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• Synthesis of new indol-3-acetyl-arylsulfonohydrazide derivatives. • In vitro α-glucosidase and α-amylase inhibitors. • Identification of a new α-glucosidase and α-amylase inhibitors. • Structure activity relationship established. • Molecular docking. Herein this work, indole analogs (1–16) were synthesized by treating 2-(1H-indol-3-yl)acetohydrazide with various aryl sulfonyl chloride in pyridine as solvent and screened for α-amylase and α-glucosidase inhibitory activity under positive control of standard drug acarbose (IC 50 = 12.80 ± 0.10 μ M /12.90 ± 0.10 μ M. All analogs of the series appeared with excellent to good inhibitory activity as compared to standard drug. The inhibitory activity range for α-amylase is 0.70 ± 0.01 μ M to 19.40 ± 0.40 μ M, while for α-glucosidase inhibitory activity is 1.20 ± 0.10 μ M to 20.40 ± 0.40 μ M respectively. Most of the analogs appeared with excellent inhibitory activity, and some analogs like 5, 6, 7, 8, 9, 10,13 and 14 for both enzymes displayed many folds better inhibitory activity than standard drug acarbose. The influences of substituents on inhibitory activity were superficially resonated via structure activity relationship. Docking studies were established to confirm the binding interaction between analogs and active sites of enzymes. [ABSTRACT FROM AUTHOR]

• Synthesis of benzofuran derivatives. • In vitro acetylcholinesterase and butyrylcholinesterase inhibitory activity. • Identification of a novel class of anti-alzheimer agents. • Molecular docking studies. We have synthesized novel benzofuran derivatives (1–20), characterized through different spectroscopic techniques such as 1HNMR, 13CNMR, HREI-MS and screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives showed inhibitory activities having IC 50 values ranging from 0.70 ± 0.01 to 28.10 ± 0.50 µ M (against AChE), while 0.80 ± 0.01 to 31.20 ± 0.60 µ M (against BuChE) as compared to the standard drug Donepezil (IC 50 = 2.16 ± 0.12 and 4.50 ± 0.10 µ M, respectively). Except derivative 5, all other derivatives of the series showed good inhibitory activity against both acetylcholinesterase and butyrylcholinesterase, but some analogues like 2, 4, 7, 14, 15, and 16 displayed many folds better inhibitory activity than the standard drug donepezil. The influences of substituents on inhibitory activity were superficially resonated via the structure-activity relationship. We established molecular docking and MD simulation studies to confirm the binding interaction between potent derivatives and active sites of enzymes. [Display omitted] [ABSTRACT FROM AUTHOR]

• Synthesis of new a series N -(substituted phenyl)-(5-(3,4-dichlorobenzyl)-4-(4-chlorophenyl)- 4H -1,2,4-triazol-3-ylthio)methylbenzamides has been achieved via multi-step strategy. • Characterization of novel compounds was done by various spectral techniques and their enzyme inhibitory potential was evaluated against alkaline phosphatase. • The Structure-Activity Relationship (SAR) elaborated the influence of different structural moieties of molecules on their inhibitory activity. • H-binding and electrostatic interactions between 8d, 8 g and 8i and amino acids were observed through Molecular docking. • DFT analysis was performed to assess the HOMO-LUMO energy gap in all complexes. The present research work encompass an innovative approach towards the synthesis of potent series of target compounds (8a-j) having 1,2,4-triazole and benzamide moieties as alkaline phosphatase inhibitors. The synthetic methodology was initiated by Fischer's esterification of 3,4-dichlorophenylacetic acid (1) to achieve ethyl 2-(3,4-dichlorophenyl)acetate (2) which underwent hydrazinolysis using hydrazine hydrate under reflux to 2-(3,4-dichlorophenyl)acetohydrazide (3). The compound (3) with 4-chlorophenyl isothiocyanate (4) was base-catalyzed cyclization (10% aqueous NaOH) to 4-(4-chlorophenyl)-5-(3,4-dichlorobenzyl)- 4H -1,2,4-triazole-3-thiol (5) under reflux via N -(4-chlorophenyl)-2-(2-(3,4-dichlorophenyl)acetyl)hydrazinecarbocarbothioamide, as an intermediate. Finally, a series of derivatives (8a-j) was synthesized by reacting (5) with different electrophiles; N -(aryl)-4-(chloromethyl)benzamides (7a - j) which were obtained by the reaction of substituted aryl amines (6a-j) with 4-(chloromethyl)benzoyl chloride in aqueous alkaline medium. The structural confirmation of all these novel derivatives was corroborated by contemporary spectral analysis i.e., IR, EI-MS, 1H and 13CNMR. The in vitro inhibitory potential of these benzamides against alkaline phosphatase enzyme disclosed that nine out of ten exhibited potent inhibition relative to standard used. Among these, 8i was identified as most potent molecule with IC 50 value of (0.046 ± 0.013 μ M), comparative to standard (5.241 ± 0.471 μ M). The Kinetics mechanism examined by Lineweaver-Burk Plots (LBP), which revealed that 8i inhibited alkaline phosphatase enzyme competitively by forming an enzyme-inhibitor complex. The inhibition constant K i determined from Dixon plots of this compound was 0.02 µ M. The results of computational study were in full agreement with experimental proceedings and these ligands showed good interactions with the active site of enzyme. Based on the current investigations, these potent inhibitotrs might lead to further research gateways for the discovery of non-toxic medicinal scaffolds for dealing with the alkaline phosphatase ailments such as bone diseases and liver dysfunction. DFT analysis was also performed. [ABSTRACT FROM AUTHOR]

• Synthesis of Benzimidazole derivatives. • In vitro acetylcholinesterase and butyrylcholinesterase inhibitory activity. • Identification of a novel class of Anti-Alzheimer agents. • Molecular Docking studies. • All compounds found to be potent. In search of potent anti-Alzheimer agent benzimidazole based Schiff base derivatives (1–18) were synthesized and evaluated as dual inhibitor for acetylcholinesterase and butyrylcholinesterase enzymes. All analogs among the series except analog 1 and 16 showed a variable degree of inhibitory activity with IC 50 value ranging between 0.10 ± 0.01 to 12.40 ± 0.30 µ M for acetylcholinesterase and 0.20 ± 0.01 to 11.10 ± 0.30 µ M for butyrylcholinesterase. The most potent analog found among the series was analog 8 having IC 50 value 0.10 ± 0.01 and 0.20 ± 0.01 µ M for both acetylcholinesterase and butyrylcholinesterase inhibition respectively. The structures of all synthesized analogs were confirmed through NMR and HR-EIMS. Structure activity relationship (SAR) has been established for all newly synthesized derivatives. To understand the binding interaction of most active derivatives with enzyme active site, molecular docking study were performed. The toxicity and mutagenicity of compound 8 was predicted using in silico software, namely Derek Nexus® (version 6.3). Various toxicity endpoints, including chromosomal damage, skin sensitization, hepatotoxicity were predicted. The degradation profile of compound 8 was predicted in silico by Zeneth software (version 9.0.1) resulting in a probability of the formation of seven potential degradation products. [Display omitted] [ABSTRACT FROM AUTHOR]

• Synthesis of indazole based schiff base analogues. • Identification of a new class of α-glucosidase and α-amylase inhibitors. • Analogue 22 proved to be most active α-glucosidase and α-amylase inhibitors. • Docking study was conducted to interpret the obtained results. Indazole-based Schiff base analogues (1–27) were synthesized by a three-step reaction pathway starting from 1-methyl-1 H -indazole-3-carboxylic acid as the basic compound. The structure of the new indazoles was characterized and confirmed by mass spectral analyses as well as NMR spectroscopic data. All synthesized analogues were screened for their in vitro α-glucosidase and α-amylase inhibitory activities. All analogues of the series exhibited good inhibitory potentials, with IC 50 values ranging from 0.40 ± 0.01 to 16.20 ± 0.30 µM for α-glucosidase and 0.70 ± 0.01 to 17.40 ± 0.30 µM for α-amylase as compared to the standard drug acarbose (IC 50 = 12.90 ± 0.10 and 12.80 ± 0.10 µM, respectively). The most effective analogue of the series is analogue 22 having 3‑hydroxyl groups with an IC 50 value of 0.40 ± 0.01 µM and 0.70 ± 0.01 µM for α-glucosidase and α-amylase, respectively. Structure-activity relationship was carried out, which mainly depends upon the nature, number, position, and electron donating/withdrawing effect of the substituent(s) attached to the phenyl ring. To investigate the binding interaction of the potent analogue with the active site of an enzyme, molecular docking studies were carried out. [ABSTRACT FROM AUTHOR]

• Multistep synthesis of heterocyclic 1,3,4-oxadiazole derivatives through conventional and microwave assisted methods. • Three compounds, 5a, 5n and 5q , as potent inhibitors of alpha-glucosidase, BChE and urease enzymes. • Molecular docking analysis to explore binding with active site of enzyme. • Frontier molecular orbitals to explore interacting potential of compounds. • Molecular electrostatic potential to explore interacting sites of compounds. The diverse biological activities of 1,3,4-oxadiazole derivatives are very significant due to structural complexity. Concentrating on metal free synthesis of 1,3,4-oxadiazole hybrids, 5a-s were obtained by two methodologies including conventional and microwave assisted. The microwave assisted synthesis was proved to be better option for selection in future due to time saving and excellent yield. 1,3,4-Oxadiazole, 3 , was synthesized in three consecutive phases and finally reacted with a series of electrophiles, 4a-s , acknowledged as alkyl halide to get the anticipated compounds. Final compounds were acquired through two different routes including conventional and microwave assisted methods. IR, 1H-NMR, 13C-NMR and elemental analysis were performed for the structural elucidation of synthesized derivatives. B3LYP method and the basis set of 6-311++G (d,p) were used for natural bond orbital and structural optimization. The time-dependent density functional theory (TD-DFT) helped for the calculation of frontier molecular orbitals (FMOs) and molecular electrostatic potential (MEP) at the same level of selected compounds as potential candidates against the enzymes taken into account. The screenings of all the nineteen derivatives were performed against alpha-glucosidase, urease and butyryl cholinesterase enzymes. Six compounds actively inhibited alpha-glucosidase in comparison with acarbose; four actively inhibited urease in comparison with thiourea; and five actively inhibited butyryl cholinesterase in comparison with eserine. Three compounds, 5n, 5a and 5q showed good inhibition potential and found the best in the synthesized series. [Display omitted] [ABSTRACT FROM AUTHOR]

• Synthesis of benzimidazole-based thiadiazole derivatives. • Exploring in vitro acetylcholinesterase and butyrylcholinesterase inhibition profile of the synthesized compounds. • To find out the binding mode of interactions of most active compounds with targeted enzymes using molecular docking approach. A new series of benzimidazole-based thiadiazole hybrids analogues (6a–p) as effective Alzheimer's inhibitors were synthesized and then evaluated for their inhibition profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes as compared to Donepezil as standard drug. All the synthesized benzimidazole-based thiadiazole analogues showed varied range of inhibitory potentials against targeted AChE & BuChE enzymes with IC 50 values ranging from 1.32 ± 0.10 µM to 19.26 ± 0.60 µM (for AChE) and 1.94 ± 0.10 µM to 21.33 ± 0.70 µM (for BuChE) when compared to standard Donepezil (IC 50 = 2.16 ± 0.050 µM for AChE) & 4.50 ± 0.10 µM for BuChE). As structure-activity relationship (SAR) studies revealed that the analogues 4d (bearing ortho ‑hydroxy and para -NO 2 on N -aryl ring along with ortho -NO 2 substitution on another aryl ring) and 6k (that holds ortho ‑hydroxy & para -NO 2 substitutions on N -aryl ring and 3,4-diCl moieties on another aryl ring) were emerged as the most potent analogues of AChE & BuChE enzymes having IC 50 values of 1.32 ± 0.10 µM & 1.84 ± 0.20 µM (against AChE) and 1.94 ± 0.10 µM & 2.23 ± 0.20 µM (against BuChE) respectively. Furthermore, the active analogues were subjected to molecular docking studies in order to explore the binding interactions possess by potent analogues with the active sites of amino acids of targeted AChE & BuChE enzymes and result obtained shows that these active analogues furnished that several key interactions with targeted enzymes active sites. Additionally, all the synthesized analogues were elucidated structurally using variety of spectroscopic (1H NMR & 13C NMR) and spectrometric (HREI-MS) analysis. [ABSTRACT FROM AUTHOR]

• Several oxadiazole-based thiourea derivatives containing imidazopyridine moiety were synthesized. • Also, all derivatives were tested to determine their ability to inhibit α-amylase, α-glucosidase and 2- diphenyl-1-picrylhydrazyl (DDPH) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging enzymes. • A molecular docking simulation of the most potent derivatives was performed to determine whether they are able to bind to the active site of targeted enzymes. A series of new imidazopyridine based oxadiazole derivatives (5a-l) were designed and synthesized. Their structures were confirmed by spectral data and then subjected to in vitro assessment including α-glucosidase, α-amylase inhibitory, and 2- diphenyl-1-picrylhydrazyl (DDPH) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities. The inhibitory activity results revealed that all the synthesized analogs displayed significant α-glucosidase and α-amylase inhibition with IC 50 values of 0.90 ± 0.10 to 18.10 ± 0.20 µM (for α-glucosidase) and 1.10 ± 0.10 to 19.70 ± 0.20 µM (for α-amylase) respectively as compared to standard acarbose with IC 50 values of 11.50 ± 0.30 µM (α-glucosidase) and 12.20 ± 0.30 µM (for α-amylase).The synthesized analogs also showed significant DPPH and ABTS radical scavenging activities with IC 50 values in the range of 1.05 ± 0.05 to 4.56 ± 3.12 µM (for DDPH) and 1.15 ± 0.05 to 4.89 ± 2.89 µ M (for ABTS) respectively, incomparison to standard ascorbic acid with IC 50 = 1.83 ± 1.32 µM (for DDPH) and 1.84 ± 1.16 µM (for ABTS) respectively. After crucial analysis of varying substitution effects on inhibitory (α-glucosidase &α-amylase) and radical scavenging (DPPH & ABTS) potentials respectively, the structure-activity relationship (SAR) was established. Through the in silico molecular docking analysis, the ability of the synthesized analogs to inhibit α-glucosidase and α -amylase was also examined.There was a good correlation between in vitro and in silico studies for synthesized analogs 5i and 5d Further studies are required to determine whether these potent analogs could be a potential treatment for diabetes disease. [ABSTRACT FROM AUTHOR]

• Synthesis of hybrid 4-quinolinyl bearing 1,3,4-thiadiazole-2-amine. • In vitro α-amylase and α-glucosidase enzymes study. • Identification of a new α-amylase and α-glucosidase inhibitors. • Structure activity relationship established. • Molecular dockingADMET profile, drug likeness and Molecular dynamics study Synthesized scaffolds (1–19) of 4-quinolinyl based 1,3,4-thiadiazole-2-amine were evaluated in vitro for their α -amylase and α -glucosidase inhibition. All the newly synthesized scaffolds (1–19) were found to illustrate variable degree of inhibitory profile against α -amylase and α -glucosidase enzymes ranging from 1.30 ± 0.05 to 45.60 ± 0.80 µ M and 2.70 ± 0.10 µ M to 47.60 ± 0.90 µ M. Among the series, compounds 2 (IC 50 = 2.20 ± 0.10 µ M), (IC 50 = 8.40 ± 0.20 µ M), 3 (IC 50 = 4.10 ± 0.10 µ M), (IC 50 = 5.60 ± 0.10 µ M), 4 (IC 50 = 1.30 ± 0.05 µM), (IC 50 = 2.90 ± 0.10 µM) and 5 (IC 50 = 1.90 ± 0.10 µM), (IC 50 = 2.70 ± 0.10 µM) were found to be the most potent inhibitors of α -amylase and α -glucosidase enzymes. The elevated inhibitory profile of these scaffolds might be due to presence of flouro and chloro group at different positions of phenyl ring attached to 1,3,4-thiadiazole ring. Various types of spectroscopic techniques such as 1H-, 13C- NMR and HREI-MS spectroscopy were used to confirm the structure of all the newly developed scaffolds. To find SAR, molecular docking studies were performed to understand the binding mode of potent inhibitors with active site of enzymes and results supported the experimental data. Molecular dynamics study were performed to further investigate the orientation and binding interaction of the synthesized analogues with active site of α -amylase and α -glucosidase enzyme. ADMET prediction and in silico drug likeness analysis of the synthesized analogues demonstrated that these analogues have satisfactory ADMET profile and drug likeness. [ABSTRACT FROM AUTHOR]

• A library of chalcone derivatives was synthesized. • All the target analogs exhibited excellent a-glucosidase and cholinesterase inhibition. • A kinetic study of the most active analogs 2C and 7C showed competitive inhibitions. • These target analogs exhibit remarkable in vitro and in vivo activities. • Molecular docking and QSAR studies of these target analogs were performed. In the present study, a series of fascinating chalcone derivatives 1C-14C has been designed and synthesized by Claisen-Schmidt condensation. The target compounds were screened for in vitro α-glucosidase and cholinesterase inhibitory activities. For the first time, the enzyme inhibitory activities of the target derivatives were assessed for antihyperglycemic and neuroprotective activities on streptozotocin (STZ) induced diabetic animal models using in vivo mechanism-based assays. Based on α-glucosidase and cholinesterase inhibitory activities, the compounds 2C, 3C, 13C and 14C were chosen in vivo for further evaluation of antidiabetic and neuroprotective activities in STZ-induced diabetic Wistar rats. All these evaluated compounds demonstrated significant antidiabetic and antiamnesic activities and found nontoxic in nature. The target compounds were then tested in vivo for cognitive function in a STZ-induced amnesic animal paradigm, where four compounds 2C, 3C, 13C , and 14C considerably reduced the amnesic effects as measured by the Y-Maze Paradigm and novel object discrimination (NOD) tasks. Furthermore, the structure-activity relationship of these substituted chalcone derivatives was established. According to kinetic studies, 2C and 7C have K i values of 0.017±0.00078 µM and 0.00060±0.00004 µM, respectively, and were competitive inhibitors of cholinesterase and α-glucosidase. Molecular docking study revealed that the co-crystallized ligand and potent compounds exhibited same binding orientation within the target enzyme's active site (α-glucosidase (PDB ID: 3AJ7), AChE (PDB ID: 1ACL) and BChE (PDB ID: 4TPK)). The QSAR studies were conducted based on anti-glucosidase and anti-cholinesterases (AChE, BChE) assays. The value of coefficient of multiple determinant (R2) 0.9999 depicts a strong relationship between 1C-14C structures and selected properties. Most of these substances are selective inhibitors of cholinesterase that may be used for age-related problems and to treat the progressive neurodegenerative disorder. [Display omitted] [ABSTRACT FROM AUTHOR]

• New benzofuran–based Schiff bases derivatives were and synthesized. • Evaluation of α-glucosidase and α-amylase enzymes inhibition structure-activity relationship. • Molecular docking study was presented to explain numerous key binding interactions. Inhibition of α-glucosidase and α-amylase enzymes is one of the significant approaches in designing anti-diabetic drugs because of its role in decreasing the carbohydrate digestion. In the present study we designed a new series of benzofuran Schiff base and evaluated them for their inhibitory potentials against α-amylase and α-glucosidase enzymes. Compounds 1–22 exhibited a varying degree of inhibitory activity with IC 50 value ranging from 1.10 ± 0.10 to 24.60 ± 0.70 µ m for α-amylase and 1.40 ± 0.10 to 24.00 ± 0.70 µ m for α-glucosidase when compared with the standard drug acarbose having an IC 50 value of 11.50 ± 0.30 and 12.20 ± 0.30 µ m for α-amylase and α-glucosidase respectively. The most potent analogue among the series was analogue 12 having IC 50 value of 1.10 ± 0.10 µ m for α-amylase and 1.40 ± 0.10 µ m for α -glucosidase. Similarly, analogues 1, 8 and 19 were also identified as potent analogues having IC 50 values of 2.20 ± 0.10, 2.10 ± 0.10 and 2.10 ± 0.10 for α-amylase and 2.70 ± 0.10,1.90 ± 0.10 and 2.50 ± 0.10 for α-glucosidase respectively. Analogues 11 (= 4.70 ± 0.10, 4.40 ± 0.10), 17 (IC 50 = 5.20 ± 0.10, 5.70 ± 0.10) and 22 (= 4.80 ± 0.10, 4.50 ± 0.10) exhibited moderate inhibition. Structure-activity relationship (SAR) of this series has been established which is mainly based on the position and nature of substituent on phenyl ring. In order to analyze the mode of inhibition of these compounds docking studies were carried out. Binding mode analysis of the most active inhibitors showed that these are well accommodated into the binding site of enzyme. [ABSTRACT FROM AUTHOR]

• Synthesis of Isatin bearing thiosemicarbazide analogs. • In vitro alpha glucosydase activity. • Identification of a new class of alpha glucosydase activity. • Structure activity relationship established. • Molecular docking. A new series of isatin based thiosemicarbazide derivatives 1–15 were synthesized and characterized by 1H NMR, 13C NMR and HR-EIMS. The synthetic derivatives were evaluated for α- glucosidase inhibitory potential. All compounds showed excellent α- glucosidase inhibitory potential having IC 50 values ranging between 1.20 ± 0.10 to 35.60 ± 0.80 µ M when compared with the standard acarbose having IC 50 value 38.60 ± 0.20 µ M. Compound 3, 4, 5, 9, 10, 12 and 15 having IC 50 values 2.20 ± 0.10, 3.5 ± 0.10, 1.20 ± 0.10, 5.20 ± 0.20, 3.60 ± 0.10, 4.60 ± 0.20 and 3.90 ± 0.10 µ M, respectively, was found many fold better than the standard acarbose having IC 50 value 38.60 ± 0.20 µ M. Structure activity relationship has been also established for all newly synthesized compounds, mainly based on substitution pattern on phenyl ring. Through molecular docking study the binding mode of active derivatives with α- glucosidase enzyme active site was confirmed. Image, graphical abstract [ABSTRACT FROM AUTHOR]

• Erythrina suberosa is a medicinal plant known to possess antiulcer activity. • Various fractions of plant flowers are screened for antioxidant and anti-urease activities. • The most active n -hexane fraction is subjected to GC-MS analysis and molecular docking studies. • In the light of docking results, anti-urease activity is suggested due to synergistic effect of secondary metabolites in the n -hexane fraction. The plants of the Erythrina genus possess tremendous pharmacological properties and thus are utilized in traditional medicines owing to their bioactivities. In the present study, methanolic extract (EsM) of flowers of Erythrina suberosa Roxb. and its fractions (n -hexane (EsH), chloroform (EsC) and aqueous (EsW) parts) were tested for preliminary phytochemical analysis, antioxidant and urease inhibition activities. The EsM extract was found to be most active for antioxidant activity, whereas the EsH extract showed the highest anti-urease potential with an inhibition value of 62.9 % (at a concentration of 100 µg/ml), while the other extracts were least active. The EsH extract being most active against urease enzyme, was further subjected to gas chromatography-mass spectrometry (GC-MS) analysis, which revealed the tentative presence of 18 secondary metabolites of various classes. Furthermore, the in-silico studies of the major compounds as detected in EsH extract by GC-MS analysis were performed to correlate the potential interaction of compounds with the active site of the enzyme. The selected compounds were docked against the urease enzyme, and their affinities were compared. Binding affinity data and interaction patterns of all the studied phytochemicals indicated that these compounds could inhibit urease enzyme synergistically and can be further studied to prevent ulcer and related problems. It is, therefore concluded that E. suberosa flowers possess interesting antioxidant and anti-urease potential and thus could further be adopted for industrial and biopharmaceutical applications. [ABSTRACT FROM AUTHOR]