Imidazole-thiadiazole hybrids: A multitarget de novo drug design approach, in vitro evaluation, ADME/T, and in silico studies.

A library of imidazole-thiadiazole compounds (1-24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives 5-7, 9-11, 18, and 19 displayed potent inhibitory activities with IC50 values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against α-glucosidase, and α-amylase enzymes, respectively, compared to the standard acarbose (IC50 = 14.8 ± 0.01 µM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC50 = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC50 = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC50 = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC50 = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities via CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development.

Rhodanine-benzamides as potential hits for α-amylase enzyme inhibitors and radical (DPPH and ABTS) scavengers.

A series of 3-substituted and 3,5-disubstituted rhodanine-based derivatives were synthesized from 3-aminorhodanine and examined for α-amylase inhibitory, DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activities in vitro. These derivatives displayed significant α-amylase inhibitory potential with IC50 values of 11.01-56.04 µM in comparison to standard acarbose (IC50 = 9.08 ± 0.07 µM). Especially, compounds 7 (IC50 = 11.01 ± 0.07 µM) and 8 (IC50 = 12.01 ± 0.07 µM) showed highest α-amylase inhibitory activities among the whole series. In addition to α-amylase inhibitory activity, all compounds also demonstrated significant scavenging activities against DPPH and ABTS radicals, with IC50 values ranging from 12.24 to 57.33 and 13.29-59.09 µM, respectively, as compared to the standard ascorbic acid (IC50 = 15.08 ± 0.03 µM for DPPH; IC50 = 16.09 ± 0.17 µM for ABTS). These findings reveal that the nature and position of the substituents on the phenyl ring(s) are crucial for variation in the activities. The structure-activity relationship (SAR) revealed that the compounds bearing an electron-withdrawing group (EWG) at para substitution possessed the highest activity. In kinetic studies, only the km value was changed, with no observed changes in Vmax, indicating a competitive inhibition. Molecular docking studies revealed important interactions between compounds and the α-amylase active pocket. Further advanced research needs to perform on the identified compounds in order to obtain potential antidiabetic agents.

Biochemical evaluation and ligand binding studies on glycerophosphodiester phosphodiesterase from Staphylococcus aureus using STD-NMR spectroscopy and molecular docking analysis.

Glycerophosphodiester phosphodiesterase (GDPD) is a highly conserved enzyme in both prokaryotic and eukaryotic organisms. It catalyses the hydrolysis of various glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols, which serve as building blocks in several biosynthetic pathways. This enzyme is a well-known virulence factor in many pathogenic bacteria, including Staphylococcus aureus, and is thus considered a potential drug target. In this study, competent E. coli BL21(DE3)pLysS expression cells were used to express the GDPD enzyme from vancomycin-resistant Staphylococcus aureus (VRSA), which was then purified using size exclusion and anion exchange chromatography. The hydrolytic activity of GDPD was evaluated on the non-physiological substrate bis(p-nitrophenyl) phosphate (BpNPP), which indicated functional activity of the enzyme. 79 drugs were evaluated for their inhibitory potential against GDPD enzyme by the colorimetric assay. Out of 79 drugs, 13 drugs, including tenofovir (1), adenosine (2), clioquinol (11), bromazepam (12), lamotrigine (13), sulfadiazine (14), azathioprine (15), nicotine (16), sitagliptin PO4 (17), doxofylline (18), clindamycin phosphate (19), gentamycin sulphate (20), and ceftriaxone sodium (21) revealed varying degrees of inhibitory potential with IC50 values in the range of 400 ± 0.007-951 ± 0.016 µM. All drugs were also evaluated for their binding interactions with the target enzyme by saturation transfer difference (STD-NMR) spectroscopy. 10 drugs demonstrated STD interactions and hence, showed binding affinity with the enzyme. Exceptionally, tenofovir (1) was identified to be a better inhibitor with an IC50 value of 400 ± 0.007 µM, as compared to the standard EDTA (ethylenediaminetetraacetic acid) (IC50 = 470 ± 0.008 µM). Moreover, molecular docking studies have identified key interactions of the ligand (tenofovir) with the binding site residues of the enzyme.

Potential anti-amoebic effects of synthetic 1,4-benzothiazine derivatives against Acanthamoeba castellanii.

A rare but lethal central nervous system disease known as granulomatous amoebic encephalitis (GAE) and potentially blinding Acanthamoeba keratitis are diseases caused by free-living Acanthamoeba. Currently, no therapeutic agent can completely eradicate or prevent GAE. Synthetic compounds are a likely source of bioactive compounds for developing new drugs. This study synthesized seventeen 1,4-benzothiazine derivatives (I -XVII) by a base-catalyzed one-pot reaction of 2-amino thiophenol with substituted bromo acetophenones. Different spectroscopic techniques, such as EI-MS, 1H-, and 13C NMR (only for the new compounds), were used for the structural characterization and conformation of compounds. These compounds were assessed for the first time against Acanthamoeba castellanii. All compounds showed anti-amoebic potential in vitro against A. castellanii, reducing its ability to encyst and excyst at 100 µM. Compounds IX, X, and XVI showed the most potent activities among all derivatives and significantly reduced the viability to 5.3 × 104 (p < 0.0003), 2 × 105 (p < 0.006), and 2.4 × 105 (p < 0.002) cells/mL, respectively. The cytotoxicity profile revealed that these molecules showed lower to moderate cytotoxicity, i.e., 36 %, 2 %, and 21 %, respectively, against human keratinocytes in vitro. These results indicate that 1,4-benzothiazines showed potent in vitro activity against trophozoites and cysts of A. castellanii. Hence, these 1,4-benzothiazine derivatives should be considered to develop new potential therapeutic agents against Acanthamoeba infections.

Synthesis of new bis(dimethylamino)benzophenone hydrazone for diabetic management: In-vitro and in-silico approach.

Inhibiting α-glucosidase is a reliable method for reducing blood sugar levels in diabetic individuals. Bis(dimethylamino)benzophenone derivatives 1-27 were synthesized from bis(dimethylamino)benzophenone via two-step reaction. Different spectroscopic techniques, including EI-MS and 1H NMR, were employed to characterize all synthetic derivatives. The elemental composition of synthetic compounds was confirmed by elemental analysis and results were found in agreement with the calculated values. The synthetic compounds 1-27 were evaluated for α-glucosidase inhibitory activity, except five compounds all derivatives showed good to moderate inhibitory potential in the range of IC50 = 0.28 ± 2.65 - 0.94 ± 2.20 µM. Among them, the most active compounds were 5, 8, 9, and 12 with IC50 values of 0.29 ± 4.63, 0.29 ± 0.93, 0.28 ± 3.65, and 0.28 ± 2.65, respectively. Furthermore, all these compounds were found to be non-toxic on human fibroblast cell lines (BJ cell lines). Kinetics study of compounds 8 and 9 revealed competitive type of inhibition with Ki values 2.79 ± 0.011 and 3.64 ± 0.012 µM, respectively. The binding interactions of synthetic compounds were also confirmed through molecular docking studies that indicated that compounds fit well in the active site of enzyme. Furthermore, a total of 30ns MD simulation was carried out for the most potent complexes of the series. The molecular dynamics study revealed that compound-8 and compound-12 were stable during the MD simulation.

Indenoquinoxaline-phenylacrylohydrazide hybrids as promising drug candidates for the treatment of type 2 diabetes: In vitro and in silico evaluation of enzyme inhibition and antioxidant activity.

Existing drugs that are being used to treat type-2 diabetes mellitus are associated with several side effects; thus, exploring potential drug candidates is still an utter need these days. Hybrids of indenoquinoxaline and hydrazide have never been explored as antidiabetic agents. In this study, a series of new indenoquinoxaline-phenylacrylohydrazide hybrids (1-30) were synthesized, structurally characterized, and evaluated for α-amylase and α-glucosidase inhibitory activities, as well as for their antioxidant properties. All scaffolds exhibited varying degrees of inhibitory activity against both enzymes, with IC50 values ranging from 2.34 to 61.12 µM for α-amylase and 0.42 to 54.72 µM for α-glucosidase. Particularly, compounds 10, 16, 17, 18, 24, and 25 demonstrated the highest efficacy in inhibiting α-amylase, while compounds 6, 7, 8, 10, 12, 14, 13, 16, 17, 18, 24, and 25 were the most effective α-glucosidase inhibitors, compared to standard acarbose. Moreover, most of these compounds displayed substantial antioxidant potential compared to standard butylated hydroxytoluene (BHT). Kinetics studies revealed competitive inhibition modes by compounds. Furthermore, a comprehensive in silico study and toxicity prediction were also conducted, further validating these analogs as potential drug candidates. The structured compounds demonstrated enhanced profiles, underscoring their potential as primary candidates in drug discovery.

Indole-pyridine carbonitriles: multicomponent reaction synthesis and bio-evaluation as potential hits against diabetes mellitus.

Background: Diabetes mellitus is a significant health disorder; therefore, researchers should focus on discovering new drug candidates. Methods: A series of indole-pyridine carbonitrile derivatives, 1-34, were synthesized through a one-pot multicomponent reaction and evaluated for antidiabetic and antioxidant potential. Results: In this library, 12 derivatives - 1, 2, 4, 5, 7, 8, 10-12, 14, 15 and 31 - exhibited potent inhibitory activities against α-glucosidase and α-amylase enzymes, in comparison to acarbose (IC50 = 14.50 ± 0.11 µM). Furthermore, kinetics, absorption, distribution, metabolism, excretion and toxicity and molecular docking studies were used to interpret the type of inhibition, binding energies and interactions of ligands with target enzymes. Conclusion: These results indicate that the compounds may be promising hits for controlling diabetes mellitus and its related complications.

Evaluation of synthetic aminoquinoline derivatives as urease inhibitors: in vitro, in silico and kinetic studies.

Background: Quinoline and acyl thiourea scaffolds have major chemical significance in medicinal chemistry. Quinoline-based acyl thiourea derivatives may potentially target the urease enzyme. Materials & methods: Quinoline-based acyl thiourea derivatives 1-26 were synthesized and tested for urease inhibitory activity. Results: 19 derivatives (1-19) showed enhanced urease enzyme inhibitory potential (IC50 = 1.19-18.92 µM) compared with standard thiourea (IC50 = 19.53 ± 0.032 µM), whereas compounds 20-26 were inactive. Compounds with OCH3, OC2H5, Br and CH3 on the aryl ring showed significantly greater inhibitory potential than compounds with hydrocarbon chains of varying length. Molecular docking studies were conducted to investigate ligand interactions with the enzyme's active site. Conclusion: The identified hits can serve as potential leads against the drug target urease in advanced studies.

Multitargeted inhibition of key enzymes associated with diabetes and Alzheimer's disease by 1,3,4-oxadiazole derivatives: Synthesis, in vitro screening, and computational studies.

A library of 22 derivatives of 1,3,4-oxadiazole-2-thiol was synthesized, structurally characterized, and assessed for its potential to inhibit α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and antioxidant activities. Most of the tested compounds demonstrated good to moderate inhibition potential; however, their activity was lower than that of the standard acarbose. Significantly, compound 3f exhibited the highest inhibition potential against α-glucosidase and α-amylase enzymes, with IC50 values of 18.52 ± 0.09 and 20.25 ± 1.05 µM, respectively, in comparison to the standard acarbose (12.29 ± 0.26; 15.98 ± 0.14 µM). Compounds also demonstrated varying degrees of inhibitory potential against AChE (IC50 = 9.25 ± 0.19 to 36.15 ± 0.12 µM) and BChE (IC50 = 10.06 ± 0.43 to 35.13 ± 0.12 µM) enzymes compared to the standard donepezil (IC50 = 2.01 ± 0.12; 3.12 ± 0.06 µM), as well as DPPH (IC50 = 20.98 ± 0.06 to 52.83 ± 0.12 µM) and ABTS radical scavenging activities (IC50 = 22.29 ± 0.18 to 47.98 ± 0.03 µM) in comparison to the standard ascorbic acid (IC50 = 18.12 ± 0.15; 19.19 ± 0.72). The kinetic investigations have demonstrated that the compounds exhibit competitive-type inhibition for α-amylase, noncompetitive-type inhibition for α-glucosidase and AChE, and mixed-type inhibition for BChE. Additionally, a molecular docking study was performed on all synthetic oxadiazoles to explore the interaction details of these compounds with the active sites of the enzymes.

Diphenyl-substituted triazine derivatives: synthesis, α-glucosidase inhibitory activity, kinetics and in silico studies.

Background: Diabetes mellitus (DM) is a chronic disorder, considered to be a major global health challenge in the 21st century. α-Glucosidase enzyme is a well-known drug target to treat Type II DM. Methods: A new library of biphenyl-substituted triazines was synthesized and confirmed by various spectroscopic techniques. Results: All compounds showed potent α-glucosidase inhibitory activity, with IC50 values ranging from 35.35 ± 0.34 to 564.41 ± 0.91 µM, as the standard acarbose, IC50 value of 750.7 ± 0.13 µM. Our in silico study has predicted key interactions with the enzyme's active site. Drug-likeness and absorption, distribution, metabolism, excretion and toxicity were also studied. Conclusion: This study has identified a range of potential hits against the α-glucosidase enzyme that may serve as antidiabetic agents after further investigations.

Multicomponent diastereoselective synthesis of tetrahydropyridines as α-amylase and α-glucosidase enzymes inhibitors.

Background: Researchers seeking new drug candidates to treat diabetes mellitus have been exploring bioactive molecules found in nature, particularly tetrahydropyridines (THPs). Methods: A library of THPs (1-31) were synthesized via a one-pot multicomponent reaction and investigated for their inhibition potential against α-glucosidase and α-amylase enzymes. Results: A nitrophenyl-substituted compound 5 with IC50 values of 0.15 ± 0.01 and 1.10 ± 0.04 µM, and a Km value of 1.30 mg/ml was identified as the most significant α-glucosidase and α-amylase inhibitor, respectively. Kinetic studies revealed the competitive mode of inhibition, and docking studies revealed that compound 5 binds to the enzyme by establishing hydrophobic and hydrophilic interactions and a salt bridge interaction with His279. Conclusion: These molecules may be a potential drug candidate for diabetes in the future.

Synthetic piperidine-substituted chalcones as potential hits for α-amylase inhibitory and antioxidant activities.

Background: In medicinal chemistry, searching for new therapeutic entities to treat diabetes mellitus is of great concern. The piperidinyl-substituted chalcone scaffold has piqued our interest as a potential antidiabetic agent. Methods: A variety of piperidinyl-substituted chalcones 2-28 were synthesized and tested for α-amylase inhibitory and 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical-scavenging activities. Results: Compared with the standard acarbose, all compounds inhibited α-amylase, with IC50 values of 9.86-35.98 µM. Docking studies revealed an important binding interaction with the enzyme's catalytic site. The compounds also demonstrated promising radical-scavenging potential against  2,2-diphenyl-1-picrylhydrazyl and  2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals. Conclusion: This study has identified potential lead candidates for further advanced research searching for antidiabetic agents.

Regioselective syntheses of 2-oxopyridine carbonitrile derivatives and evaluation for antihyperglycemic and antioxidant potential.

A library of 2-oxopyridine carbonitriles 1-34 was synthesized by regioselective nucleophilic substitution reactions. In the first step, a one-pot multicomponent reaction yield pyridone intermediates. The resulting pyridone intermediates were then reacted with phenacyl halides in DMF and stirred at 100 °C for an hour to afford the desired compounds in good yields. Structures of synthetic molecules were characterized by EI-MS, HREI-MS, 1H NMR, and 13C NMR, and all thirty-four (34) compounds were found to be new. All synthetic compounds were examined for antidiabetic and antioxidant potential. The compounds exhibited α-glucosidase inhibitory potential in the range of IC50 = 3.00 ± 0.11-43.35 ± 0.67 µM and α-amylase inhibition potential in the range of IC50 = 9.20 ± 0.14-65.56 ± 1.05 µM. Among the tested compounds, 1 showed the most significant α-glucosidase inhibitory activity, with an IC50 value of 3.00 ± 0.11 µM, while the most active compound against α-amylase was 6, with an IC50 value = 9.20 ± 0.14 µM. The kinetic studies and analysis indicated that the compounds followed the competitive mode of inhibition. In addition, the molecular docking studies showed the interaction profile of all molecules with the binding site residues of α-glucosidase and α-amylase enzymes.

Synthetic benzofuran-linked chalcones with dual actions: a potential therapeutic approach to manage diabetes mellitus.

Background: Identification of molecules having dual capabilities to reduce postprandial hyperglycemia and oxidative stress is one of the therapeutic approaches to treat diabetes mellitus. In this connection, a library of benzofuran-linked chalcone derivatives were evaluated for their dual action. Methods: A series of substituted benzofuran-linked chalcones (2-33) were synthesized and tested for α-amylase inhibitory as well as 2,2-diphenylpicrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities. Results: All compounds showed α-amylase inhibitory activity ranging from IC50 = 12.81 ± 0.03 to 87.17 ± 0.15 µM, compared with the standard acarbose (IC50 = 13.98 ± 0.03 µM). Compounds also demonstrated radical scavenging potential against DPPH and ABTS radicals. Conclusion: The identified compounds may serve as potential leads for further advanced research.

Design, synthesis and bio-evaluation of indolin-2-ones as potential antidiabetic agents.

Background: Diabetes mellitus is a serious global health concern, and this is expected to impact more than 300 million people by 2025. The current study focuses on identifying substituted indolin-2-one-based inhibitors for two indispensable drug targets, α-amylase and α-glucosidase. Methods: The structures of synthetic compounds were confirmed by spectroscopic techniques and evaluated for enzyme inhibition activities. Kinetic and in silico studies were also performed. Results: All compounds exhibited good-to-moderate inhibitory potential. Most importantly, compounds 1, 2, 6, 16 and 17 were identified as potent α-glucosidase inhibitors (IC50 = 9.15 ± 0.12-13.74 ± 0.12 µM). Conclusion: This study identified that these synthetic compounds might serve as potential lead molecules for antidiabetic agents.

Syntheses, in vitro, and in silico studies of rhodanine-based schiff bases as potential α-amylase inhibitors and radicals (DPPH and ABTS) scavengers.

A two-step reaction method was used to synthesize a series of rhodanine-based Schiff bases (2-33) that were characterized using spectroscopic techniques. All compounds were assessed for α-amylase inhibitory and radical scavenging (DPPH and ABTS) activities. In comparison to the standard acarbose (IC50 = 9.08 ± 0.07 µM), all compounds demonstrated good to moderate α-amylase inhibitory activity (IC50 = 10.91 ± 0.08-61.89 ± 0.102 µM). Compounds also demonstrated significantly higher DPPH (IC50 = 10.33 ± 0.02-96.65 ± 0.03 µM) and ABTS (IC50 = 12.01 ± 0.12-97.47 ± 0.13 µM) radical scavenging activities than ascorbic acid (DPPH, IC50 = 15.08 ± 0.03 µM; ABTS, IC50 = 16.09 ± 0.17 µM). The limited structure-activity relationship (SAR) suggests that the position and nature of the substituted groups on the phenyl ring have a vital role in varying inhibitory potential. Among the series, compounds with an electron-withdrawing group at the para position showed the highest potency. Kinetic studies revealed that the compounds followed a competitive mode of inhibition. Molecular docking results are found to agree with experimental findings, showing that compounds reside in the active pocket due to the main rhodanine moiety.

Bioevaluation of synthetic pyridones as dual inhibitors of α-amylase and α-glucosidase enzymes and potential antioxidants.

Herein, a library of novel pyridone derivatives 1-34 was designed, synthesized, and evaluated for α-amylase and α-glucosidase inhibitory as well as antioxidant activities. Pyridone derivatives 1-34 were synthesized via a one-pot multi-component reaction of variously substituted aromatic aldehydes, acetophenone, ethyl cyanoacetate, and ammonium acetate in absolute ethanol. Synthetic compounds 1-34 were structurally characterized by different spectroscopic techniques. Most of the tested compounds showed more promising inhibition potential than the standard acarbose (IC50 = 14.87 ± 0.16 µM) but compounds 13 and 12 were found to be the most potent compounds with IC50 values of 9.20 ± 0.14 µM and 3.05 ± 0.18 µM against α-amylase and α-glucosidase enzymes, respectively. Compounds 1-34 also displayed moderate antioxidant potential in the range of IC50 = 96.50 ± 0.45 to 189.98 ± 1.00 µM in comparison to the control butylated hydroxytoluene (BHT) (IC50 = 66.50 ± 0.36 µM), in DPPH radical scavenging activities. Additionally, all synthetic derivatives were subjected to a molecular docking study to investigate the interaction details of compounds 1-34 (ligands) with the active site of enzymes (receptors). These results indicate that the newly synthesized pyridone class may serve as promising lead candidates for controlling diabetes mellitus and as antioxidants.

3-substituted coumarin derivatives over-activate the HslV protease: A potential drug target for antibacterial activity.

The bacterial HslVU complex consists of two different proteins, i.e., the HslV protease and the HslU ATPase. The functional HslVU enzyme complex forms only when the HslU c-terminal helix is inserted into the cavity located between two adjacent HslV monomers in order to allosterically activate the HslV protease. Based on its essential role in maintaining microbial proteostasis as well its absence from human beings, it is considered a promising therapeutic target for designing antibacterial agents. The goal of the present study was to find out potential drug candidates that could over-activate the HslV protease and produce aberrant proteolysis in pathogenic bacteria. Derivatives of 3-substituted coumarin have been identified as potential HslV protease activators based on their highest docking scores, ideal interaction patterns, and significant in-vitro HslV activation potential. Their ED50 values were in the sub-micromolar range, i.e., 0.4-0.48µM. The conformational stability of the contacts between the HslV dimer and the active compounds was further confirmed by molecular dynamics studies. Correspondingly, the ADMET characteristics of these lead molecules considerably demonstrated their significant non-toxic drug-like abilities. This research not only identified small non-peptidic HslV protease activators but also improved the understanding of the mode of action of 3-substituted coumarin derivatives as antibacterials.

Efficient one-pot synthesis of arylated pyrazole-fused pyran analogs: as leads to treating diabetes and Alzheimer's disease.

Background: To discover novel lead molecules against diabetes, Alzheimer's disease and oxidative stress, a library of arylated pyrazole-fused pyran derivatives, 1-20, were synthesized in a one-pot reaction. Materials & methods:1H-NMR spectroscopic and electron ionization mass spectrometry techniques were used to characterize the synthetic hybrid molecules 1-20. Analogs were screened against four indispensable therapeutic targets, including α-amylase, α-glucosidase, acetylcholinesterase and butyrylcholinesterase enzymes. Results: Except for derivatives 17 and 18, all other compounds exhibited varying degrees of inhibitory activities against target enzymes. The kinetic studies revealed that the synthetic molecules followed a competitive-type mode of inhibition for α-amylase and acetylcholinesterase enzymes, as well as a non-competitive mode of inhibition for α-glucosidase and butyrylcholinesterase enzymes. In addition, molecular docking studies identified crucial binding interactions of ligands with the enzyme's active site. Conclusion: These molecules may serve as a potential drug candidate to cure diabetes, Alzheimer's disease and oxidative stress in the future.

Hydrazinyl thiazole linked indenoquinoxaline hybrids: Potential leads to treat hyperglycemia and oxidative stress; Multistep synthesis, α-amylase, α-glucosidase inhibitory and antioxidant activities.

A library of hydrazinyl thiazole-linked indenoquinoxaline hybrids 1-36 were synthesized via a multistep reaction scheme. All synthesized compounds were characterized by various spectroscopic techniques including EI-MS (electron ionization mass spectrometry) and 1H NMR (nuclear magnetic resonance spectroscopy). Compounds 1-36 were evaluated for their inhibitory potential against α-amylase, and α-glucosidase enzymes. Among thirty-six, compounds 2, 9, 10, 13, 15, 17, 21, 22, 31, and 36 showed excellent inhibition against α-amylase (IC50 = 0.3-76.6 µM) and α-glucosidase (IC50 = 1.1-92.2 µM). Results were compared to the standard acarbose (IC50 = 13.5 ± 0.2 µM). All compounds were also evaluated for their DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity and compounds 2, 9, 10, 17, 21, 31, and 36 showed (SC50 = 7.58-125.86 µM) as compared to the standard ascorbic acid (SC50 = 21.50 ± 0.18 µM). Among this library, compounds 9 and 10 with a hydroxy group on the phenyl rings and thiosemicarbazide bearing intermediate 21 were identified as the most potent inhibitors against α-amylase, and α-glucosidase enzymes. The remaining compounds were found to be moderately active. The molecular docking studies were conducted to understand the binding mode of active inhibitors and kinetic studies of the active compounds followed competitive modes of inhibition.