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

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3580 ◽  
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.

scholarly journals Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties

2021 ◽  
Vol 22 (10) ◽  
pp. 5082
Author(s):  
Andrea Angeli ◽  
Victor Kartsev ◽  
Anthi Petrou ◽  
Mariana Pinteala ◽  
Volodymyr Brovarets ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Inhibitory Activity ◽  
Binding Mode ◽  
Carbonic Anhydrases ◽  
Inhibition Activity ◽  
Physiological Conditions ◽  
Computational Procedures ◽  
Living Organisms ◽  
Human Isoforms

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.

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

2019 ◽  
Vol 9 (1) ◽  
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.

scholarly journals Aryl-4,5-dihydro-1H-pyrazole-1-carboxamide Derivatives Bearing a Sulfonamide Moiety Show Single-digit Nanomolar-to-Subnanomolar Inhibition Constants against the Tumor-associated Human Carbonic Anhydrases IX and XII

2020 ◽  
Vol 21 (7) ◽  
pp. 2621
Author(s):  
Priya Hargunani ◽  
Nikhil Tadge ◽  
Mariangela Ceruso ◽  
Janis Leitans ◽  
Andris Kazaks ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Inhibitory Activity ◽  
Phenyl Ring ◽  
Drug Targets ◽  
Binding Mode ◽  
Docking Studies ◽  
Carbonic Anhydrases ◽  
Single Digit ◽  
Ca Ix ◽  
Shed Light

A series of new 3-phenyl-5-aryl-N-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide derivatives was designed here, synthesized, and studied for carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity against the human (h) isozymes I, II, and VII (cytosolic, off-target isoforms), and IX and XII (anticancer drug targets). Generally, CA I was not effectively inhibited, whereas effective inhibitors were identified against both CAs II (KIs in the range of 5.2–233 nM) and VII (KIs in the range of 2.3–350 nM). Nonetheless, CAs IX and XII were the most susceptible isoforms to this class of inhibitors. In particular, compounds bearing an unsubstituted phenyl ring at the pyrazoline 3 position showed 1.3–1.5 nM KIs against CA IX. In contrast, a subset of derivatives having a 4-halo-phenyl at the same position of the aromatic scaffold even reached subnanomolar KIs against CA XII (0.62–0.99 nM). Docking studies with CA IX and XII were used to shed light on the derivative binding mode driving the preferential inhibition of the tumor-associated CAs. The identified potent and selective CA IX/XII inhibitors are of interest as leads for the development of new anticancer strategies.

Acyl selenoureido benzensulfonamides show potent inhibitory activity against carbonic anhydrases from the pathogenic bacterium Vibrio cholerae

2017 ◽  
Vol 75 ◽  
pp. 170-172 ◽  
Author(s):  
Andrea Angeli ◽  
Ghulam Abbas ◽  
Sonia Del Prete ◽  
Fabrizio Carta ◽  
Clemente Capasso ◽  
...  
Keyword(s):  
Vibrio Cholerae ◽  
Inhibitory Activity ◽  
Pathogenic Bacterium ◽  
Carbonic Anhydrases ◽  
Potent Inhibitory Activity

Benzylaminoethylureido‐Tailed Benzenesulfonamides Show Potent Inhibitory Activity against Bacterial Carbonic Anhydrases

ChemMedChem ◽  
2020 ◽  
Vol 15 (24) ◽  
pp. 2444-2447
Author(s):  
Majid Ali ◽  
Andrea Angeli ◽  
Murat Bozdag ◽  
Fabrizio Carta ◽  
Clemente Capasso ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Carbonic Anhydrases ◽  
Potent Inhibitory Activity

scholarly journals Activation Effects of Carnosine- and Histidine-Containing Dipeptides on Human Carbonic Anhydrases: A Comprehensive Study

2020 ◽  
Vol 21 (5) ◽  
pp. 1761 ◽  
Author(s):  
Giulio Vistoli ◽  
Giancarlo Aldini ◽  
Laura Fumagalli ◽  
Clelia Dallanoce ◽  
Andrea Angeli ◽  
...  
Keyword(s):  
Computational Study ◽  
Complex Structure ◽  
Imidazole Ring ◽  
Binding Mode ◽  
Carbonic Anhydrases ◽  
Enzyme Active Site ◽  
Structure Activity ◽  
Human Isoforms ◽  
Micromolar Range ◽  
Comprehensive Study

l-Carnosine (β-Ala-l-His) and several other histidine-containing peptides, including two N-methylated forms on the imidazole ring (l-anserine and l-balenine), two derivatives modified on the carboxyl function (carcinine and l-carnosinamide), two analogues differing in the length of the N-terminal residue (l-homocarnosine and Gly-l-His) and the N-acetyl derivatives, were investigated as activators of four isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The four human isoforms hCA I, II, VA and IX were activated in the low to high micromolar range, with a rather complex structure activity relationship. A performed computational study allowed us to rationalize these results and to propose a binding mode of these activators within the enzyme active site. Similarly to other CA activators, the here studied peptides could find relevant pharmacological applications such as in the management of CA deficiencies, for therapy memory and enhancing cognition or for artificial tissues engineering.

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

2020 ◽  
Vol 17 ◽  
Author(s):  
Mina Saeedi ◽  
Azadeh Eslami ◽  
Seyedeh Sara Mirfazli ◽  
Mahsa Zardkanlou ◽  
Mohammad Ali Faramarzi ◽  
...  
Keyword(s):  
Active Site ◽  
Inhibitory Activity ◽  
Competitive Inhibition ◽  
Docking Study ◽  
Amino Acid Residues ◽  
Reference Drug ◽  
Design And Synthesis ◽  
Glucosidase Inhibitors ◽  
Study Results

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.

Biological evaluation and docking studies of some benzoxazole derivatives as inhibitors of acetylcholinesterase and butyrylcholinesterase

2016 ◽  
Vol 71 (11-12) ◽  
pp. 409-413 ◽  
Author(s):  
Ozlem Temiz-Arpaci ◽  
Mustafa Arisoy ◽  
Duygu Sac ◽  
Fatima Doganc ◽  
Meryem Tasci ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Protein Interactions ◽  
Broad Spectrum ◽  
Active Site ◽  
Inhibitory Activity ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Molar Concentration ◽  
Reference Drug ◽  
Similar Activity

Abstract A series of 2,5-disubstituted-benzoxazole derivatives (1–13) were evaluated as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results demonstrated that the compounds exhibited a broad spectrum of AChE and BChE inhibitory activity ranging between 6.80% and 90.21% except one compound which showed no activity against AChE at the specified molar concentration. Another derivative displayed a similar activity to that of reference drug (galanthamine) for inhibition of AChE and BChE. In addition, molecular docking of the compounds into active site of AChE was performed using recombinant human AChE (PDB ID: 4ey6) in order to understand ligand–protein interactions.

scholarly journals Phosphonic Analogues of Phenylglycine as Inhibitors of Aminopeptidases: Comparison of Porcine Aminopeptidase N, Bovine Leucine Aminopeptidase and Aminopeptidase from Barley Seeds

2019 ◽  
Author(s):  
Weronika Wanat ◽  
Michał Talma ◽  
Małgorzata Pawełczak ◽  
Paweł Kafarski
Keyword(s):  
Free Energy ◽  
Gibbs Free Energy ◽  
Aromatic Ring ◽  
Active Site ◽  
Inhibitory Activity ◽  
Leucine Aminopeptidase ◽  
Binding Mode ◽  
Aminopeptidase N ◽  
Zinc Ions ◽  
Similar Activity

Inhibitory activity of 14 phosphonic analogues of phenylglycine, substituted in aromatic ring by fluorine and chlorine, was determined towards porcine aminopeptidase N. The obtained data served as a basis for studying their interaction with the enzyme as modelled by the use of Schrödinger Release 2018 program. The observed linearity between modelled Gibbs free energy differences and inhibitory constants indicated the usefulness of this program. The obtained binding mode was compared with this modelled for bovine lens leucine aminopeptidase. Although both enzymes differ in the number of zinc ions present in the active site, they are considered to exhibit similar activity towards substrates and inhibitors. Our studies seem to support that  supposition since the modes of binding of the studied inhibitors are quite similar. Additionally, inhibitory activity of the phosphonic analogues of phenylglycine towards barley aminopetpidase was determined showing that this enzyme could be considered as neutral aminopeptidase.

Synthesis, Antibacterial Activity and Molecular Docking of Phospholidinones in Stigmastane Series

2019 ◽  
Vol 15 (3) ◽  
pp. 259-264 ◽  
Author(s):  
Azhar U. Khan ◽  
Mahboob Alam ◽  
Soonheum Park ◽  
Poonam Dwivedi ◽  
Sunil K. Sharma ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Molecular Docking ◽  
Active Site ◽  
Docking Study ◽  
Binding Mode ◽  
Eukaryotic Cell ◽  
Amino Acid Residues ◽  
Phosphorous Oxychloride ◽  
Living Organisms ◽  
Semi Solid

<P>Introduction: Steroid compounds are widely distributed in nature throughout scientific history. Living organisms such as animals and vegetables have steroids that show a significant effect on their vital activities. Sterols are key components of all eukaryotic cell membranes. Methods: Steroidal compounds; 3β-oxo-[1’,3’,2’-oxathiaphos-phalidine-2’-one] stigmast-5-ene and 3β- oxo[1`,3`,2`-dioxaphosphalidine-2`-one]-stigmast-5-ene were successfully prepared using easily accessible 3β-hydroxy stigmast-5-ene with phosphorous oxychloride (POCl3), 2- mercaptoethanol/ethylene glycol and triethylamine (Et3N) in dry diethyl ether. Products were obtained in semi-solid state and characterized using physicochemical techniques. Results: The results of the bioassay showed that the synthesized compound containing the sulfur atom had antibacterial activity. Molecular docking was also done in order to show in silico antibacterial activity and to make out the probable binding mode of compound with the amino acid residues of protein. Conclusion: The results of the docking study showed that synthesized compound 2 had minimal binding energy with substantial affinity for the active site.</P>

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