The present manuscript describes the synthesis, α-amylase inhibition, in silico studies and in-depth quantitative structure–activity relationship (QSAR) of a library of aroyl hydrazones based on benzothiazole skeleton. All the compounds of the developed library are characterized by various spectral techniques. α‐Amylase inhibitory potential of all compounds has been explored, where compound 7n exhibits remarkable α-amylase inhibition of 87.5% at 50 µg/mL. Robust QSAR models are made by using the balance of correlation method in CORAL software. The chemical structures at different concentration with optimal descriptors are represented by SMILES. A data set of 66 SMILES of 22 hydrazones at three distinct concentrations are prepared. The significance of the index of ideality of correlation (IIC) with applicability domain (AD) is also studied at depth. A QSAR model with best Rvalidation2 = 0.8587 for split 1 is considered as a leading model. The outliers and promoters of increase and decrease of endpoint are also extracted. The binding modes of the most active compound, that is, 7n in the active site of Aspergillus oryzae α-amylase (PDB ID: 7TAA) are also explored by in silico molecular docking studies. Compound 7n displays high resemblance in binding mode and pose with the standard drug acarbose. Molecular dynamics simulations performed on protein–ligand complex for 100 ns, the protein gets stabilised after 20 ns and remained below 2 Å for the remaining simulation. Moreover, the deviation observed in RMSF during simulation for each amino acid residue with respect to Cα carbon atom is insignificant.
In search of potent α-amylase inhibitors, herein we report the synthesis, molecular docking and QSAR study of some thiazole clubbed pyrazole hybrids (TCPH) i.e., 1-((1-phenyl-3-aryl-1H-pyrazole-4-yl)methylene)-2-(4-arylthiazole-2-yl)hydrazine (4a–4r) as an α-amylase inhibitors. Among the different analogues, compounds 4g and 4h were found to be most potent at 50 µg/mL with 89.15% and 88.42% of inhibition. The Monte Carlo optimisation method was applied to build robust QSAR models for the prediction of percentage inhibition of TCPH at different concentration with various statistical parameters. The Simplified Molecular Input Line Entry System (SMILES) was applied to symbolise the molecular structure, descriptor calculation and model development. The role of the index of ideality correlation (IIC) was also studied which revealed a model for split 3 as a leading model with best R2 i.e., 0.9198. The compound 4l at different concentration (TCPH11, TCPH29 and TCPH47) was outside the applicability domain (AD) for the developed QSAR models for split 4 only. The SMILES attributes at three different concentrations were also detected. These attributes are the promoters of percentage increase/decrease in inhibition efficiency of the inhibitors. The docking simulation of most active compounds (4g and 4h) were performed within the active site of Aspergillus oryzae α-amylase (PDB ID: 7TAA) to analyse the binding conformation and interactions responsible for their activity. As a result, it was found that the binding interactions found between 4g, 4h and α-amylase were similar to those responsible for α-amylase inhibition by acarbose.Communicated by Ramaswamy H. Sarma
After publication of the original article [1], the following error was reported in the Results section of the Abstract: "antifungal activity against one yeast i.e. Aspergillus niger" should read: "antifungal activity against one fungus i.e. Aspergillus niger". The authors would like to confirm all antifungal activity has been screened against fungi not yeast.
Acyl hydrazones are an important class of heterocyclic compounds promising pharmacological characteristics. Malaria is a life-threatening mosquito-borne blood disease caused by a plasmodium parasite. In some places, malaria can be treated and controlled with early diagnosis. However, some countries lack the resources to do this effectively. The present work involves the design and synthesis of some novel acyl hydrazone based molecular hybrids of 1,4-dihydropyridine and pyrazole (5a–g). These molecular hybrids were synthesised by condensation of 1,4-dihydropyridin-4-yl-phenoxyacetohydrazides with differently substituted pyrazole carbaldehyde. The final compound (5) showed two conformations (the major, E, s-cis and the minor, E, s-trans) as revealed by NMR spectral data and further supported by the energy calculations (MOPAC2016 using PM7 method). All the synthesised compounds were screened for their in vitro antimalarial activities against chloroquine-sensitive malaria parasite Plasmodium falciparum (3D7) and antimicrobial activity against Gram positive bacteria i.e. Bacillus cereus, Gram negative bacteria i.e. Escherichia coli and antifungal activity against one fungus i.e. Aspergillus niger. All these compounds were found more potent than chloroquine and clotrimazole, the standard drugs. In vitro antiplasmodial IC50 value of the most potent compound 5d was found to be 4.40 nM which is even less than all the three reference drugs chloroquine (18.7 nM), pyrimethamine (11 nM) and artimisinin (6 nM). In silico binding study of compound 5d with plasmodial cysteine protease falcipain-2 indicated the inhibition of falcipain-2 as the probable reason for the antimalarial potency of compound 5d. All the compounds had shown good to excellent antimicrobial and antifungal activities.
The present manuscript describes the synthesis, α-amylase inhibition, in silico studies and in-depth quantitative structure–activity relationship (QSAR) of a library of aroyl hydrazones based on benzothiazole skeleton. All the compounds of the developed library are characterized by various spectral techniques. α‐Amylase inhibitory potential of all compounds has been explored, where compound 7n exhibits remarkable α-amylase inhibition of 87.5% at 50 µg/mL. Robust QSAR models are made by using the balance of correlation method in CORAL software. The chemical structures at different concentration with optimal descriptors are represented by SMILES. A data set of 66 SMILES of 22 hydrazones at three distinct concentrations are prepared. The significance of the index of ideality of correlation (IIC) with applicability domain (AD) is also studied at depth. A QSAR model with best Rvalidation2 = 0.8587 for split 1 is considered as a leading model. The outliers and promoters of increase and decrease of endpoint are also extracted. The binding modes of the most active compound, that is, 7n in the active site of Aspergillus oryzae α-amylase (PDB ID: 7TAA) are also explored by in silico molecular docking studies. Compound 7n displays high resemblance in binding mode and pose with the standard drug acarbose. Molecular dynamics simulations performed on protein–ligand complex for 100 ns, the protein gets stabilised after 20 ns and remained below 2 Å for the remaining simulation. Moreover, the deviation observed in RMSF during simulation for each amino acid residue with respect to Cα carbon atom is insignificant. Communicated by Ramaswamy H. Sarma
Postprandial hyperglycemia can be controlled by delaying the absorption of glucose resulting from carbohydrate digestion. α-Amylase is the initiator of the hydrolysis of polysaccharides, and therefore developing α-amylase inhibitors can lead to development of new treatments for metabolic disorders like diabetes mellitus. In the present work, we set out to rationally develop α-amylase inhibitors based on the thiazolidine-4-one scaffold. The structures of all these newly synthesized hybrids were confirmed by spectroscopic analysis (IR,
Abstract The present study describes a multicomponent synthesis of molecular hybrid containing pyrazole, thiazole moiety using hydrazone as a linker, which have been synthesized by condensation of 1-phenyl-3-(aryl)-1H-pyrazole-4-carbaldehydes 1a-b, thiosemicarbazide and α-bromoketones 2a-c.The target hybrid compounds, 1-((1-phenyl-3-aryl-1H-pyrazole-4-yl)methylene)-2-(4-arylthiazole-2-yl)hydrazine 3a-f are characterized by 1H-NMR, 13C NMR, FT-IR and mass. Apoptosis inducing ability and cytotoxic nature of all the hybrid compounds having thiazole, pyrazole and hydrazone were assessed by using biological assays viz morphological, fluorescence and tunel assays on granulosa cells of ovarian antral follicles of goat (Capra hircus) in vitro. Apoptosis was recognized and quantified using differential staining of ethidium bromide and acridine orange where apoptotic cells exhibited red fluorescence and live normal cells with intact cell membrane and normal nucleus displayed bright green fluorescence. Among the tested compounds, compound 3e and 3b showed the maximum potency to induce apoptosis with percentage of apoptosis 25.61±2.95and 23.45±1.46 respectively followed by 3f (20.95±0.40) and 3d (20.44±1.60) in comparison with control (5.14±0.44).
Abstract Molecular hybrids based on thiazolidin‐4‐one and pyrazolyl pharmacophore ( THZP ) as new antidiabetic agents were synthesized. Two sets of signals came into view in 1 H NMR of THZP8‐THZP14 exhibited the presence of a configurational isomeric mixture of 2 E ,5 Z (38.24%‐41.58%) and 2Z,5Z isomers (58.42%‐61.76%), which was further endorsed by density functional theory (DFT) studies. All the compounds exhibit promising nonlinear optical properties (NLO). Further, the biological potential of THZPs was explored in terms of α‐amylase and α‐glucosidase inhibition. DFT‐based descriptors were calculated to describe the reactivity, and a relationship was developed with biological activities. THZP9 and THZP14 showed remarkable inhibition of α‐amylase and α‐glucosidase with IC 50 9.90μM and 4.84μM, respectively, as compared with standard drug acarbose.
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