteurs statistiquement significatifs de l'hépatite chronique. Il a été conclu à partir de cette étude que les niveaux réels de cuivre dans le foie sont positivement associés aux scores de rhodanine et que les scores de rhodanine peuvent être un prédicteur utile de l'hépatite chronique.(Traduit par Docteur Serge Messier).

Synthesis, Crystal Structures, Lipophilic Properties and Antimicrobial Activity of 5-Pyridylmethylidene-3-rhodanine-carboxyalkyl Acids Derivatives.

The constant increase in the resistance of pathogenic bacteria to the commonly used drugs so far makes it necessary to search for new substances with antibacterial activity. Taking up this challenge, we obtained a series of rhodanine-3-carboxyalkyl acid derivatives containing 2- or 3- or 4-pyridinyl moiety at the C-5 position. These compounds were tested for their antibacterial and antifungal activities. They showed activity against Gram-positive bacteria while they were inactive against Gram-negative bacteria and yeast. In order to explain the relationship between the activity of the compounds and their structure, for selected derivatives crystal structures were determined using the X-ray diffraction method. Modeling of the isosurface of electron density was also performed. For all tested compounds their lipophilicity was determined by the RP-TLC method and by calculation methods. On the basis of the carried-out research, it was found that the derivatives with 1.5 N···S electrostatics interactions between the nitrogen atom in the pyridine moiety and the sulfur atom in the rhodanine system showed the highest biological activity.

Anticancer Profile of Rhodanines: Structure-Activity Relationship (SAR) and Molecular Targets-A Review.

The rhodanine core is a well-known privileged heterocycle in medicinal chemistry. The rhodanines, as subtypes of thiazolidin-4-ones, show a broad spectrum of biological activity, including anticancer properties. This review aims to analyze the anticancer features of the rhodanines described over the last decade in the scientific literature. The structure-activity relationship of rhodanine derivatives, as well as some of the molecular targets, were discussed. The information contained in this review could be of benefit to the design of new, effective small molecules with anticancer potential among rhodanine derivatives or their related heterocycles.

Synthesis and Antibacterial Evaluation of Rhodanine and Its Related Heterocyclic Compounds against S.†aureus and A.†baumannii.

Antimicrobial resistance is a serious challenge to modern medicine. Besides imposing high financial burden, multidrug resistant infections are directly responsible for high morbidity and mortality. Even though a number of antibiotics are currently available to treat infections caused by ESKAPE organisms, more and more bacterial strains are becoming resistant to these drugs. Prevailing circumstances pose an urgent unmet need for the development of newer antimicrobials to treat the infections caused by MDR organisms. Rhodanine and structurally related 5-membered heterocycles possess wide range of pharmacological activities. A number of these derivatives have shown good to potent inhibition against various microorganisms. They are reported to alter the function of DNA gyrase B, metallo-ß-lactamases, penicillin binding protein (PBP), Mur ligases, RNA polymerase, Enoyl ACP reductases, 1-deoxy-d-xylulose-5-phosphate reductoisomerase. etc which are vital in bacterial growth, survival and replication. In this study, we have generated a library of Rhodanine and related 5 membered heterocyclic derivatives and screened them against a panel of pathogens. Among all the compounds, 2a-i, 3a-b, 3g, 4, 6b-c, 6e, 6g, 12a-b and 14b-c have demonstrated good to moderate inhibition against S. aureus (MIC 0.125-8 µg/mL). Further, compound 17b demonstrated moderate activity against A. baumannii (MIC 8 µg/mL). In addition, compounds 2a, 2e, 4, 6c, 6g and 14b have shown good to mild inhibition against MDR S. aureus including VRSA (MIC 0.5-16 µg/mL) with good selectivity index 20-1600. In addition, compound 2e inhibited the growth gradually after 6 h in time kill kinetic studies and not antagonized with the tested FDA approved drugs.

Discovery of Cinnamylidene Derivative of Rhodanine with High Anthelmintic Activity against Rhabditis sp.

The treatment of parasitic infections requires the application of chemotherapy. In view of increasing resistance to currently in-use drugs, there is a constant need to search for new compounds with anthelmintic activity. A series of 16 cinnamylidene derivatives of rhodanine, including newly synthesized methoxy derivatives (1-11) and previously obtained chloro, nitro, and diethylamine derivatives (12-16), was investigated towards anthelmintic activity. Compounds (1-16) were evaluated against free-living nematodes of the genus Rhabditis sp. In the tested group of rhodanine derivatives, only compound 2 shows very high biological activity (LC50 = 0.93 µg/µL), which is higher than the reference drug albendazole (LC50 = 19.24 µg/µL). Crystal structures of two compounds, active 2 and inactive 4, were determined by the X-ray diffraction method to compare molecular geometry and search for differences responsible for observed biological activity/inactivity. Molecular modelling and selected physicochemical properties prediction were performed to assess the potential mechanism of action and applied in the search for an explanation as to why amongst all similar compounds only one is active. We can conclude that the tested compound 2 can be further investigated as a potential anthelmintic drug.

Review of anticancer potentials and structure-activity relationships (SAR) of rhodanine derivatives.

Rhodanine has been recognized as a privileged scaffold in medicinal chemistry due to its well-known ability to demonstrate a broad range of biological activities. The possibility of structural diversification has contributed to the significance of rhodanine structure in effective drug discovery and design. Many studies have confirmed the potential of rhodanine-derived compounds in the treatment of different types of cancer through the apoptosis induction mechanism. Furthermore, most of the rhodanine derivatives exhibited remarkable anticancer activity in the micromolar range while causing negligible cytotoxicity to normal cells. This review critically describes the anticancer activity profile of reported rhodanine compounds and the structure-activity relationships (SAR) to highlight the value of rhodanine as the core structure for future cancer drug development as well as to assist the researchers in rational drug design.

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.

Virtual screening of epalrestat mimicking selective ALR2 inhibitors from natural product database: auto pharmacophore, ADMET prediction and molecular dynamics approach.

Epalrestat is the only effective aldose reductase (ALR2) inhibitor available in the market for the treatment of diabetic neuropathy. Clinical effectiveness of epalrestat in diabetic neuropathy encouraged us to develop some more ALR2 inhibitors with a better therapeutic profile. Herein, we utilized the pharmacophoric features of epalrestat to search some novel ALR2 inhibitors from an InterBioScreen database of natural compounds. ADME and PAINS filters were applied to provide drug-likeness and to remove toxicophores from the screened hits. The pharmacophoric features of 4-hydroxy-2-nonenal (HNE), a well-known substrate of ALR1, were also explored to identify selective ALR2 inhibitors. The structure-based analysis was then adopted to find out the molecules showing interactions with ALR2 which are crucial for their therapeutic activity. These interaction patterns and binding modes were compared with that of epalrestat. Molecular dynamics (MD) analysis was also carried out to get more insight into the interactions of screened hits in the catalytic domain of ALR2. Additionally, the top hits were docked and simulated with aldehyde reductase (ALR1) to determine their selectivity for ALR2 over ALR1. Overall, five hits including STOCKIN-44771, STOCKIN-46041, STOCKIN-59369, STOCKIN-69620 and STOCKIN-88220 were found to possess a good therapeutic profile in terms of key interactions, binding energies and drug-likeness. Two hits, STOCKIN-46041 and STOCKIN-59369, were identified as the most selective ALR2 inhibitors when assessed their selectivity profile.Communicated by Ramaswamy H. Sarma.

Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics.

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I20 as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I20 and tubulin Arg ß369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.

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.

Protective Effects of Novel Substituted Triazinoindole Inhibitors of Aldose Reductase and Epalrestat in Neuron-like PC12 Cells and BV2 Rodent Microglial Cells Exposed to Toxic Models of Oxidative Stress: Comparison with the Pyridoindole Antioxidant Stobadine.

Aldose reductase (AR) catalyzes the conversion of glucose to sorbitol in a NADPH-dependent reaction, thereby increasing the production of reactive oxygen species (ROS). Since AR activation is linked to redox dysregulation and cell damage in neurodegenerative diseases, AR inhibitors (ARIs) constitute promising therapeutic tools for the treatment of these disorders. Among these compounds, the novel substituted triazinoindole derivatives cemtirestat (CMTI) and COTI, as well as the clinically employed epalrestat (EPA) and the pyridoindole-antioxidant stobadine (STB), were tested in both PC12 cells and BV2 microglia exposed to four different neurotoxic models. These include (1) oxidative stress with hydrogen peroxide (H2O2), (2) mitochondrial complex IV inhibition with NaN3, (3) endoplasmic reticulum-stress and lipotoxicity induced by palmitic acid/bovine serum albumin (PAM/BSA), and (4) advanced carbonyl compound lipotoxicity by 4-hydroxynonenal (4-HNE). All toxic compounds decreased cell viability and increased ROS formation in both PC12 and BV2 cells in a concentration-dependent manner (1-1000 µM; NaN3 < H2O2≈PAM/BSA < 4-HNE). In PC12 cells, EPA increased cell viability in all toxic models only at 1 µM, whereas CMTI restored baseline viability in all toxic models. COTI afforded protection against lipotoxicity, while STB only prevented H2O2-induced toxicity. Except for the 4-HNE model, EPA prevented ROS generation in all other toxic models, whereas CMTI, COTI, and STB prevented ROS production in all toxic models. In BV2 cells, EPA and CMTI restored baseline cell viability in all toxic models tested, while COTI and STB did not prevent the loss of viability in the NaN3 model. All ARIs and STB efficiently prevented ROS formation in all toxic models in a concentration-independent manner. The differential protective effects evoked by the novel ARIs and STB on the toxic models tested herein provide novel and relevant comparative evidence for the design of specific therapeutic strategies against neurodegenerative events associated with neurological disorders.

Structure prediction, molecular simulations of RmlD from Mycobacterium tuberculosis, and interaction studies of Rhodanine derivatives for anti-tuberculosis activity.

Tuberculosis is the most dangerous disease causing maximum deaths than any other, caused by single infectious agent. Due to multidrug resistant of Mycobacterium tuberculosis strains, there is a need of new drugs and drug targets. In this work, we have selected RmlD (α-dTDP-6-deoxy-lyxo-4-hexulose reductase) in the dTDP Rhamnose pathway as drug target to control tuberculosis using Rhodanine analogues. In order to study interaction of RmlD with Rhodanine analogues, a three-dimensional model based on crystal structures such as 1VLO from Clostridium, 1KBZ from Salmonella typhimurium, and 2GGS from Sulfolobus was generated using Modeller 9v7. The modeled structure reliability has been checked using programs such as Procheck, What if, Prosa, Verify 3D, and Errat. In an attempt to find new inhibitors for RmlD enzyme, docking studies were done with a series of Rhodanine and its analogues. Detailed analysis of enzyme-inhibitor interactions identified specific key residues, SER5, VAL9, ILE51, HIS54, and GLY55 which were important in forming hydrogen bonds in binding affinity. Homology modeling and docking studies on RmlD model provided valuable insight information for designing better inhibitors as novel anti-tuberculosis drugs by rational method.

Synthesis, Molecular Docking and Molecular Dynamics Simulation of 2- Thioxothiazolidin-4-One Derivatives against Gp41.

INTRODUCTION: Gp41 and its conserved hydrophobic groove on the N-terminal heptad repeat region are attractive targets in the design of HIV-1 entry inhibitors. Linearly extended molecules have shown potent anti-HIV-1 activity for their effective interactions with the gp41 binding pocket. Rhodanine ring attached to substituted pyrrole or furan rings has been proved a preferred moiety to be inserted inside the molecular structure of the gp41 inhibitors. OBJECTIVES: Based on the previous findings we are going to describe some rhodanine derivatives in which a substituted imidazole ring is introduced in place of the pyrrole or furan rings. The compounds' flexibility is increased by inserting methylene groups inside the main scaffold. METHODS: Molecular docking and molecular dynamics simulations approaches were exploited to investigate the chemical interactions and the stability of the designed ligands-gp41 complex. All compounds were synthesized and their chemical structures were elucidated by 1HNMR, 13CNMR, FTIR and Mass spectroscopy. Biological activities of the compounds against HIV-1 and HIV-2 and their cellular toxicities against the T-lymphocyte (MT-4) cell line were determined. RESULTS: All the designed compounds showed proper and stable chemical interactions with gp41 according to the in silico studies. The results of the biological tests proved none of the compounds active against HIV-1 replication in cell cultures. CONCLUSION: Since all the studied compounds were potently toxic for the host cell; it was therefore not possible to assess their anti-HIV activities.

5-Aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety as potential PTP1B inhibitors.

Two series of 5-aryl-furan derivatives bearing a phenylalanine- or isoleucine-derived rhodanine moiety were identified as competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors. Among the compounds studied, 5g was found to have the best PTP1B inhibitory potency (IC50 = 2.66 ± 0.16 µM) and the best cell division cycle 25 homolog B (CDC25B) inhibitory potency (IC50 = 0.25 ± 0.02 µM). Enzymatic data together with molecular modeling results demonstrated that the introduction of a sec-butyl group at the 2-position of the carboxyl group remarkably improved the PTP1B inhibitory activity.