Present investigation describes about the synthesis of some novel spiroazetidinones tethered with furans. These compounds were designed, based on the structure of β-lactam, which shows
Background: The south Indian Telugu states will celebrate a new year called ‘Ugadi’ which is a south Indian traditional festival. The ingredients used in ugadi pachadi have often also been used in food as well as traditional Ayurveda and Siddha medicinal preparations. Coronaviruses (CoVs) are a diverse family of enveloped positive-sense single-stranded RNA viruses which can infect humans and have the potential to cause large-scale outbreaks. Objective: Considering the benefits of ugadi pachadi, we investigated the binding modes of various phytochemical constituents reported from its ingredients against five targets of SARS-CoV-2. Methods: Flexible-ligand docking simulations were achieved through AutoDock version 1.5.6. Following 50ns of molecular dynamics simulation using GROMACS 2018.1 software and binding free energy (ΔGbind) of the protein-ligand complexes were calculated using the g_mmpbsa tool. ADME prediction was done using Qikprop of Schrodinger. Results: From the molecular docking and MM/PBSA results compound Eriodictin exhibited the highest binding energy when complexed with nucleocapsid N protein (6M3M) (-6.8 kcal/mol, -82.46 kJ/mol), bound SARS-CoV-2-hACE2 complex (6M0J) (-7.4 kcal/mol, -71.10 kJ/mol) and Mpro (6XR3) (-8.6 kcal/mol, -140.21 kJ/mol). Van der Waal and electrostatic energy terms highly favored total free energy binding. Conclusion: The compounds Eriodictin, Vitexin, Cycloart-3, 24, 27-triol, Agigenin, Mangiferin, Mangiferolic acid, Schaftoside, 27-Hydroxymangiferonic acid, Quercetin, Azadirachtol, Cubebin, Isomangiferin, Isoquercitrin, Malicarpin, Orientin and procyanidin dimer exhibited satisfactory binding energy values when compared with standard molecules. The further iterative optimization of high-ranked compounds following validation by in vitro and in vivo techniques assists in discovering therapeutic anti-SARS-CoV-2 molecules.
Background: Tuberculosis is a catastrophe sprawled across the world. The World Health Organization Global Tuberculosis Report 2017 inferred that there were an estimated 10.4 million people suffered from tuberculosis including 490000 Multidrug-Resistant TB (MDR-TB) cases. Several new lead molecules like dinitrobenzamide derivatives were found to be highly active against multidrugresistant strains of M. tuberculosis. To further explore the pharmacophoric space around the dinitobenzamide moiety, a series of compounds have been synthesized by linking it with the thiazolidin- 4-one. The presented work is an effort to study the biological effect of thiazolidin-4-one scaffold on dinitrobenzamide derivatives as antitubercular agents. A molecular modeling study was also performed on the synthesized molecules to reveal the requirements for further lead optimization. Methods: The thiazolidin-4-one linked 3,5-dinitrobenzamide derivatives have been synthesized by onepot three-component condensation reaction of an amine, substituted aldehydes and thioglycolic acid in presence of N, N'-Dicyclohexylcarbodiimide (DCC). These compounds were evaluated against Mycobacterium tuberculosis H37Ra. A pharmacophore modeling approach has been used in order to explore the collection of possible pharmacophore queries of thiazolidin-4-one linked 3, 5-dinitrobenzamide derivatives against M. tuberculosis. The synthesized compounds were docked on to the M. tuberculosis DprE1 enzyme to identify the structural features requirement of these analogs against this potential target of M. tuberculosis. Results: The synthesized compounds showed the antitubercular activity in the range of 6.25-50 μg/ml. The pharmacophore modeling suggests that the presence of aromatic moiety, thiazolidin-4-one ring and one of the nitro groups are significant for inhibiting the enzymatic activity. While docking studies showed that hydrophobic and hydrogen bond interactions of the aromatic moiety and nitro group crucial to inactivate the DprE1 enzyme. Conclusion: The study showed that the linking of thiazolidin-4-one with dinitrobenzamide leads to compounds active against M. tuberculosis. These findings also suggested that further lead optimization would be carried out by focusing on the aromatic system along with electron-rich substituents placed on the thiazolidin-4-one for making better hydrophobic and hydrogen bond interactions with the DprE1 target.
For eight compounds 1-(substituted phenyl)-3-chloro-5,9-bis(furan-2-ylmethylidene)-1-azaspiro[3.5] nonan-2-ones (3a -3h) in set, Lipinski parameters were calculated. The chemical structures of the above mentioned derivatives were given as input and desired Lipinski parameters were selected. These studies were carried out using DS accord for excel (ADME screening) provided by Accelrys Discovery studio software. Parameters were calculated based on the chemical structure. From the results obtained, drugs which are likely to be orally active can be identified. All the calculated parameters depend solely on the chemical structure of the derivatives and determine their oral activity providing a relationship between the structure and its activity.
The methanolic extract of leaves of C.dicoccum was evaluated for its hepatoprotective activity against paracetamol induced hepatotoxicity since it is reported to cause oxidative stress in the animal thereby altering the enzymatic levels. Fresh leaves were collected, shade dried and extract was prepared by cold maceration followed by drying in a rota-vapour using methanol to obtain MECD as a sticky semi-solid mass. Thirty rats were taken and divided into 5 equal groups where, Group I, II, and III served as Normal Control, Negative control (PCM 3g/kg), and Positive control (Silymarin 200mg/kg) respectively; whereas, Group IV and V served as test groups where the rats were pre-treated orally with MECD 200mg/kg and 400mg/kg respectively for six days before administering PCM. On the 8 th day all groups except Group I was administered with PCM (3g/kg). 48 hours post PCM induction, the animals were anesthetized, blood samples were obtained via retro-orbital sinus plexus and then the rats were sacrificed. The serum was assessed for the evaluation parameters like AST, ALT, ALP, and bilirubin levels. Apart from these; SOD, CAT, and MDA levels were also evaluated and it was concluded that treatment with MECD restored the levels to normal thereby exhibiting hepatoprotective activity. Moreover, histopathological evaluation was carried out to assess the liver for inflammation, infiltration, or necrosis where the MECD treated rats showed promising results.
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