Background Poly(ADP-ribose) polymerases (PARPs), a nuclear protein belongs to a new class of drugs, which mainly target tumours with DNA repair defects. They are mainly involved in the multiple cellular processes in addition to the DNA repair process. They act directly on the base excision repair, which is considered as one of the important pathway for cell survival in breast cancer. These belong to the active members of DNA repair assembly and evolved as a key target in the anti-cancer drug discovery. 1,3,4-Oxadiazoles are also well known anticancer agents. Results A novel series of 1,3,4-oxadiazoles linked to Schiff bases (T1-21) were designed and subjected to In-silico analysis against PARP-1 (PDB ID:5DS3) enzyme targeting against breast cancer. Molecular docking study for the designed compounds (T1-21) was performed by In-silico ADMET screening by QikProp module, Glide module and MM-GBSA binding free energy calculations by using Schrodinger suit 2019–2. The PARP-1 enzyme shows the binding affinity against the newly designed molecules (T1-21) based on the glide scores. Compounds T21, T12 showed very good glide score by the molecular docking studies and compared with the standard Tamoxifen. The binding free energies by the MM-GBSA assay were found to be consistent. The pharmacokinetic (ADMET) parameters of all the newly designed compounds were found to be in the acceptable range. Conclusion The selected 1,3,4-oxadiazole-schiff base conjugates seems to be one of the potential source for the further development of anticancer agents against PARP-1 enzyme. The results revealed that some of the compounds T21, T17, T14, T13, T12, T8 with good glide scores showed very significant activity against breast cancer
A novel series of benzothiazole-rhodanine derivatives (A1-A10) were designed and synthesized, with the aim of developing possible antidiabetic agents and the spectral characterization of these compounds was done using infrared spectroscopy (IR), proton-nuclear magnetic resonance ( 1 H-NMR), carbon-nuclear magnetic resonance (C 13 -NMR), and high resolution mass spectroscopy (HR-MS) techniques. In vitro hypoglycemic potential of the compounds was evaluated by performing α-amylase and α-glucosidase enzyme inhibitory assays. In addition, these compounds were subjected to in silico analysis. Based on the results, compounds A5, A6, and A9 displayed good activity in comparison with the standard acarbose. Based on Lineweaver-Burk plots, it was concluded that compounds A5 and A9 displayed competitive type of enzyme inhibition. Molecular dynamic simulations were conducted to evaluate the stability of the ligand-protein complex by the calculation of the root mean square deviation, root means square fluctuation, and solvent accessible surface area.diabetes mellitus, in silico analysis, molecular dynamics, pharmacophore, rhodanines | INTRODUCTIONDiabetes mellitus (DM) is a chronic metabolic disorder that causes a significant challenge for the healthcare system across the globe. Such a high prevalence of diabetes has boosted the search for novel alternatives. Owing to high blood glucose in diabetes, a series of complications such as blindness, high blood pressure, kidney, and stroke disorders may result. 1 Diabetes was anticipated to affect 415 million people in 2015, with type 2 diabetes (T2DM) accounting for more than 90% of cases, with the number expected to rise to 642 million by 2040. For controlling glycemia, there has been a development of a few synthetic drugs such as acarbose, metformin, and sitagliptin. However, many side effects have been resulted due to the consumption of these drugs, such as flatulence, diarrhea, and hypoglycemia. It is well-known that postprandial hyperglycemia is an important contributing factor to the progression of T2DM, therefore, postprandial management of hyperglycemia is one of the therapeutic approaches to combating T2DM diabetes. α-amylase and α-glucosidase are the two main carbohydrate digestive enzymes associated with postprandial hyperglycemia in T2DM patients. The alpha-1, 4-glycosidic bond
The title compounds 1,3,4-oxadiazole derivatives (C1-5) were synthesized by the cyclization of 4-hydroxy benzhydrazide (1) with various substituted aromatic aldehydes (2) in the presence of ceric ammonium nitrate. The structures of the newly synthesized compounds were established based on FT-IR, 1H-NMR, and Mass spectral data. In silico analysis was carried out using the Schrodinger 2018-3 suite device Maestro and docked to the binding site of the Human GABAA receptor (PDB ID:4COF). The toxicity of the compounds was predicted using the LAZAR (Lazy structure-activity relationship) program. The invivo anticonvulsant study was performed by means of a maximal electroshock test and pentylenetetrazole (PTZ)-induced seizures. Compounds C4&C5 showed the highest docking score of −5.676 and −5.277, respectively, and compounds C4&C5 showed the most increased in vivo anticonvulsant activity when compared with the reference drugs in both the PTZ and MES test methods. HIGHLIGHTS A new series of 1,3,4-oxadiazoles (C1-C5) were synthesized by reacting aromatic aldehydes and 4-hydroxy benzhydrazide using cerric ammonium nitrate as (CAT) catalyst and characterized by spectral data All the new compounds were subjected for In-silico analysis and docked to Human GABAA receptor (PDB ID:4COF) In-vivo anticonvulsant activity was carried out for all the new compounds by using maximal electroshock (MES) and pentylenetetrazole (PTZ) models Some of the tested compounds C4&C5 displayed promising anticonvulsant activity GRAPHICAL ABSTRACT
Parkinson’s disease is considered as common age-related progressive neuronal disorder characterized by motor, sensory, and cognitive dysfunction. Current medication for PD offers only symptomatic relief but no cure. Although it is considered that these medicines can produce acute or chronic side effects, and becomes less effective over a time. Owing to this concerns, the discovery of novel molecule is of considerable interest. Depletion of dopamine is one of the major cause of PD which is regulated by Monoamines. In this regards monoamine oxidase (MAO-B) inhibitors are of great interest to combat PD. Among several known molecules Pyrazolone has been evident for the MAO-B inhibitory potential. Therefore, in the present study MAO-B is selected as a key target to examine the interaction of Pyrazolone derivatives with crystal structure of MAO-B. For this purpose, Molecular docking, Quick prop module, and Mechanics/generalized born surface area (MM-GBSA) parameters are analyzed, to evaluate Molecular interaction, Pharmacokinetic parameters, and Binding energy. Further results show that compounds attached with chloride and nitrogen group have better binding efficiency, therefore they can be selected as a promising drug candidate for the treatment of PD.
In this present study, a novel series of chalcones (C1-10) were synthesized by reacting 4-nitro acetophenone and various substituted aromatic aldehydes in an alcohol medium. The title compounds, pyrimidine derivatives (PD1-10), were obtained by the cyclization of chalcones (C1-10) with guanidine carbonate in an alcoholic medium. Each of the newly synthesized compounds was structurally assigned in accordance with FT-IR, 1 H-NMR and mass spectral data. All the synthesized compounds were subjected to in silico analysis among which, some of the synthesized compounds were chosen and evaluated for in vivo anticonvulsant study by employing PTZ-induced seizure and MES seizure models. Compounds PD2 and PD7 demonstrated significant anticonvulsant activity when compared to the standard.
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