In our effort to identify potent fluorinated small molecules as antidiabetic compounds, a novel fluorinated series of 2-chloro-6-(trifluoromethyl)benzyloxy arylidene derived Rhodanine and Rhodanine-acetic acid derivatives were synthesized and screened for α-glucosidase and α-amylase inhibitory activity. Newly synthesized compounds were characterized by 1 HNMR, 13 C NMR, and LCMS spectral data. Among the tested compounds, (Z)-5-(4-(2-chloro-6-(trifluoromethyl)benzyloxy) benzylidene)-2-thioxothiazolidin-4-one(5 a) and 2-((Z)-5-(4-(2chloro-6-(trifluoromethyl)benzyloxy)benzylidene)-4-oxo-2-thioxothiazoli-din-3-yl)acetic acid(6 a) emerged as most promising α-glucosidase inhibitors with IC 50 values 4.76 � 0.64 μM and 4.91 � 0.45 μM, respectively. Further, the kinetic inhibition experiments against yeast α-glucosidase for compounds 5 a and 6 a indicated that these are competitive inhibitors with inhibitory constant (Ki) 0.54 μg and 1.15 μg respectively.Molecular docking studies on α-glucosidase was performed by homology modelingfor the most potent compounds 5 a and 6 a to understand the putative binding mode. The study revealed substantial binding of the compounds to the active site of α-glucosidase, indicating that the position of the substituent plays a key role in its inhibitory potential.
Three different series of some novel N-substituted rhodanines were designed for anticancer activity and prepared from the corresponding dithiocarbamates. The synthesized compounds were analyzed by IR, NMR and MASS to confirm their structures. All the titled compounds were found to be of Z configuration based on NMR spectral analysis. All the synthesized rhodanines were screened for in vitro anticancer activity against MCF-7 breast cancer cells at the concentration of 10µg. Compounds showed moderate to significant cytotoxicity. Amongst them, interestingly, compounds 10, 22 and 33 with cinnamoyl substitution at 5 th position of thiazolidine ring system showed significant activity. Further, we subjected all these compounds for the CoMSIA study to study their 3D quantitative structure activity relationships (3D QSAR). The illustration about the design of novel rhodanines, synthesis, analysis, activity against MCF-7 cells and SAR via CoMSIA study are reported here.
Background: The outbreak of the coronavirus (SARS-CoV-2) has drastically affected the human population and caused enormous economic deprivation. It belongs to the β-coronavirus family and causes various problems such as acute respiratory distress syndrome and has resulted in a global pandemic. Though various medications have been under trial for combating COVID-19, specific medicine for treating COVID-19 is unavailable. Thus, the current situation urgently requires effective treatment modalities. Nigella sativa, a natural herb with reported antiviral activity and various pharmacological properties, has been selected in the present study to identify a therapeutic possibility for treating COVID-19. Methods: The present work aimed to virtually screen the bioactive compounds of N. sativa based on the physicochemical properties and docking approach against two SARS-CoV-2 enzymes responsible for crucial functions: 3CLpro (Main protease) and NSP15 (Nonstructural protein 15 or exonuclease). However, simulation trajectory analyses for 100ns were accomplished by using the YASARA STRUCTURE tool based on the AMBER14 force field with 400 snapshots every 250ps. RMSD and RMSF plots were successfully obtained for each target. Results: The results of molecular docking have shown higher binding energy of dithymoquinone (DTQ), a compound of N. sativa against 3CLpro and Nsp15, i.e., −8.56 kcal/mol and −8.31 kcal/mol, respectively. Further, the dynamic simulation has shown good stability of DTQ against both the targeted enzymes. In addition, physicochemical evaluation and toxicity assessment also revealed that DTQ obeyed the Lipinski rule and did not have any toxic side effects. Importantly, DTQ was much better in every aspect among the 13 N. sativa compounds and 2 control compounds tested. Conclusions: The results predicted that DTQ is a potent therapeutic molecule that could dual-target both 3CLpro and NSP15 for anti-COVID therapy.
BackgroundAn alarming requirement for finding newer antidiabetic glitazones as agonists to PPARγ are on its utmost need from past few years as the side effects associated with the available drug therapy is dreadful. In this context, herein, we have made an attempt to develop some novel glitazones as PPARγ agonists, by rational and computer aided drug design approach by implementing the principles of bioisosterism. The designed glitazones are scored for similarity with the developed 3D pharmacophore model and subjected for docking studies against PPARγ proteins. Synthesized by adopting appropriate synthetic methodology and evaluated for in vitro cytotoxicity and glucose uptake assay. Illustrations about the molecular design of glitazones, synthesis, analysis, glucose uptake activity and SAR via 3D QSAR studies are reported.ResultsThe computationally designed and synthesized ligands such as 2-(4-((substituted phenylimino)methyl)phenoxy)acetic acid derivatives were analysed by IR, 1H-NMR, 13C-NMR and MS-spectral techniques. The synthesized compounds were evaluated for their in vitro cytotoxicity and glucose uptake assay on 3T3-L1 and L6 cells. Further the activity data was used to develop 3D QSAR model to establish structure activity relationships for glucose uptake activity via CoMSIA studies.ConclusionThe results of pharmacophore, molecular docking study and in vitro evaluation of synthesized compounds were found to be in good correlation. Specifically, CPD03, 07, 08, 18, 19, 21 and 24 are the candidate glitazones exhibited significant glucose uptake activity. 3D-QSAR model revealed the scope for possible further modifications as part of optimisation to find potent anti-diabetic agents.
Background:Thiazolidinediones and its bioisostere, namely, rhodanines have become
ubiquitous class of heterocyclic compounds in drug design and discovery. In the present study, as
part of molecular design, a series of novel glitazones that are feasible to synthesize in our laboratory
were subjected to docking studies against PPAR-γ receptor for their selection.Methods and Results:As part of the synthesis of selected twelve glitazones, the core moiety, pyridine
incorporated rhodanine was synthesized via dithiocarbamate. Later, a series of glitazones were
prepared via Knovenageal condensation. In silico docking studies were performed against PPARγ
protein (2PRG). The titled compounds were investigated for their cytotoxic activity against 3T3-L1
cells to identify the cytotoxicity window of the glitazones. Further, within the cytotoxicity window,
glitazones were screened for glucose uptake activity against L6 cells to assess their possible antidiabetic
activity.Conclusion:Based on the glucose uptake results, structure activity relationships are drawn for the
title compounds.
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