Design and Synthesis of Novel 5-Arylisoxazole-1,3,4-thiadiazole Hybrids as α-Glucosidase Inhibitors

Background: α-Glucosidase inhibitors have occupied a significant position in the treatment of type 2 diabetes. In this respect, development of novel and efficient non sugar-based inhibitors are highly in demand. Objective: Design and synthesis of new 5-arylisoxazole-1,3,4-thiadiazole hybrids possessing α-glucosidase inhibitory activity was developed. Methods: Different derivatives were synthesized by the reaction of various 5-arylisoxazole-3-carboxylic acids and ethyl 2- ((5-amino-1,3,4-thiadiazol-2-yl)thio)acetate. Finally, they were evaluated for their α-glucosidase inhibitory activity. Results: It was found that ethyl 2-((5-(5-(2-chlorophenyl)isoxazole-3-carboxamido)-1,3,4-thiadiazol-2-yl)thio)acetate (5j) was the most potent compound (IC50 = 180.1 µM) comparing with acarbose as the reference drug (IC50 = 750.0 µM). Also, kinetic study of 5j revealed a competitive inhibition and docking study results indicated desired interactions of that compound with amino acid residues located close to active site of α-glucosidase. Conclusion: Good α-glucosidase inhibitory activity obtained by the title compounds introduced them as an efficient scaffold which merits to be considered in anti-diabetic drug discovery developments.

Download Full-text

Novel coumarin containing dithiocarbamate derivatives as potent α-glucosidase inhibitors for management of type 2 diabetes

Medicinal Chemistry ◽

10.2174/1573406416666200826101205 ◽

2020 ◽

Vol 16 ◽

Author(s):

Marjan Mollazadeh ◽

Maryam Mohammadi-Khanaposhtani ◽

Yousef Valizadeh ◽

Afsaneh Zonouzi ◽

Mohammad Ali Faramarzi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Kinetic Study ◽

Active Site ◽

Docking Study ◽

Secondary Amines ◽

Molecular Docking Study ◽

Glucosidase Inhibitors ◽

Dithiocarbamate Derivatives

Background: α-Glucosidase is a hydrolyze enzyme that plays a crucial role in degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in the carbohydrate mediated diseases such as diabetes mellitus. Objective: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. Methods: These compounds were obtained of reaction between 4-(bromomethyl)-7-methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). Results: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 μM) in comparison to acarbose as standard inhibitor (IC50 = 750.0 ± 9.0 µM). Among them, secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound compete with substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Also, molecular docking study predicted that this compound as well interacted with α-glucosidase active site pocket. Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for design potent α-glucosidase inhibitors for treatment of type 2 diabetes.

Download Full-text

Synthesis of 2-(4-hydroxyphenyl)ethyl 3,4,5-Trihydroxybenzoate and Its Inhibitory Effect on Sucrase and Maltase

Processes ◽

10.3390/pr8121603 ◽

2020 ◽

Vol 8 (12) ◽

pp. 1603

Author(s):

Wen-Tai Li ◽

Yu-Hsuan Chuang ◽

Jiahn-Haur Liao ◽

Jung-Feng Hsieh

Keyword(s):

Active Site ◽

Docking Study ◽

Competitive Inhibitor ◽

Inhibitory Effect ◽

Kinetics Study ◽

Amino Acid Residues ◽

Inhibition Kinetics ◽

Molecular Docking Study ◽

Hydrogen Bond Interactions ◽

Glucosidase Inhibitors

We report on the synthesis of an active component, 2-(4-hydroxyphenyl)ethyl 3,4,5-trihydroxybenzoate (HETB), from Rhodiola crenulata. Subsequent analysis revealed that HETB exhibits α-glucosidase inhibitory activities on maltase and sucrase, with potency exceeding that of the known α-glucosidase inhibitors (voglibose and acarbose). An inhibition kinetics study revealed that HETB, acarbose, and voglibose bind to maltase and sucrase, and HETB was shown to be a strong competitive inhibitor of maltase and sucrase. In a molecular docking study based on the crystal structure of α-glucosidase from Saccharomyces cerevisiae, we revealed the HETB binding in the active site of maltase via hydrogen-bond interactions with five amino acid residues: Ser 240, Asp 242, Glu 277, Arg 315, and Asn 350. For HETB docked to the sucrase active site, seven hydrogen bonds (with Asn 114, Glu 148, Gln 201, Asn 228, Gln 381, Ile 383, and Ser 412) were shown.

Download Full-text

Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

Medicinal Chemistry ◽

10.2174/1573406415666190724142951 ◽

2020 ◽

Vol 16 (7) ◽

pp. 892-902 ◽

Cited By ~ 3

Author(s):

Aida Iraji ◽

Mahsima Khoshneviszadeh ◽

Pegah Bakhshizadeh ◽

Najmeh Edraki ◽

Mehdi Khoshneviszadeh

Keyword(s):

Molecular Docking ◽

Active Site ◽

Competitive Inhibition ◽

Docking Study ◽

Biological Evaluation ◽

Primary Response ◽

Ratio Method ◽

Molecular Docking Study ◽

Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting step of the melanin formation. Natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti– tyrosinase agents. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

Download Full-text

Phenoxyethyl Piperidine/Morpholine Derivatives as PAS and CAS Inhibitors of Cholinesterases: Insights for Future Drug Design

Scientific Reports ◽

10.1038/s41598-019-56463-2 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 7

Author(s):

Yaghoub Pourshojaei ◽

Ardavan Abiri ◽

Khalil Eskandari ◽

Zahra Haghighijoo ◽

Najmeh Edraki ◽

...

Keyword(s):

Conformational Changes ◽

Active Site ◽

Inhibitory Activity ◽

Reference Drug ◽

Catalytic Active Site ◽

Electric Eel ◽

Interesting Candidate ◽

Future Drug ◽

Morpholine Derivatives

AbstractAcetylcholinesterase (AChE) catalyzes the conversion of Aβ peptide to its aggregated form and the peripheral anionic site (PAS) of AChE is mainly involved in this phenomenon. Also catalytic active site (CAS) of donepezil stimulates the break-down of acetylcholine (ACh) and depletion of ACh in cholinergic synapses are well established in brains of patients with AD. In this study, a set of compounds bearing phenoxyethyl amines were synthesized and their inhibitory activity toward electric eel AChE (eeAChE) and equine butyrylcholinesterase (eqBuChE) were evaluated. Molecular dynamics (MD) was employed to record the binding interactions of best compounds against human cholinesterases (hAChE and hBuChE) as well as donepezil as reference drug. In vitro results revealed that compound 5c is capable of inhibiting eeAChE activity at IC50 of 0.50 µM while no inhibitory activity was found for eqBuChE for up to 100 µM concentrations. Compound 5c, also due to its facile synthesis, small structure and high selectivity for eeAChE would be very interesting candidate in forthcoming studies. The main interacting parts of compound 5c and compound 7c (most potent eeAChE and eqBuChE inhibitors respectively) with receptors which confer selectivity for AChE and BuChE inhibition were identified, discussed, and compared with donepezil’s interactions. Also during MD simulation it was discovered for the first time that binding of substrates like donepezil to dual CAS and PAS or solely CAS region might have a suppressive impact on 4-α-helical bundles near the tryptophan amphiphilic tetramerization (WAT) domain of AChE and residues which are far away from AChE active site. The results proposed that residues involved in donepezil interactions (Trp86 and Phe295) which are located in CAS and mid-gorge are the mediator of conformational changes in whole protein structure.

Download Full-text

Designing of Nitroimidazole Derivatives as a Promising Target for Treatment of Tuberculosis

Asian Journal of Organic & Medicinal Chemistry ◽

10.14233/ajomc.2019.ajomc-p173 ◽

2019 ◽

Vol 4 (2) ◽

pp. 55-60

Author(s):

Monika Kakadiya ◽

Singh Ramiya ◽

Malleshappa Noolvi ◽

T.Y. Pasha

Keyword(s):

Reactive Nitrogen Species ◽

Bacterial Resistance ◽

Latent Tuberculosis ◽

Docking Study ◽

Amino Acid Residues ◽

Nitrogen Species ◽

Reference Drug ◽

Promising Target ◽

Mdr Tb ◽

High Level

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, with high level of mortality worldwide, currently with approximately 10 million cases of tuberculosis. These rate of incidence are due to several factors such as bacterial resistance, AIDS, latent tuberculosis that reoccur in patient. Deazaflavin dependent nitroreductase (Ddn) is an emerging target in the field of antitubercular agent. Ddn catalyses the reduction of nitroimidazoles resulting in intra-cellular release of lethal reactive nitrogen species. Nitroimidazole class drug- delamanid and pretonamid are used in the treatment of MDR-TB. In this present study, 26 new nitroimidazole derivatives were designed and docked into Ddn enzyme. In docking study, compounds 3, 5, 15, 16, 17, 18 and 21 showed similar interaction with amino acid residues such as Tyr 65, Ser 78, Tyr 136 as pretonamid reference drug and highest docking score and better ADMET compatibility. The ADMET prediction docking study of new designed compound revealed that the compounds 3, 16, 17 and 21 showed good binding with Ddn. In future it may be good and effective lead for development of antitubercular agent.

Download Full-text

Ethyl p-methoxycinnamate from Kaempferia galanga inhibits angiogenesis through tyrosine kinase

Zinc supplementation improves heme biosynthesis in rats exposed to lead ◽

10.18051/univmed.2015.v34.43-51 ◽

2016 ◽

Vol 34 (1) ◽

pp. 43 ◽

Cited By ~ 2

Author(s):

Juni Ekowati ◽

Suko Hardjono ◽

Iwan Sahrial Hamid

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

Tyrosine Kinases ◽

Angiogenesis Inhibitor ◽

Docking Study ◽

Vascular Endothelial ◽

Reference Drug ◽

Molegro Virtual Docker ◽

Kaempferia Galanga ◽

Study Results

BACKGROUND Many tumors express on their receptor tyrosine kinases vascular endothelial growth factor activity associated with angiogenesis. Inhibition of angiogenesis through reduction of tyrosine kinase activity is a promising strategy for cancer therapy. The present study aimed to determine the mechanism and potency of ethyl p-methoxycinnamate (EPMC) isolated from Kaempferia galanga as angiogenesis inhibitor. METHODS A laboratory experimental study was conducted using chorio-allantoic membranes (CAMs) of nine-day old chicken eggs induced by 60ng basic fibroblast growth factor (bFGF). Ethyl p-methoxycinnamate (EPMC) potency was determined at dosages of 30, 60, 90 and 120 μg and compared with celecoxib 60 μg as reference drug and one negative bFGF-induced control group. Neovascularization and endothelial cell count in CAM blood vessels were evaluated. To predict the antiangiogenic mechanism of EPMC, a docking study was performed with the Molegro Virtual Docker program on tyrosine kinase as receptor (PDB 1XKK). RESULTS Angiogenesis stimulation by bFGF was prevented significantly (p<0.05) by EPMC at dosages of 30, 60, 90 and 120 μg and this activity was dose dependent. Molecular docking showed interaction between EPMC functional groups and tyrosine kinase amino acids at Met766, Met793, Thr854, Thr790, Gln791 and Ala743. There was an association between EPMC antiangiogenic activity and docking study results. CONCLUSIONS Ethyl p-methoxycinnamate is a potential new angiogenesis inhibitor through interaction with tyrosine kinase. EPMC could be a promising therapeutic agent for treatment of angiogenesis-related diseases.

Download Full-text

DOCKING ANTIOXIDANT ACTIVITY ON HYDROXY (DIPHENYL) ACETICACID AND ITS DERIVATIVES

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i7.18299 ◽

2017 ◽

Vol 10 (7) ◽

pp. 263 ◽

Cited By ~ 1

Author(s):

Sudha Rajendran ◽

Nithya G ◽

Brindha Devi P ◽

Charles C Kanakam

Keyword(s):

Antioxidant Activity ◽

Active Site ◽

Data Bank ◽

Docking Study ◽

Protein Crystal ◽

Molecular Docking Study ◽

Ligand Interaction ◽

Active Site Pocket ◽

Study Results

Objectives: The antioxidant activity of the synthesized compounds along with the standard compound for comparison is reported. There is comparison of binding analysis and the ligand interaction of the compound. Methods: The protein crystal structure complexed with 4-methyl-6-[2-(5-morpholin-4-ylpyridin-3-yl)ethyl]pyridin-2-amine inhibitor was selected from Protein Data Bank (5FVP) for our study. Results: The docking studies and structure-activity relationship reveals that the compound 2’-chloro-4-methoxy-3nitro benzilic acid after three different docking strategies reveals that the score was found to be higher compared with others.Conclusion: Based on the in vitro antioxidant results, the compounds synthesized were investigated for the molecular docking study to identify the amino acid interactions in the active site pocket of nitric oxide synthase enzyme. Based on the docking score results, all the compounds were oriented toward the active site pocket occupied by the cocrystallized ligand

Download Full-text

Extending the Inhibition Profiles of Coumarin-Based Compounds Against Human Carbonic Anhydrases: Synthesis, Biological, and In Silico Evaluation

Molecules ◽

10.3390/molecules24193580 ◽

2019 ◽

Vol 24 (19) ◽

pp. 3580 ◽

Cited By ~ 2

Author(s):

Kartsev ◽

Geronikaki ◽

Bua ◽

Nocentini ◽

Petrou ◽

...

Keyword(s):

Active Site ◽

Inhibitory Activity ◽

Binding Mode ◽

Carbonic Anhydrases ◽

Reference Drug ◽

Physiological Conditions ◽

Computational Procedures ◽

Living Organisms ◽

Human Isoforms ◽

Potent Inhibitory Activity

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.

Download Full-text

Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors

Pharmaceuticals ◽

10.3390/ph14040292 ◽

2021 ◽

Vol 14 (4) ◽

pp. 292

Author(s):

Mai H. A. Mousa ◽

Nermin S. Ahmed ◽

Kai Schwedtmann ◽

Efseveia Frakolaki ◽

Niki Vassilaki ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Inhibitory Activity ◽

Antiviral Effect ◽

Optimized Design ◽

Amino Acid Residues ◽

Design And Synthesis ◽

Carbamate Group ◽

Direct Acting ◽

Alkyl Carbamate

Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors; the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC50) = 36 pM and a selectivity index of >2.78 × 106). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC50 = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group.

Download Full-text

Design, Synthesis and Molecular Modeling Studies of Thiosemicarbazone & Thiazole Derivatives as Potential Anti-Malarial Agents

10.21203/rs.3.rs-705040/v1 ◽

2021 ◽

Author(s):

Kamalpreet Kaur ◽

Vivek Asati

Keyword(s):

Antimalarial Activity ◽

Docking Study ◽

Docking Studies ◽

Amino Acid Residues ◽

Thiazole Derivatives ◽

Design Synthesis ◽

Standard Drug ◽

Reference Drug ◽

Electron Withdrawing Group ◽

Drug Compound

Abstract A series of novel thiosemicarbazone & thiazole derivatives (Kp1-10) have been designed, synthesized and evaluated for potential anti-malarial activity. The antimalarial activity of the synthesized thiazole derivatives (Kp1-10) was assessed against human pathogenic malarial strain viz. Plasmodium falciparum while quinine was taken as the standard drug. compound Kp-9 was found to be most promising which exhibited strongest inhibitory activity against P. falciparumwith an IC50 value of 0.29µg/mL which was higher than the reference drug quinine (1.26µg/mL). The SAR studyrevealed that thesubstitution with electron withdrawing group at phenyl increases anti-malarial activity as shown in compound Kp-9. The result of molecular docking studies showed that compounds Kp-9, Kp-1, Kp-3, Kp-4 showed good docking scores with protein (PDB code: 5TBO). The compound Kp-9 showed highest docking score (-9.519). Whereas, compounds Kp-1, Kp-3, Kp-4 and Kp-10 showed good docking scores (-8.764, -8.406, -9.062, -9.435 respectively) with critical interactions with the amino acid residues such as VAL532, ILE237, LEU531, HIE185, TYR528, ASN274, ARG265. The results of biological activity and docking study revealed that the presence of electron withdrawing group at 4th position of phenyl ring attached is crucial for better anti-malarial activity and favorable drug-like profile which can emerge as a potential drug molecule in further development.

Download Full-text