rhodanine and 2-4-thiazolidinedione

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.. 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.. 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.. 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.

Topics: Anti-Bacterial Agents; Antifungal Agents; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Rhodanine; Thiazolidinediones

A combined molecular docking, QM, and QM/MM dynamics modeling complemented with electron-density based descriptors computed at the B3LYP/6-311G++(d,p) level of theory have been carried out in order to understand the ability of the drugs rhodanine (RD) and 2,4-thiazolidinedione (TZD) in the effective treatment of type 2 diabetes mellitus. The global HOMO/LUMO descriptors provided just a very rough estimate of the chemical reactivity of both molecules, while the features of electron density studied in terms of its Laplacian and electrostatic potential allowed identifying the local electron rich/poor sites which were associated with the regions of electrophilic/nucleophilic attacks in RD and TZD. These results were thoroughly checked using the novel physically-grounded functional descriptors such as the phase-space Fisher information density and the internal kinetic electronic pressure density, which confirmed the information on bonding and lone electron pair details. The molecular docking, QM, and QM/MM dynamics analyses revealed the detailed picture of interactions of the drugs with the amino acid residues of the active site of the human pancreatic alpha-amylase protein (hPAA). The main difference in behavior of RD and TZD molecules is related to the hydrogen bond between the NH group of the ligand and Asp197. In hPAA complex with RD the proton from the NH group, which carries large positive charge (~ +0.45 e), spontaneously transfers to the carboxyl group of Asp197 and stays there, while in complex with TZD this proton frequently changes its position with the more preferable formation of covalent bond with the N atom. Upon deprotonation of the ligand, its hydrogen bonds with Arg195 and His299 become stronger. This process influences the binding with the difference of the binding constants of RD and TZD about 200 times with the higher value corresponding to the RD molecule. Thus, the cumulative results lead to the conclusion that rhodanine would have a higher binding affinity than the 2,4-thiazolidinedione molecule in the active site of human pancreatic alpha-amylase.

Topics: Catalytic Domain; Diabetes Mellitus, Type 2; Humans; Hydrogen Bonding; Hypoglycemic Agents; Molecular Docking Simulation; Pancreatic alpha-Amylases; Rhodanine; Thiazolidinediones

Herein we outline the antibacterial activity of amino acid containing thiazolidinediones and rhodanines against Gram-positive bacteria Staphylococcus aureus ATCC 31890, Staphylococcus epidermidis and Bacillus subtilis ATCC 6633. The rhodanine derivatives were generally more active than the analogous thiazolidinediones. Compounds of series 5 showed some selectivity for Bacillus subtilis ATCC 6633, the extent of which is enhanced by the inclusion of a non-polar amino acid at the 5-position of the core thiazolidinediones and rhodanines scaffolds. SAR data of series 8 demonstrated improved activity against the clinically more significant Staphylococci with selectivity over Bacillus subtilis ATCC 6633 induced by introduction of a bulky aryl substituent at the 5-position of the core scaffolds.

Topics: Amino Acids; Anti-Bacterial Agents; Bacillus subtilis; Benzylidene Compounds; Microbial Sensitivity Tests; Molecular Structure; Rhodanine; Staphylococcus aureus; Staphylococcus epidermidis; Thiazolidinediones

We present a new class of inhibitors of pancreatic cholesterol esterase (CEase) based on 'priviledged' 5-benzylidenerhodanine and 5-benzylidene-2,4-thiazolidinedione structural scaffolds. The lead structures (5-benzylidenerhodanine 4a and 5-benzylidene-2,4-thiazolidinedione 4b) were identified in an in-house screening and these inhibited CEase with some selectivity over another serine hydrolase, acetylcholinesterase (AChE) (4a, CEase IC(50)=1.76 μM vs AChE IC(50)=5.14 μM and 4b, CEase IC(50)=5.89 μM vs AChE IC(50) >100 μM). A small library of analogs (5a-10a) containing a core amino acid in place of the glycerol group of the lead structures, was prepared to explore other potential binding interaction with CEase. These analogs inhibited CEase with IC(50) values ranging from 1.44 to 85 μM, with the majority exhibiting some selectivity for CEase versus AChE. The most potent compound of the library (10a) had 17-fold selectivity over AChE. We also report molecular docking (with CEase) and detailed kinetic analysis on the amino acid analogs to further understand the associated structure-activity relationships.

Topics: Acetylcholinesterase; Animals; Cattle; Enzyme Inhibitors; Kinetics; Mice; Models, Molecular; Pancreas; Rhodanine; Sterol Esterase; Structure-Activity Relationship; Swine; Thiazolidinediones

The search for new anti-inflammatory drugs has been constant in several research centers. The use of the Bioisostery concept allows the elaboration of new bioactive compounds with different properties through the introduction of substitute groups in one or more positions of a main molecule with known biological activity. Preliminary works accomplished at our laboratory with 2,4-thiazolidinedione isosters demonstrated inhibitory activity on edema formation for N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2,4-thiazolidinedione (GS28) and N-tryptophyl-5-(3,5-di-tert-butyl-4-hydroxybenzylidene) rhodanine (GS26). We verified the antiedematogenic and ulcerogenic activity of these two compounds in Wistar rats. The carrageenan induced paw edema suffered significant (p<0.05) inhibition (28.36% on average) for GS28 (100 mg/kg; v.o.) during the entire time of the experiment. GS26 (50 and 100 mg/kg; v.o.) significantly inhibited (p<0.05) the paw edema dextran induced (22.1 and 27.8%, for the respective doses) after 180 min. The compounds GS26 and GS28 did not show ulcerogenic activity on gastric mucous. The results suggest antiedematogenic action for both compounds without the appearance of gastric lesions.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Dose-Response Relationship, Drug; Edema; Female; Male; Rats; Rats, Wistar; Rhodanine; Stomach Ulcer; Thiazolidinediones

Topics: Rhodanine; Thiazoles; Thiazolidinediones