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Helicobacter pylori causes severe stomach disorders and the use of enzyme inhibitors for treatment is one of the possible therapies. The great biological potential of imine analogs as urease inhibitors has been the focus of researchers in past years. In this regard, we have synthesized twenty-one derivatives of dichlorophenyl hydrazide. These compounds were characterized by different spectroscopic techniques i.e. NMR and HREI-MS. Compounds 2 and 10 were found to be the most active in the series. Structure-activity relationship has been established for all compounds based on different substituents attached to the phenyl ring that play a vital role in enzyme inhibition. From the structure-activity relationship, it has been observed that these analogs showed excellent potential for urease and can be an alternate therapy in the future. The molecular docking study was performed to further explore the binding interactions of synthesized analogs with enzyme active sites.Communicated by Ramaswamy H. Sarma.

Acetylcholinesterase prevails in the healthy brain, with butyrylcholinesterase reflected to play a minor role in regulating brain acetylcholine (ACh) levels. However, BuChE activity gradually increases in patients with (AD), while AChE activity remains unaffected or decays. Both enzymes therefore represent legitimate therapeutic targets for ameliorating the cholinergic deficit considered to be responsible for the declines in cognitive, behavioural, and global functioning characteristic of AD. Current study described the synthesis of indole-based sulfonamide derivatives ( 1-23 ) and their biological activity. Synthesis of these scaffolds were achieved by mixing chloro-substituted indole bearing amine group with various substituted benzene sulfonyl chloride in pyridine, under refluxed condition to obtained desired products. All products were then evaluated for AchE and BuchE inhibitory potential compare with positive Donepezil as standard drug for both AchE and BchE having IC 50 = 0.016 ± 0.12 and 0.30 ± 0.010  μ M respectively. In this regard analog 9 was found potent having IC 50 value 0.15 ± 0.050  μ M and 0.20 ± 0.10 for both AchE and BuChE respectively. All other derivatives also found with better potential. All compounds were characterized by various techniques such as 1 H, 13 C-NMR and HREI-MS. In addition, biological activity was maintained to explore the bioactive nature of scaffolds and their protein-ligand interaction (PLI) was checked through molecular docking study.Communicated by Ramaswamy H. Sarma.

We have synthesized benzo[ d ]oxazole derivatives ( 1-21 ) through a multistep reaction. Alteration in the structure of derivatives was brought in the last step via using various substituted aromatic aldehydes. In search of an anti-Alzheimer agent, all derivatives were evaluated against acetylcholinesterase and butyrylcholinesterase enzyme under positive control of standard drug donepezil (IC 50 = 0.016 ± 0.12 and 4.5 ± 0.11 µM) respectively. In case of acetylcholinesterase enzyme inhibition, derivatives 8 , 9 and 18 (IC 50 = 0.50 ± 0.01, 0.90 ± 0.05 and 0.3 ± 0.05 µM) showed very promising inhibitory potentials. While in case of butyrylcholinesterase enzyme inhibition, most of the derivatives like 6, 8, 9, 13, 15, 18 and 19 (IC 50 = 2.70 ± 0.10, 2.60 ± 0.10, 2.20 ± 0.10, 4.25 ± 0.10, 3.30 ± 0.10, 0.96 ± 0.05 and 3.20 ± 0.10 µM) displayed better inhibitory potential than donepezil. Moreover, derivative 18 is the most potent one among the series in both inhibitions. The binding interaction of derivatives with the active gorge of the enzyme was confirmed via a docking study. Furthermore, the binding interaction between derivatives and the active site of enzymes was correlated through the SAR study. Structures of all derivatives were confirmed through spectroscopic techniques such as 1 H-NMR, 13 C-NMR and HREI-MS, respectively.Communicated by Ramaswamy H. Sarma.

This work reports the convenient approach for the synthesis of thiazole based thiourea derivatives (1-21) from 2-bromo-1-(4-fluorophenyl)thiazole-1-one and phenyl isothiocyanates. The scope and diversity were achieved from readily available phenyl isothiocyanates. This protocol involves an oxidative C-S bond formation. Moreover, hybrid thiazole based thiourea scaffolds (1-21) according to literature known protocol were screened in vitro for anticancer Potential against breast cancer, antiglycation and antioxidant inhibitory profile. All newly developed scaffolds were showed moderate to good inhibitory potentials ranging from 0.10 ± 0.01 µM to 11.40 ± 0.20 µM, 64.20 ± 0.40 µM to 385.10 ± 1.70 µM and 8.90 ± 0.20 µM to 39.20 ± 0.50 µM against anticancer, antiglycation and antioxidant respectively. Among the series, compounds 12 (IC 50 = 0.10 ± 0.01 µM), 10 (IC 50 = 64.20 ± 0.40 µM) and 12 (IC 50 = 8.90 ± 0.20 µM) with flouro substitution at phenyl ring of thiourea were identified to be the most potent among the series having excellent anticancer, antiglycation and antioxidant potential. The structure of all the newly synthetics scaffolds were confirmed by using different types of spectroscopic techniques such as HREI-MS, 1 H- and 13 C-NMR spectroscopy. To find structure-activity relationship, molecular docking studies were carried out to understand the binding mode of active inhibitors with active site of enzymes and results supported the experimental data.Communicated by Ramaswamy H. Sarma.

Usnic acid (UA) lately piqued the interest of researchers for its extraordinary biological characteristics, including anticancer activity. Here, the mechanism was clarified through network pharmacology,molecular docking and molecular dynamic simulation. Sixteen proteins were selected through network pharmacology study as they are probable to interact with UA. Out of these proteins, 13 were filtered from PPI network analysis based on their significance of interactions ( p  < 0.05). KEGG pathway analysis has also aided us in determining the three most significant protein targets for UA, which are BCL2, PI3KCA and PI3KCG. Therefore molecular docking and molecular dynamic (MD) simulations throughout 100 ns were performed for usnic acid onto the three proteins mentioned. However, UA's docking score in all proteins is lower than their co-crystalised ligand, especially for BCL2 (-36.5158 kcal/mol) and PI3KCA (-44.5995 kcal/mol) proteins. The only exception is PI3KCG which has comparable results with the co-crystallised ligand with (-41.9351 kcal/mol). Furthermore, MD simulation has also revealed that usnic acid does not stay fit in the protein throughout the simulation trajectory for PI3KCA protein evident from RMSF and RMSD plots. Nevertheless, it still poses good ability in inhibiting BCL2 and PI3KCG protein in MD simulation. In the end, usnic acid has exhibited good potential in the inhibition of PI3KCG proteins, rather than the other proteins mentioned. Thus further study on structural modification of usnic acid could enhance the ability of usnic acid in the inhibition of PI3KCG as anti-colorectal and anti-small cell lung cancer drug candidate.Communicated by Ramaswamy H. Sarma.

In search of potent urease inhibitor indole analogues ( 1-22 ) were synthesized and evaluated for their urease inhibitory potential. All analogues ( 1-22 ) showed a variable degree of inhibitory interaction potential having IC 50 value ranging between 0.60 ± 0.05 to 30.90 ± 0.90  µ M when compared with standard thiourea having IC 50 value 21.86 ± 0.90  µ M. Among the synthesized analogues, the compounds 1, 2, 3, 5, 6, 8, 12, 14, 18, 20 and 22 having IC 50 value 3.10 ± 0.10, 1.20 ± 0.10, 4.60 ± 0.10, 0.60 ± 0.05, 5.30 ± 0.20, 2.50 ± 0.10, 7.50 ± 0.20, 3.90 ± 0.10, 3.90 ± 0.10, 2.30 ± 0.05 and 0.90 ± 0.05  µ M respectively were found many fold better than the standard thiourea. All other analogues showed better urease interaction inhibition. Structure activity relationship (SAR) has been established for all analogues containing different substituents on the phenyl ring. To understand the binding interaction of most active analogues with enzyme active site docking study were performed.Communicated by Ramaswamy H. Sarma.

Inhibition of α-amylase enzyme is of key significance for the therapy of diabetes mellitus (DM). Numerous indole-based compounds have earlier been described for broad range of bioactivities. From our previous study, we knew that indole and thiadiazole are potent inhibitors of diabetics II. We design the hybrid molecules of them and synthesized 18 derivatives of indole-based-thiadiazole ( 1 - 18 ). All synthesized compounds were characterized using different spectroscopic methods and evaluated for their α-amylase inhibitory activities. All synthetic compounds, except 4 , 13 , 15 and 16 , were found to be strongly active (IC 50 values in the range of 0.80 ± 0.05 - 9.30 ± 0.20 µM) than the standard drug, acarbose (IC 50 = 11.70 ± 0.10 µM). Nevertheless, compound 18 was found to be inactive. The modes of binding interactions of five most active compounds 2 , 3 , 5 , 10 and 17 were also studies through molecular docking study. In brief, current study identifies a novel class of α-amylase inhibitors which can be further studied for the treatment of hyperglycemia and obesity.Communicated by Ramaswamy H. Sarma.

The main protease of SARS-CoV-2 is one of the important targets to design and develop antiviral drugs. In this study, we have selected 40 antiviral phytochemicals to find out the best candidates which can act as potent inhibitors against the main protease. Molecular docking is performed using AutoDock Vina and GOLD suite to determine the binding affinities and interactions between the phytochemicals and the main protease. The selected candidates strongly interact with the key Cys145 and His41 residues. To validate the docking interactions, 100 ns molecular dynamics (MD) simulations on the five top-ranked inhibitors including hypericin, cyanidin 3-glucoside, baicalin, glabridin, and α-ketoamide-11r are performed. Principal component analysis (PCA) on the MD simulation discloses that baicalin, cyanidin 3-glucoside, and α-ketoamide-11r have structural similarity with the apo-form of the main protease. These findings are also strongly supported by root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and solvent accessible surface area (SASA) investigations. PCA is also used to find out the quantitative structure-activity relationship (QSAR) for pattern recognition of the best ligands. Multiple linear regression (MLR) of QSAR reveals the R 2 value of 0.842 for the training set and 0.753 for the test set. Our proposed MLR model can predict the favorable binding energy compared with the binding energy detected from molecular docking. ADMET analysis demonstrates that these candidates appear to be safer inhibitors. Our comprehensive computational and statistical analysis show that these selected phytochemicals can be used as potential inhibitors against the SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Five Schiff bases, 2-((3-chlorophenylimino)methyl)-5-(diethylamino)phenol (L1), 2-((2,4-dichlorophenylimino)methyl)-5-(diethylamino)phenol (L2), 5-(diethylamino)-2-((3,5-dimethylphenylimino)methyl)phenol (L3), 2-((2-chloro-4-methylphenylimino)methyl)-5-(diethylamino)phenol (L4), and 5-(diethylamino)-2-((2,6-diethylphenylimino)methyl)phenol (L5) were synthesized and characterized by elemental analysis, FT-IR, 1 H and 13 C NMR spectroscopy. Three of the compounds (L1, L2, and L4) were analyzed by single crystal X-ray diffraction: L1 and L2 crystallized in orthorhombic P2 1 2 1 2 1 and Pca2 1 space group, respectively, while L4 crystallized in monoclinic P2 1 /c space group. Theoretical investigations were performed for all the synthesized compounds to evaluate the structural details. Drug-DNA interaction studies results from UV-Vis spectroscopy and electrochemistry complement that the compounds bind to DNA through electrostatic interactions. The cytotoxicity of the synthesized compounds was studied against cancer cell lines (HeLa and MCF-7) and a normal cell line (BHK-21) by means of an MTT assay compared to carboplatin, featuring IC 50 values in the micromolar range. The pro-apoptotic mechanism for the active compound L5 was evaluated by fluorescence microscopy, cell cycle analysis, caspase-9 and -3 activity, reactive oxygen species production, and DNA binding studies that further strengthen the results of that L5 is a potent drug against cancer.Communicated by Ramaswamy H. Sarma.

Methotrexate is a widely used anti-metabolite in cancer chemotherapy. A series of halogenated drugs is designed from Methotrexate to assess their interactions with human dihydrofolate reductase. The aim of this study is to evaluate the performance of the modified drugs compared to the parent Methotrexate. Density Functional Theory is employed to optimize these drugs. Molecular docking calculation of these optimized drugs against dihydrofolate reductase is performed to find out binding affinity. In addition, molecular dynamics simulation is considered for the complexes of best two modified drugs with their receptors. Modifications by the halogens show significant changes in the charge distribution, dipole moment, thermodynamic stability, enthalpy and free energy. The highest binding affinity value (-36.401 KJ/mol) was obtained for M14. Hybrid quantum mechanics/molecular mechanics calculation shows a binding energy of -255.140 KJ/mol. Modified drugs have significant hydrogen and non-covalent bonding interactions with amino acids of the receptor. Molecular dynamics simulation disclosed that the root-mean-square-deviation of the alpha carbon associated with M6-1KMV and M14-1KMV complexes is 2.367 Å and 2.622 Å, respectively. Moreover, the interactions between modified drugs and receptor are mostly persevered in 25 nanosecond molecular dynamics simulation. Ensemble-based docking also confirmed that modified drugs show strong non-bonding interactions with different crystallographic and molecular dynamics based conformers. The best scored drugs show considerable pharmacokinetic properties. Modified derivatives M5, M6, M8, M10, M13 and M14 show the better binding affinity and a good number of hydrogen and other non-bonding interactions with the target protein which are similar to other anticancer drugs.Communicated by Ramaswamy H. Sarma.