Identification of Novel Natural Product Inhibitors against Matrix Metalloproteinase 9 Using Quantum Mechanical Fragment Molecular Orbital-Based Virtual Screening Methods.

Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases involved in multiple cellular processes. Among the MMP isoforms, MMP-9 regulates cancer invasion, rheumatoid arthritis, and osteoarthritis by degrading extracellular matrix proteins present in the tumor microenvironment and cartilage and promoting angiogenesis. Here, we identified two potent natural product inhibitors of the non-catalytic hemopexin domain of MMP-9 using a novel quantum mechanical fragment molecular orbital (FMO)-based virtual screening workflow. The workflow integrates qualitative pharmacophore modeling, quantitative binding affinity prediction, and a raw material search of natural product inhibitors with the BMDMS-NP library. In binding affinity prediction, we made a scoring function with the FMO method and applied the function to two protein targets (acetylcholinesterase and fibroblast growth factor 1 receptor) from DUD-E benchmark sets. In the two targets, the FMO method outperformed the Glide docking score and MM/PBSA methods. By applying this workflow to MMP-9, we proposed two potent natural product inhibitors (laetanine 9 and genkwanin 10) that interact with hotspot residues of the hemopexin domain of MMP-9. Laetanine 9 and genkwanin 10 bind to MMP-9 with a dissociation constant (KD) of 21.6 and 0.614 µM, respectively. Overall, we present laetanine 9 and genkwanin 10 for MMP-9 and demonstrate that the novel FMO-based workflow with a quantum mechanical approach is promising to discover potent natural product inhibitors of MMP-9, satisfying the pharmacophore model and good binding affinity.

Identification of novel C-2 symmetric Bis-Azo-Azamethine molecules as competitive inhibitors of mushroom tyrosinase and free radical scavengers: synthesis, kinetics, and molecular docking studies.

Tyrosinase is a multi-copper enzyme found in plants, animals and microorganisms, plays a critical role in the melanogenesis and browning process critical to cosmetics and food industries. Many natural, semi-synthetic and synthetic inhibitors have been discovered. To this end, a small library of symmetrical Bis-Azo-Azamethine hybrids 5a-j was synthesized and characterized through spectroscopic and analytical data and explored for mushroom tyrosinase and free radical scavenging activity. All of the molecules 5a-j explicated better potential compared to the standard Kojic acid. On the whole, compound 5i having IC50 value 0.002 ± 0.004 µM was found to be the most potent derivative. The Kinetic studies were performed for 5i and indicating the mode of inhibition in a competitive manner. Structure Activity Relationship (SAR) analysis and docking studies were carried out. Thus compound 5i bearing bulky naphthyl groups was most potent and, The molecular docking indicated formation of two hydrogen bonds with Arg268 and one hydrophobic interaction with Glu322. The carbonyl oxygen of 5i interacts with Arg268 and form two hydrogen bonds having lengths 2.44 and 2.62 Å, respectively. In the same way, compounds 5a-j were appraised for DPPH free radical scavenging ability and five of them 5d, 5e, 5h, 5i and 5j were found to exhibit higher % scavenging potency compared with vitamin C, as the standard. Interesting compound 5i was again the most potent in the series. The current investigation points towards the role of naphthyl group in design of new inhibitors of melanogenesis and the antioxidants with improved efficacy.Communicated by Ramaswamy H. Sarma.

Synthesis, Kinetics, Binding Conformations and Structure-activity Relationship of Potent Tyrosinase Inhibitors: Aralkylated 2-aminothiazole-ethyltriazole Hybrids.

Considering the diversified pharmacological importance of thiazole and triazole heterocyclic moieties, a unique series of S-aralkylated bi-heterocyclic hybrids, 7a-l, was synthesized in a convergent manner. The structures of newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, IR, and EI-MS spectral studies. The structure-activity relationship of these compounds was envisaged by analyzing their inhibitory effects against tyrosinase, whereby all these molecules exhibited potent inhibitory potentials relative to the standard used. The Kinetics mechanism was ascertained by Lineweaver-Burk plots, which revealed that 7g inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0057µM. These bi-heterocyclic molecules also disclosed good binding energy values (kcal /mol) when assessed computationally. So, these molecules can be considered promising medicinal scaffolds for the treatment of skin disorders.

Novel 1,3,4-oxadiazole compounds inhibit the tyrosinase and melanin level: Synthesis, in-vitro, and in-silico studies.

In this research work, we have designed and synthesized some biologically useful of 1,3,4-Oxadiazoles. The structural interpretation of the synthesized compounds has been validated by using FT-IR, LC-MS, HRMS, 1H NMR and 13C NMR techniques. Moreover, the in-vitro mushroom tyrosinase inhibitory potential of the target compounds was assessed. The in-vitro study reveals that, all compounds demonstrate an excellent tyrosinase inhibitory activity. Especially, 2-(5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-ylthio)-N-phenylacetamide (IC50 = 0.003 ± 0.00 µM) confirms much more significant potent inhibition activity compared with standard drug kojic acid (IC50 = 16.83 ± 1.16 µM). Subsequently, the most potent five oxadiazole compounds were screened for cytotoxicity study against B16F10 melanoma cells using an MTT assay method. The survival rate for the most potent compound was more pleasant than other compounds. Furthermore, the western blot results proved that the most potent compound considerably decreased the expression level of tyrosinase at 50 µM (P < 0.05). The molecular docking investigation exposed that the utmost potent compound displayed the significant interactions pattern within the active region of the tyrosinase enzyme and which might be responsible for the decent inhibitory activity towards the enzyme. A molecular dynamic simulation experiment was presented to recognize the residual backbone stability of protein structure.

Novel 1,2,4-triazole analogues as mushroom tyrosinase inhibitors: synthesis, kinetic mechanism, cytotoxicity and computational studies.

We have created a novel series of mushroom tyrosinase inhibitors with 1,2,4-triazole as fundamental skeleton. The target compound 1,2,4-triazol-3-ylthio)-N-phenyl acetamide derivatives 9(a-l) were synthesized by the reaction of 4- and 5-substituted 1,2,4-triazole-3-thiol derivatives 6(a-c) with 2-chloro-N-sub/un-substituted phenyl acetamide derivatives 8(a-d) under basic condition. By using the analytical techniques for instance, FTIR, LC-MS, 1H NMR and 13C NMR, the structural verification was evaluated. The novel series of the target compounds 9(a-l) has been scanned for biological activity (mushroom tyrosinase inhibition potential) which demonstrates adequate results. Interestingly, compound 9k (IC50 = 0.0048 ± 0.0016 µM) exhibits 3500 times more activity compared with standard drug kojic acid (IC50 = 16.8320 ± 1.1600 µM) against mushroom tyrosinase inhibitor. Furthermore, the cytotoxicity experiment was carried out for the highly effective target compounds (9d, 9i, 9j and 9k) by using MTT assay method for A375 human melanoma cells to define the nontoxic performance of the most effective compounds ranging from 1 to 25 µM. Furthermore, the molecular docking study delivers the thought concerning the interface of the ligand with an enzyme. Also, the dynamic simulation was accomplished for compound 9k to govern the plausible binding model.

Synthesis, computational studies and enzyme inhibitory kinetics of benzothiazole-linked thioureas as mushroom tyrosinase inhibitors.

Herein, we report synthesis of a set of benzothiazole-thiourea hybrids with aromatic and aliphatic side chains (BT1 to BT9) using an elegant synthetic strategy. The newly synthesized benzothiazole-thiourea conjugates were subjected to In-vitro tyrosinase inhibition and free radical scavenging activity. Majority of the compounds indicated inhibition considerably improved than the standard; compound (Kojic acid with IC50 = 16.8320 ± 1.1600 µM) BT2 with IC50 = 1.3431 ± 0.0254 µM was found to be the best inhibitor. A non-competitive mode of inhibition of BT2 was disclosed with Ki value of 2.8 µM. In order to study enzyme-inhibitor interactions SAR analysis molecular docking was carried out. The amino groups of thiourea were involved in hydrogen bonding with Glu322 showing the bond length of 1.74 and 2.70 Å, respectively. Moreover, the coupling of π-π was displayed between benzothiazole and benzene rings of His244 and His263, respectively. The outcome of this study might help to develop new inhibitors of melanogenesis, important for cosmetic and food products. Communicated by Ramaswamy H. Sarma.

Novel Bi-heterocycles as Potent Inhibitors of Urease and Less Cytotoxic Agents: 3-({5-((2-Amino-1,3-thiazol-4-yl)methyl)-1,3,4-oxadiazol-2-yl}sulfanyl)-N-(un/substituted-phenyl)propanamides.

The synthesis of a novel series of bi-heterocyclic propanamides, 7a-l, was accomplished by S-substitution of 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol (3). The synthesis was initiated from ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (1) which was converted to corresponding hydrazide, 2, by hydrazine hydrate in methanol. The refluxing of hydrazide, 2, with carbon disulfide in basic medium, resulted in 5-[(2-amino-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-thiol (3). A series of electrophiles, 6a-l, was synthesized by stirring un/substituted anilines (4a-l) with 3-bromopropanoyl chloride (5) in a basic aqueous medium. Finally, the targeted compounds, 7a-l, were acquired by stirring 3 with newly synthesized electrophiles, 6a-l, in DMF using LiH as a base and an activator. The structures of these bi-heterocyclic propanamides were confirmed through spectroscopic techniques, such as IR, 1H-NMR, 13C-NMR, and EI-MS. These molecules were tested for their urease inhibitory potential, whereby, the whole series exhibited very promising activity against this enzyme. Their cytotoxic behavior was ascertained through hemolysis and it was observed that all these were less cytotoxic agents. The in-silico molecular docking analysis of these molecules was also in full agreement with their in-vitro enzyme inhibition data.

Synthesis of novel xanthene based analogues: Their optical properties, jack bean urease inhibition and molecular modelling studies.

In this work, a series of the rhodamine 6G based derivatives 5a-5g, were synthesized. The structural framework of the synthesized compounds was established by using 1H NMR, 13C NMR, FT-IR, and LC-MS analytical methods. The spectroscopic properties of the target compounds were determined by using absorption and fluorescence study in four different solvents. Furthermore, the synthesized derivatives were assessed for in-vitro screening against jack bean urease inhibition and in-silico molecular docking study. The result reveals that all the compounds exhibit good urease inhibitory activity against this enzyme but among the series, the compound 5a &5c with an IC50 values of 0.1108 ±â€¯0.0038 µM and 0.1136 ±â€¯0.0295 µM shows to be most auspicious inhibitory activity compared to a standard drug (Thiourea) having IC50 value 4.7201 ±â€¯0.0546 µM. Subsequently, the molecular docking experiment was analysed to distinguish the enzyme-inhibitor binding interaction.

Synthesis and characterization of new 4H-chromene-3-carboxylates ensuring potent elastase inhibition activity along with their molecular docking and chemoinformatics properties.

A new series of 4H-chromene-3-carboxylate derivatives were synthesized using multicomponent reaction of salicylaldehyde, ethyl acetoacetate and dimedone in ethanol with K3PO4 as a catalyst at 80 °C. The structures of all newly synthesized compounds were confirmed by spectral techniques viz. IR, 1H NMR, 13C NMR, and LCMS analysis. The newly synthesized compounds 4a to 4j were screened against elastase enzyme. Interestingly, all these compounds found to be potent elastase inhibitors with much lower IC50 value. The compound 4b was found to be most potent elastase inhibitor (IC50 = 0.41 ± 0.01 µM) amongst the synthesized series against standard Oleanolic Acid (IC50 value = 13.45 ± 0.0 µM). The Kinetics mechanism for compound 4b was analyzed by Lineweaver-Burk plots which revealed that compound inhibited elastase competitively by forming an enzyme-inhibitor complex. Along with this, all the synthesized compounds (4a - 4j) exhibits excellent DPPH free radical scavenging ability. The inhibition constant Ki for compound 4b was found to be 0.6 µM. The computational study was comprehensible with the experimental results with good docking energy values (Kcal/mol). Therefore, these molecules can be considered as promising medicinal scaffolds for the treatment of skin-related maladies.

Design and Synthesis of New Porphyrin Analogues as Potent Photosensitizers for Photodynamic Therapy: Spectroscopic Approach.

New porphyrin analogues have been designed and synthesized using pyrrole, various aldehydes and propionic acid. The formation of desired compounds was analyzed by utilizing the spectral analysis such as IR, NMR and Mass spectroscopy. The studies on absorption and fluorescence emission of synthesized porphyrins were used to evaluate photophysical characteristics such as molar excitation coefficient and Stokes shift. The estimated values of fluorescence lifetime and fluorescence quantum yield of synthesized porphyrins were found to be variable due to the presence of change in the electron donating and withdrawing characters. The efficiency of generation of singlet oxygen by each synthesized porphyrin as photosensitizer was measured in terms of singlet oxygen quantum yield through photooxidation of 9,10-dimethylantharacene. The obtained singlet oxygen quantum yield values were found to be higher in case of porphyrins those have more electron withdrawing characters rather than donating characters as compared to reference 5,10,15,20-tetraphenylporphyrin (H2TPP). The singlet oxygen quantum yield values of synthesized porphyrins varied from 0.52 to 0.66. Pleasingly, some of synthesized porphyrins are found to be photostable and competent to discover as PDT agents as compared to reference H2TPP.

Synthesis of Bi-heterocyclic Sulfonamides as Tyrosinase Inhibitors: Lineweaver-Burk Plot Evaluation and Computational Ascriptions.

The designed bi-heterocyclic sulfonamides were synthesized through a two-step protocol and their structures were ascertained by spectral techniques including IR, 1H NMR and 13C NMR along with CHN analysis. The in vitro inhibitory effects of these sulfonamides were evaluated against tyrosinase and kinetics mechanism was analyzed by Lineweaver-Burk plots. The binding modes of these molecules were ascribed through molecular docking studies. These synthesized bi-heterocyclic molecules were identified as potent inhibitors relative to the standard (kojic acid) and compound 5 inhibited the tyrosinase non-competitively by forming an enzyme-inhibitor complex. The inhibition constant Ki (0.09 µM) for compound 5 was calculated from Dixon plots. Computational results also displayed that all compounds possessed good binding profile against tyrosinase and interacted with core residues of target protein.

Synthesis and biological evaluation of 1,2,4-triazolidine-3-thiones as potent acetylcholinesterase inhibitors: in vitro and in silico analysis through kinetics, chemoinformatics and computational approaches.

We have designed and synthesized a novel acidic ionic liquid and explored its catalytic efficiency for the synthesis of 1,2,4-triazolidine-3-thione derivatives. A simple reaction between aldehydes and thiosemicarbazide for short time in 60:40 v/v water/ethanol at room temperature offers target 1,2,4-triazolidine-3-thione derivatives. The formation of target compounds is confirmed by NMR, IR and ESI-MS analysis. Pleasingly, synthesized compounds show noteworthy acetylcholinesterase (AChE) inhibitory activity with much lower IC50 values 0.0269 ± 0.0021-1.1725 ± 0.0112 µM than standard Neostigmine methylsulphate. In addition, synthesized 1,2,4-triazolidine-3-thiones exhibits significant free radical scavenging activity as compared to standard vitamin C. The studies on validation of Lipinski's rule through chemoinformatics properties and molecular docking analysis are in support of in vitro analysis. Therefore, overall present study illustrates synthesis of some new 1,2,4-triazolidines-3-thiones which can serve as a template for drug designing such as AChE inhibitors. Herein, we proposed ionic liquid-catalyzed ease of synthetic approach for medicinally important 1,2,4-triazolidine-3-thiones and their bio-evaluations.

Synthesis, molecular docking, dynamic simulations, kinetic mechanism, cytotoxicity evaluation of N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl} butanamides as tyrosinase and melanin inhibitors: In vitro, in vivo and in silico approaches.

In the current research work, different N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}butanamides have been synthesized according to the protocol described in scheme 1. The synthesis was initiated by reacting various substituted anilines (1a-e) with 4-chlorobutanoyl chloride (2) in aqueous basic medium to give various electrophiles, 4-chloro-N-(substituted-phenyl)butanamides (3a-e). These electrophiles were then coupled with 1-[(E)-3-phenyl-2-propenyl]piperazine (4) in polar aprotic medium to attain the targeted N-(substituted-phenyl)-4-{(4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl}butanamides (5a-e). The structures of all derivatives were identified and characterized by proton-nuclear magnetic resonance (1H NMR), carbon-nuclear magnetic resonance (13C NMR) and Infra-Red (IR) spectral data along with CHN analysis. The in vitro inhibitory potential of these butanamides was evaluated against Mushroom tyrosinase, whereby all compounds were found to be biologically active. Among them, 5b exhibited highest inhibitory potential with IC50 value of 0.013 ± 0.001 µM. The same compound 5b was also assayed through in vivo approach, and it was explored that it significantly reduced the pigments in zebrafish. The in silico studies were also in agreement with aforesaid results. Moreover, these molecules were profiled for their cytotoxicity through hemolytic activity, and it was found that except 5e, all other compounds showed minimal toxicity. The compound 5a also exhibited comparable results. Hence, some of these compounds might be worthy candidates for the formulation and development of depigmentation drugs with minimum side effects.

Synthesis and exploration of a novel chlorobenzylated 2-aminothiazole-phenyltriazole hybrid as migratory inhibitor of B16F10 in melanoma cells.

In the study presented here, a novel chlorobenzylated bi-heterocyclic hybrid molecule (7) was synthesized and its structural confirmation was carried out by IR, 1H-NMR, 13C-NMR and CHN analysis data. This compound 7 was subjected to biological study with B16F10 mouse melanoma cells. The anti-proliferative results showed that 7 showed no significant toxicity at concentrations ranging of 0-44 µM. The treatment of B16F10 cells with 7 at aforementioned concentration range indicated that migration of cells was significantly lower than that of the control cells in a dose dependent manner. The possible migration inhibitory effect of these melanoma cells was further evaluated through gelatinolytic activity of MMP-2 and MMP-9 secreted from B16F10 cells. It was inferred from our results that 7 was not affecting the expression and activity of these enzymes. Some other zinc-dependent matrix metalloproteinases (MMPs) were involved in the inhibitory progression. Taken together, compound 7 inhibited migrations of B16F10 mouse melanoma cells. Therefore, it may deserve consideration as a potential agent for the treatment of cancer.

Designing of promising medicinal scaffolds for Alzheimer's disease through enzyme inhibition, lead optimization, molecular docking and dynamic simulation approaches.

In the designed research work, a series of 2-furoyl piperazine based sulfonamide derivatives were synthesized as therapeutic agents to target the Alzheimer's disease. The structures of the newly synthesized compounds were characterized through spectral analysis and their inhibitory potential was evaluated against butyrylcholinesterase (BChE). The cytotoxicity of these sulfonamides was also ascertained through hemolysis of bovine red blood cells. Furthermore, compounds were inspected by Lipinki Rule and their binding profiles against BChE were discerned by molecular docking. The protein fluctuations in docking complexes were recognized by dynamic simulation. From our in vitro and in silico results 5c, 5j and 5k were identified as promising lead compounds for the treatment of targeted disease.

Ultrasound mediated efficient synthesis of new 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamides as potent tyrosinase inhibitors: Mechanistic approach through chemoinformatics and molecular docking studies.

We have carried out the synthesis of new 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamide derivatives by the reaction between isatoic anhydride, 2-furoic hydrazide and substituted salicylaldehydes in ethanol: water (5:5 v/v) solvent system using p-TSA as a catalyst under ultrasound irradiation at room temperature. The structures of newly synthesized compounds were confirmed through spectral techniques such as IR, 1H NMR, 13C NMR, and LCMS. The important features of this protocol include simple and easy workup procedure, reaction carried out at ambient temperature, use of ultrasound and high yield of oxoquinazolin-3(4H)-yl)furan-2-carboxamides in short reaction time. The synthesized compounds 4a-4j were screened against tyrosinase enzyme and all these compounds found to be potent inhibitors with much lower IC50 value of 0.028 ±â€¯0.016 to 1.775 ±â€¯0.947 µM than the standard kojic acid (16.832 ±â€¯1.162 µM). The kinetics mechanism for compound 4e was analyzed by Lineweaver-Burk plots which revealed that compound inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. Along with this all the synthesized compounds (4a-4j) were scanned for their DPPH free radical scavenging ability. The outputs received through in vitro and in silico analysis are coherent to the each other with good binding energy values (kcal/mol) posed by synthesized ligands.

Densely substituted piperidines as a new class of elastase inhibitors: Synthesis and molecular modeling studies.

Elastase is the only enzyme that has the capability to degrade elastin and collagen, the two proteins essential for skin and bones. The synthesis of some densely substituted piperidines functionalized with the trifluoromethyl group (4a-j) was carried out. The newly prepared compounds were subjected to elastase enzyme inhibitory potential and antioxidant activity assays. Among the series, 4i (IC50 = 0.341 ± 0.001 µM) exhibited the maximum inhibition against elastase. Binding analysis delineated that the fluorine atom of ligand 4i showed hydrogen and hydrophobic bonds with Thr41 and Thr96, with bond distances of 3.84 and 5.631 Å, respectively. The obtained results indicate that these trifluoromethyl functionalized piperidine derivatives could be considered as potential candidates to treat skin disorders.

Synthesis, molecular docking and kinetic studies of novel quinolinyl based acyl thioureas as mushroom tyrosinase inhibitors and free radical scavengers.

The enzyme tyrosinase plays a vital role in melanin biosynthesis and enzymatic browning of vegetables and fruits. A series of novel quinolinyl thiourea analogues (11a-j) were synthesized by reaction of 3-aminoquinoline and corresponding isothiocyanates, in moderate to excellent yields with different substitutions and their inhibitory effect on mushroom tyrosinase and free radical scavenging activity were evaluated. The compound N-(quinolin-3-ylcarbamothioyl)hexanamide (11c) exhibited the maximum tyrosinase inhibitory effect (IC50 = 0.0070 ±â€¯0.0098 µM) compared to other derivatives and the reference Kojic acid (IC50 = 16.8320 ±â€¯0.0621 µM). The docking studies were carried out and the compound (11c) showed most negative estimated free energy of -7.2 kcal/mol in mushroom tyrosinase active site. The kinetic analysis revealed that the compound (11c) inhibits the enzyme tyrosinase non-competitively to form the complex of enzyme and inhibitor. The results revealed that 11c could be identified as putative lead compound for the design of efficient tyrosinase inhibitors.

Metal-Based Scaffolds of Schiff Bases Derived from Naproxen: Synthesis, Antibacterial Activities, and Molecular Docking Studies.

We report here the synthesis, characterization, and antibacterial evaluation of transition metal complexes of Ni, Cu, Co, Mn, Zn, and Cd (6a⁻f), using a Schiff base ligand (5) derived from naproxen (an anti-inflammatory drug) and 5-bromosalicylaldehyde by a series of reactions. The ligand and the synthesized complexes were characterized by elemental analysis, UV-Visible, FTIR, and XRD techniques. The ligand 5 behaves as a bidentate donor and coordinates with metals in square planar or tetrahedral fashion. In order to evaluate its bioactivity profile, we screened the Schiff base ligand and its metal complexes (6a⁻f) against different species of bacteria and the complexes were found to exhibit significant antibacterial activity. The complexes showed more potency against Bacillus subtilis as compared to the other species. Moreover, we modeled these complexes' binding affinity against COX1 protein using computational docking.

Novel C-2 Symmetric Molecules as α-Glucosidase and α-Amylase Inhibitors: Design, Synthesis, Kinetic Evaluation, Molecular Docking and Pharmacokinetics.

A series of symmetrical salicylaldehyde-bishydrazine azo molecules, 5a-5h, have been synthesized, characterized by 1H-NMR and 13C-NMR, and evaluated for their in vitro α-glucosidase and α-amylase inhibitory activities. All the synthesized compounds efficiently inhibited both enzymes. Compound 5g was the most potent derivative in the series, and powerfully inhibited both α-glucosidase and α-amylase. The IC50 of 5g against α-glucosidase was 0.35917 ± 0.0189 µM (standard acarbose IC50 = 6.109 ± 0.329 µM), and the IC50 value of 5g against α-amylase was 0.4379 ± 0.0423 µM (standard acarbose IC50 = 33.178 ± 2.392 µM). The Lineweaver-Burk plot indicated that compound 5g is a competitive inhibitor of α-glucosidase. The binding interactions of the most active analogues were confirmed through molecular docking studies. Docking studies showed that 5g interacts with the residues Trp690, Asp548, Arg425, and Glu426, which form hydrogen bonds to 5g with distances of 2.05, 2.20, 2.10 and 2.18 Å, respectively. All compounds showed high mutagenic and tumorigenic behaviors, and only 5e showed irritant properties. In addition, all the derivatives showed good antioxidant activities. The pharmacokinetic evaluation also revealed promising results.