☆ 4.6 Article

Synthesis and carbonic anhydrase isoenzymes I and II inhibitory effects of novel benzylamine derivatives

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY (2014)

Journal

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY

Volume 29, Issue 2, Pages 168-174

Publisher

TAYLOR & FRANCIS LTD

DOI: 10.3109/14756366.2012.763163

Keywords

Benzylamine; carbonic anhydrase; enzyme inhibition; sulfonamide

Categories

Biochemistry & Molecular Biology Chemistry, Medicinal

Funding

Ataturk University (BAP) [2009/84, 2009/251]
Scientific and Technological Research Council of Turkey (TUBITAK) [109T241]

Ask authors/readers for more resources

Protocol

Community support

Reagent

Community support

Abstract

Synthesis and carbonic anhydrase inhibitory properties of novel diarylmethylamines 22-25 and sulfonamide derivatives 26-28 were investigated. Acylation of methoxy-substituted benzenes with benzene carboxylic acids, reduction of ketones with NaBH4, conversion of alcohols to azides, Pd-C catalyzed hydrogenation of azides afforded title compounds 22-25. Compounds 22, 24 and 25 were converted to sulfonamide derivatives 26-28 with MeSO2Cl. The inhibitory effects of novel benzylamine derivatives 22-28 were tested on human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes hCA I and II. The results demonstrated that compound 28 was found to be the best inhibitor against both hCA I (K-i: 3.68 mM) and hCA II (K-i: 9.23 mM).

Authors

I am an author on this paper

Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6

Not enough ratings

Secondary Ratings

Novelty

-

Significance

-

Scientific rigor

-

Rate this paper

Recommended

Article Chemistry, Physical

Sulfonamide-phosphonate hybrids as new carbonic anhydrase inhibitors: In vitro enzymatic inhibition, molecular modeling, and ADMET prediction

Samira Zareei, Maryam Mohammadi-Khanaposhtani, Mehdi Adib, Mohammad Mahdavi, Parham Taslimi

Summary: In this study, a series of new sulfonamide-phosphonate hybrids were synthesized and evaluated for their inhibitory effects on carbonic anhydrase enzymes. The results demonstrated that these compounds exhibited potent inhibitory activity against human carbonic anhydrase, with certain compounds showing even greater potential. Molecular docking studies further revealed significant interactions between these compounds and the active site of the enzymes.

JOURNAL OF MOLECULAR STRUCTURE (2023)

Add to Collection

Article Chemistry, Multidisciplinary

Copper(II) sulfonamide complexes having enzyme inhibition activities on carbonic anhydrase I: synthesis, characterization and inhibition studies

Demet Uzun, Ayla Balaban Gunduzalp, Gokhan Parlakgumus, Ummuhan ozdemir Ozmen, Neslihan Ozbek, Ebru Aktan

Summary: In this study, three copper(II) sulfonamide complexes were synthesized and characterized using various analytical methods. Computational studies were conducted to gain insight into their structures. One of the copper(II) complexes exhibited significant activity on CA I isoenzyme.

JOURNAL OF THE IRANIAN CHEMICAL SOCIETY (2022)

Add to Collection

Article Chemistry, Multidisciplinary

Calixarenes Incorporating Sulfonamide Moieties: Versatile Ligands for Carbonic Anhydrases Inhibition

Davide Sbravati, Alessandro Bonardi, Silvia Bua, Andrea Angeli, Marta Ferraroni, Alessio Nocentini, Alessandro Casnati, Paola Gratteri, Francesco Sansone, Claudiu T. Supuran

Summary: Carbonic anhydrases (CAs) are still considered as an important pharmaceutical target due to the need for selective inhibitors and their involvement in various diseases. This study successfully explored the preparation of new CA ligands by combining calixarenes with benzensulfonamide units, showing promising inhibition towards different CA isoforms. The results suggest the possibility of designing multifunctional inhibitors for this widely spread class of enzymes in the future.

CHEMISTRY-A EUROPEAN JOURNAL (2022)

Add to Collection

Article Chemistry, Medicinal

Novel triazole-sulfonamide bearing pyrimidine moieties with carbonic anhydrase inhibitory action: Design, synthesis, computational and enzyme inhibition studies

Shoaib Manzoor, Andrea Petreni, Md Kausar Raza, Claudiu T. Supuran, Nasimul Hoda

Summary: A series of new triazole-sulfonamide bearing pyrimidine derivatives were synthesized and validated as inhibitors of human carbonic anhydrase isoforms, showing promising potential as selective anticancer agents. Molecular docking studies further supported the favorable interaction between the inhibitors and active residues of the proteins.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2021)

Add to Collection

Article Chemistry, Medicinal

2-(2-Hydroxyethyl)piperazine derivatives as potent human carbonic anhydrase inhibitors: Synthesis, enzyme inhibition, computational studies and antiglaucoma activity

Niccolo Chiaramonte, Andrea Angeli, Silvia Sgambellone, Alessandro Bonardi, Alessio Nocentini, Gianluca Bartolucci, Laura Braconi, Silvia Dei, Laura Lucarini, Elisabetta Teodori, Paola Gratteri, Bernhard Wuensch, Claudiu T. Supuran, Maria Novella Romanelli

Summary: Targeting carbonic anhydrases is a strategy for treating various diseases. In this study, a new series of chiral piperazine compounds was synthesized to widen the structure-activity relationships of potent human carbonic anhydrase inhibitors. Some of the synthesized compounds showed high inhibitory activity.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2022)

Add to Collection

Article Chemistry, Multidisciplinary

Synthesis, in vitro and in silico Biological Studies of Sulfonamide Chalcones as Esterase Inhibitors

Tayfun Arslan, Murat Senturk, Lutfi Karagoz, Yalcin Karagoz, Deniz Ekinci, Asiye Efe, Emir Alper Turkoglu, Fikriye Uras

Summary: The inhibition profiles of synthesized 4-methyl benzene sulfonamide derivatives on various enzymes were investigated in this study. The results showed that these compounds exhibited different levels of inhibition on the target enzymes, indicating their potential as drug candidates. Molecular docking studies further elucidated the mechanism of action of these inhibitors on the enzymes.

CHEMISTRYSELECT (2022)

Add to Collection

Article Biochemistry & Molecular Biology

Inhibition of Carbonic Anhydrase IX Suppresses Breast Cancer Cell Motility at the Single-Cell Level

Agne Janoniene, Linas Mazutis, Daumantas Matulis, Vilma Petrikaite

Summary: Inhibition of CA IX by VD11-4-2 decreases movement speed in breast cancer cells without affecting non-cancerous cells. The inhibitor hinders cells from reaching their maximum speed and reduces cell movement towards growth factors.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2021)

Add to Collection

Article Chemistry, Physical

Synthesis, molecular docking and some metabolic enzyme inhibition properties of biphenyl-substituted chalcone derivatives

Serdar Burmaoglu, Elif Akin Kazancioglu, Mustafa Z. Kazancioglu, Ruya Saglamtas, Gozde Yalcin, Ilhami Gulcin, Oztekin Algul

Summary: This study synthesized new biphenyl-substituted chalcone derivatives and evaluated their inhibitory activity against various enzymes. The results showed that these derivatives exhibited effective inhibition against the enzymes and have potential for the development of new drugs for the treatment of diverse diseases.

JOURNAL OF MOLECULAR STRUCTURE (2022)

Add to Collection

Article Chemistry, Medicinal

Synthesis of N-alkylated pyrazolo[3,4-d]pyrimidine analogs and evaluation of acetylcholinesterase and carbonic anhydrase inhibition properties

Busra O. Aydin, Derya Anil, Yeliz Demir

Summary: In this study, new derivatives of pyrazolo[3,4-d]pyrimidine were synthesized by alkylating the N1 nitrogen atom. These compounds showed a broad spectrum of biological activity. The synthesis involved a series of steps to generate N-alkylated pyrazolo[3,4-d]pyrimidine derivatives, which were then tested for their ability to inhibit AChE and hCA isoforms. Among them, compound 10 exhibited the highest selectivity and potency as a CA I inhibitor.

ARCHIV DER PHARMAZIE (2021)

Add to Collection

Review Chemistry, Medicinal

Recent advances in the medicinal chemistry of carbonic anhydrase inhibitors

Shubham Kumar, Sandeep Rulhania, Shalini Jaswal, Vikramdeep Monga

Summary: Carbonic anhydrase is an important enzyme involved in various physiological and pathological processes, with 16 different isoforms in humans. Inhibitors targeting different isoforms of carbonic anhydrase have clinical applications in treating various diseases, but current drugs lack selectivity leading to undesired side effects. Efforts are being made to develop novel isoform-selective inhibitors of carbonic anhydrase for therapeutic implications.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2021)

Add to Collection

Article Biochemistry & Molecular Biology

Effects of Phosphorylation on the Activity, Inhibition and Stability of Carbonic Anhydrases

Xiaojing Huang, Daniel Winter, Dominic. J. J. Glover, Claudiu. T. T. Supuran, William. A. A. Donald

Summary: Carbonic anhydrases (CAs) are metalloenzymes that play important roles in cellular processes and have been implicated in various diseases. Phosphorylation, a common post-translational modification of CAs, can significantly impact their catalytic activity and drug-binding capabilities. This study highlights the potential regulatory role of phosphorylation in CA activity and its effect on small molecule drug binding.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Calcium channel blockers: molecular docking and inhibition studies on carbonic anhydrase I and II isoenzymes

Cuneyt Turkes, Yeliz Demir, Sukru Beydemir

Summary: The study found that some calcium channel blockers may act as potential inhibitors of hCA I and hCA II, with nimodipine showing the best performance. These compounds could be useful in developing new CA inhibitors.

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2021)

Add to Collection

Review Microbiology

Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in Helicobacter pylori

Cristina Campestre, Viviana De Luca, Simone Carradori, Rossella Grande, Vincenzo Carginale, Andrea Scaloni, Claudiu T. Supuran, Clemente Capasso

Summary: Bacterial carbonic anhydrases play crucial roles in various physiological processes, including modulation of CO2 concentration, pH homeostasis, and regulation of bacterial growth and virulence. Recent studies have highlighted the importance of carbonic anhydrases in bacterial pathogens associated with human infections, suggesting their potential as targets for novel anti-ulcer therapies in the era of antibiotic resistance.

FRONTIERS IN MICROBIOLOGY (2021)

Add to Collection

Article Biochemistry & Molecular Biology

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Tri-Aryl Imidazole-Benzene Sulfonamide Hybrids as Promising Selective Carbonic Anhydrase IX and XII Inhibitors

Lamya H. Al-Wahaibi, Bahaa G. M. Youssif, Ehab S. Taher, Ahmed H. Abdelazeem, Antar A. Abdelhamid, Adel A. Marzouk

Summary: A novel series of tri-aryl imidazole derivatives carrying benzene sulfonamide moiety were designed for their selective inhibitory activity against hCA IX and XII. Among them, six compounds showed potent and selective CA IX inhibition, with 5g and 5b demonstrating higher antiproliferative activity compared to other tested compounds. Docking studies of these two compounds revealed their favorable binding interactions with CA-IX, similar to that of ligand 9FK. Molecular modeling simulations supported the biological evaluation results.

MOLECULES (2021)

Add to Collection

Article Biochemistry & Molecular Biology

Sulfonamide derivatives with benzothiazole scaffold: Synthesis and carbonic anhydrase I-II inhibition properties

Cansu Ozturk, Erbay Kalay, Serpil Gerni, Neslihan Balci, Feyzi Sinan Tokali, Osman Nuri Aslan, Emrah Polat

Summary: This study synthesized a series of secondary sulfonamide derivatives containing benzothiazole scaffold and investigated their inhibition properties on human carbonic anhydrase. The results showed that some of these compounds inhibited the enzyme more effectively than the standard drug acetazolamide, with compounds 5 and 4 being the most effective.

BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Novel tetrakis-phthalocyanines bearing pyrimidine derivative: crystal XRD analysis, enzyme inhibition, molecular docking, and anticancer effects

Armagan Gunsel, Bilge Yazar, Parham Taslimi, Yavuz Erden, Tugba Taskin-Tok, Hasan Piskin, Ahmet T. Bilgicli, M. Nilufer Yarasir, Ilhami Gulcin

Summary: In this study, a novel starting material was synthesized and its structure was verified. Several new phthalocyanine compounds were synthesized and characterized using various spectroscopic methods. These compounds showed inhibitory effects on acetylcholinesterase and alpha-glycosidase enzymes, and exhibited normal cytotoxic effects on cancer cells.

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Unravelling the phenolic compound reserves, antioxidant and enzyme inhibitory activities of an endemic plant species, Achillea pseudoaleppica

Mustafa Abdullah Yilmaz, Parham Taslimi, Omer Kilic, Ilhami Gulcin, Abhijit Dey, Ercan Bursal

Summary: This ethnobotanical study investigated the chemical constituents and pharmacological activities of Achillea pseudoaleppica. The ethanol and water extracts of A. pseudoaleppica exhibited strong antioxidant properties and inhibited several enzymes. Quinic acid was identified as the most abundant phenolic compound in the extracts. The findings suggest that A. pseudoaleppica has potential therapeutic applications due to its rich phenolic content and pharmacological properties.

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Piperazine derivatives with potent drug moiety as efficient acetylcholinesterase, butyrylcholinesterase, and glutathione S-transferase inhibitors

Mahmut O. Karaytug, Neslihan Balci, Fikret Turkan, Mahmut Gurbuz, Mehmet E. Demirkol, Zeynep Namli, Lut Tamam, Ilhami Gulcin

Summary: Cholinesterases and glutathione S-transferases (GSTs) play crucial roles in the biochemical processes of the nervous system and detoxification in the human body. Piperazine derivatives show potential therapeutic effects in neurological disorders and cancer research.

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Vinyl functionalized 5,6-dimethylbenzimidazolium salts: Synthesis and biological activities

Emine O. Karaca, Zeynebe Bingol, Nevin Gurbuz, Ismail Ozdemir, Ilhami Gulcin

Summary: A series of vinyl functionalized 5,6-dimethylbenzimidazolium salts were synthesized and evaluated for their inhibition ability against various enzymes. The compounds showed effective inhibition profiles and may contribute to the development of new drugs for global disorders.

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Acetylphenyl-substituted imidazolium salts: synthesis, characterization, in silico studies and inhibitory properties against some metabolic enzymes

Ozlem Demirci, Burcu Tezcan, Yeliz Demir, Tugba Taskin-Tok, Yetkin Gok, Aydin Aktas, Bilgehan Guzel, Ilhami Gulcin

Summary: In this study, we synthesized thirteen new 1-(4-acetylphenyl)-3-alkylimidazolium salts and investigated their inhibition activities against AChE and hCAs. The synthesized compounds showed highly potent inhibition effects, with most of them outperforming the standard inhibitors.

MOLECULAR DIVERSITY (2023)

Add to Collection

Article Biology

Comprehensive Metabolite Profiling of Cinnamon (Cinnamomum zeylanicum) Leaf Oil Using LC-HR/MS, GC/MS, and GC-FID: Determination of Antiglaucoma, Antioxidant, Anticholinergic, and Antidiabetic Profiles

Muzaffer Mutlu, Zeynebe Bingol, Eda Mehtap Uc, Ekrem Koksal, Ahmet C. Goren, Saleh H. Alwasel, Ilhami Gulcin

Summary: This study evaluated the antioxidant and antidiabetic properties of cinnamon leaf essential oil and determined its inhibitory effects on enzymes associated with metabolic diseases. Phenolic contents and essential oil profiles were analyzed. Cinnamon oil showed strong radical scavenging abilities and effectively inhibited carbonic anhydrase II, acetylcholinesterase, and alpha-amylase. This multidisciplinary study is valuable for further research on antioxidant properties and enzyme inhibition profiles of important plants and their oils.

LIFE-BASEL (2023)

Add to Collection

Article Chemistry, Medicinal

Design, synthesis, a-glucosidase inhibition, pharmacokinetic, and cytotoxic studies of new indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives

Haleh Hamedifar, Maryam Mohammadi-Khanaposhtani, Maedeh Sherafati, Milad Noori, Ali Moazam, Samanesadat Hosseini, Bagher Larijani, Mir H. Hajimiri, Mohammad Mahdavi, Mehmet K. Erdogan, Ramazan Gundogdu, Mahinur Kirici, Parham Taslimi, Ilhami Gulcin

Summary: A new series of indole-carbohydrazide-phenoxy-N-phenylacetamide derivatives 7a-l were synthesized and evaluated for their alpha-glucosidase inhibitory abilities and cytotoxic effects. Most of the synthesized derivatives showed good to moderate inhibitory abilities against alpha-glucosidase. Among them, 2-methoxy-phenoxy derivatives 7l and 7h exhibited the highest inhibition effects. Compound 7k showed moderate cytotoxicity against a lung cancer cell line.

ARCHIV DER PHARMAZIE (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Comprehensive Metabolite Profiling of Berdav Propolis Using LC-MS/MS: Determination of Antioxidant, Anticholinergic, Antiglaucoma, and Antidiabetic Effects

Hasan Karagecili, Mustafa Abdullah Yilmaz, Adem Erturk, Hatice Kiziltas, Leyla Guven, Saleh H. Alwasel, Ilhami Gulcin

Summary: This study investigated the chemical composition and antioxidant activities of propolis, finding that it is rich in phenolic and flavonoid compounds with antioxidant, antimicrobial, and anticancer properties. Propolis extract also exhibited inhibitory activities against enzymes associated with diabetes, Alzheimer's disease, and glaucoma. Additionally, twenty-eight phenolic compounds were determined to be major organic compounds in propolis, making it a potential natural product for the treatment of various diseases.

MOLECULES (2023)

Add to Collection

Article Chemistry, Multidisciplinary

Design, Synthesis, Characterization and Biological Activities of Novel S-(Acyloxy)butyl-N,N-Diethyldithiocarbamate Compounds

Aliverdi Karimov, Parham Taslimi, Arzu Orujova, Khuraman Mammadova, Dursun Kisa, Vagif Farzaliyev, Afsun Sujayev, Nastaran Sadeghian, Tugba Taskin-Tok, Saleh Alwasel, Ilhami Gulcin

Summary: In this study, a series of S-(Acyloxy)butyl-N,N-Diethyldithiocarbamate compounds (P1-P7) were synthesized and characterized. The compounds were tested for their effects on metabolic enzymes and compared to reference compounds. Molecular docking simulations showed their binding interactions with AChE, BChE, and alpha-glucosidase. Compound P6 exhibited strong distant bond interactions with tacrine for AChE and BChE, while compound P4 showed good interactions with alpha-glucosidase.

CHEMISTRYSELECT (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Comprehensive Phytochemical Content by LC/MS/MS and Anticholinergic, Antiglaucoma, Antiepilepsy, and Antioxidant Activity of Apilarnil (Drone Larvae)

Hakan Inci, Ebubekir Izol, Mustafa Abdullah Yilmaz, Mehmet Ilkaya, Zeynebe Bingol, Ilhami Gulcin

Summary: This study evaluated the antioxidant and enzyme inhibition effects of Apilarnil. The antioxidant activity of Apilarnil was lower than standard molecules, but it exhibited higher radical scavenging ability in the DPPH assay. Furthermore, its enzyme inhibition effects were tested against various enzymes. The phytochemical composition of Apilarnil was also determined, with quinic acid, fumaric acid, aconitic acid, kaempferol, and quercetin being the most abundant compounds. Overall, Apilarnil showed effective antioxidant properties compared to standard antioxidants.

CHEMISTRY & BIODIVERSITY (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Synthesis and Biological Activity of Some Bromophenols and Their Derivatives Including Natural Products

Cetin Bayrak, Parham Taslimi, Namik Kilinc, Ilhami Gulcin, Abdullah Menzek

Summary: In this study, the natural bromophenol butyl 2-(3,5-dibromo-4-hydroxyphenyl)acetate (1) and indene derivatives 34 and 35 were successfully synthesized. Several known natural bromophenols and their derivatives were also synthesized. The synthesized compounds exhibited strong inhibition effects against acetylcholinesterase, butyrylcholinesterase, and α-glycosidase enzymes.

CHEMISTRY & BIODIVERSITY (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Novel Quinazolinone Derivatives: Potential Synthetic Analogs for the Treatment of Glaucoma, Alzheimer's Disease and Diabetes Mellitus

Feyzi Sinan Tokali, Parham Taslimi, Burak Tuzun, Ahmet Karakus, Nastaran Sadeghian, Ilhami Gulcin

Summary: In this study, novel quinazolinone compounds were successfully synthesized and their inhibition properties on multiple metabolic enzymes were investigated. Molecular docking study was performed to analyze the interactions of the most potent compounds with enzymes. Additionally, the ADME/T properties of the compounds were investigated.

CHEMISTRY & BIODIVERSITY (2023)

Add to Collection

Article Plant Sciences

LC-ESI-MS/MS analysis of secondary metabolites of different St. John's wort (Hypericum perforatum) extracts used as food supplements and evaluation of developmental toxicity on zebrafish (Danio rerio) embryos and larvae

Mehmet Nuri Atalara, Mine Kokturk, Fikret Altindag, Gunes Ozhan, Tevfik Ozen, Ibrahim Demirtas, Llhami Gulcini

Summary: St. John's wort, a popular medicinal plant, contains bioactive components that are beneficial for health. The extracts showed high survival rates and no significant changes in malformation and larval emergence in zebrafish experiments. However, dosage should be controlled below 10 mg/mL to avoid toxicity.

SOUTH AFRICAN JOURNAL OF BOTANY (2023)

Add to Collection

Article Pharmacology & Pharmacy

Potential antioxidant, anticholinergic, antidiabetic and antiglaucoma activities and molecular docking of spiraeoside as a secondary metabolite of onion (Allium cepa)

Lokman Durmaz, Hatice Kiziltas, Hasan Karagecili, Saleh Alwasel, Lhami Gulcin

Summary: The study found that spiraeoside in onions has antioxidant and enzyme inhibition abilities, which may have potential as a medicine for diseases such as Alzheimer's disease, diabetes, and glaucoma.

SAUDI PHARMACEUTICAL JOURNAL (2023)

Add to Collection

Article Biochemistry & Molecular Biology

Benzimidazolium Salts Bearing Nitrile Moieties: Synthesis, Enzyme Inhibition Profiling, and Molecular Docking Analysis for Carbonic Anhydrase and Acetylcholinesterase

Erkan Oner, Yetkin Gok, Yeliz Demir, Tugba Taskin-Tok, Aydin Aktas, Ilhami Gulcin, Serap Yalin

Summary: This study presents the synthesis and characterization of a series of benzimidazolium salts, and investigates their enzyme inhibition abilities against acetylcholinesterase and carbonic anhydrase. The results show that these salts have potent inhibition effects. The pharmacokinetic properties of the compounds were also predicted.

CHEMISTRY & BIODIVERSITY (2023)

Add to Collection

No Data Available

© Peeref 2019-2024. All rights reserved.