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"Sitokrom P450 isoform 2C9 (CYP2C9) merupakan enzim utamapemetabolisme fenitoin. Inhibisi enzim ini dapat menyebabkan peningkatankadar plasma fenitoin. Simetidin diketahui meningkatkan kadar plasmafenitoin dalam tubuh. Saat ini, interaksi antara fenitoin dan simetidin secaramolekuler belumlah jelas. Suatu metodologi komputasional, penambatanmolekuler, berorientasi pada afinitas ikatan struktur kompleks yang terbentukantara ligan dengan makromolekul target secara tiga dimensi (3D). Berdasaralasan tersebut, peneliti dapat menggunakannya untuk menganalisis interaksiyang terdapat pada struktur kompleks yang terbentuk. Program penambatanmolekuler yang paling banyak digunakan, AutoDock, memperlihatkanefisiensi kegunaan menilai ligan yang terikat pada situs aktifnya, sehinggadapat digunakan untuk memahami interaksi antara fenitoin dan simetidinpada CYP2C9.Struktur 3D CYP2C9 yang digunakan adalah struktur kompleksdengan flurbiprofen (PDB ID 1R9O) yang memiliki konformasi terbuka danstruktur kompleks dengan S-warfarin (PDB ID 1OG5) yang memilikikonformasi tertutup. Hasil penambatan molekuler menggunakan strukturkristal 1R9O lebih efektif dibandingkan 1OG5. Substrat fenitoin distabilkanpengikatannya pada CYP2C9 dengan adanya ikatan hidrogen, interaksidengan Arg108 sebagai residu kationik, interaksi hidrofobik khususnya dengan residu Phe114. Sedangkan inhibitor simetidin distabilkan pengikatannya pada CYP2C9 dengan adanya ikatan hidrogen denganbeberapa residu asam amino termasuk Glu300 yang juga berperan sebagairesidu anionik, serta adanya interaksi hidrofobik. Simetidin menjadi inhibitorkompetitif CYP2C9 pada situs pengenalan substrat fenitoin."

"Suatu obat dapat menggeser obat obat lain dari ikatannya dengan proteinplasma, sehingga menyebabkan kenaikan respon farmakologi secara tibatibakarena adanya kenaikan konsentrasi obat bebas. Pergeseran obatsangat penting ketika senyawa tersebut berikatan kuat dengan protein,misalnya perubahan ikatan dari 98% menjadi 94% dapat meningkatkan fraksiobat bebas menjadi tiga kali lipat, dari 2% menjadi 6%. Mengetahui adanyainteraksi antara asam mefenamat dan piroksikam dalam berikatan denganprotein plasma, dalam hal ini albumin manusia, sangatlah penting, untukmemvisualisasikan interkaksi antara kedua obat tersebut dalam berikatandengan albumin dimana telah terbukti secara in vitro. Metode in silicomenggunakan teknik penambatan molekuler menggunakan programAutoDock 4.0 menghasilkan visualisasi pengikatan yang terjadi antara asammefenamat dengan albumin, dan juga piroksikam dengan albumin, dan jugamengahasilkan nilai energi pengikatan (ΔG) dan konstanta inhibisi (Ki) darimasing-masing pengikatan. Hasi penambatan menunjukkan bahwa nilai (ΔG)dan Ki asam mefenamat dan piroksikam secara berturut-turut adalah -5,47kkal/mol, 98,59 μM dan -7,46 kkal/mol, 3,42 μM. Kesimpulan yang diperolehbahwa ikatan asam mefenamat dengan albumin dapat digantikan olehpiroksikam karena nilai (ΔG) dan Ki asam mefenamat labih tinggi daripiroksikam. Ini dapat diperkirakan bahwa interaksi akan meningkatkankonsentrasi asam mefenamat yang bebas pada plasma darah danmenyebabkan efek toksik."

"Sitokrom P450 3A4 (CYP3A4) terlibat dalam 50% metabolisme dari obat-obatan yang digunakan dalam terapi. Saat ini, struktur CYP3A4 telah diperoleh melalui teknik kristalografi dan struktur ini menunjukkan bahwa CYP3A4 memiliki situs aktif yang fleksibel sehingga memberikan berbagai kemungkinan interaksi dengan ligan. Inhibitor HIV-Protease merupakan salah satu golongan senyawa yang menghambat aktivitas CYP3A4. Interaksi inhibisi CYP3A4 oleh inhibitor HIV-Protease perlu diteliti lebih lanjut karena golongan senyawa ini sering digunakan bersama obat-obatan lain dalam terapi HIV dan masih terus dikembangkan. Metode in silico melalui teknik penambatan molekuler digunakan dalam penelitian ini untuk mempelajari inhibisi CYP3A4 oleh inhibitor HIV-Protease karena metode ini lebih efisien daripada metode in vitro dan in vivo. Hasil penambatan molekuler inhibitor HIV-Protease pada CYP3A4 menunjukkan bahwa empat interaksi hidrofobik dan sedikitnya satu ikatan hidrogen terlibat dalam inhibisi CYP3A4 oleh inhibitor HIV-Protease.Cytochrome P450 3A4 (CYP3A4) contributes to the metabolism of 50% of drugs used in therapy. Nowadays, the structures of CYP3A4 are available through crystallography technique and these structures show that CYP3A4 has a flexible active site which allows many probabilities of ligand interaction. HIV-Protease inhibitor is a group of drugs that inhibit CYP3A4's activity. Inhibition of CYP3A4 by HIV-Protease inhibitor should be studied more because these drugs are often used with other drugs in the therapy of HIV and are still being developed. In silico method through molecular docking is used in this research to study the inhibition of CYP3A4 by HIV-Protease inhibitor because this method is more efficient than in vitro and in vivo method. The result of molecular docking of HIV-Protease inhibitor to CYP3A4 shows that four hydrophobic interactions and at least one hydrogen bond are responsible for the inhibition of CYP3A4 by HIV-Protease inhibiton."

"ABSTRACT

Cytochrome P450 isoform 2C9 (CYP2C9) is a main enzyme which metabolizes phenytoin [I]. The inhibition of this enzyme will increase plasma level of phenytoin. Cimetidine is known as drug that inhibits this enzyme, resulting an increased plasma level of phenytoin [2]. Recently, the three dimentional molecular basis of interaction between phenytoin and cimetidine toward CYP2C9 has not been described well yet. The present findings may represent an important advance for understanding interaction CYP2C9 with drugs to predict its toxicity an also metabolism based on structural interaction from docking results. A computational methodology, molecular docking can be used to analyze interaction which exist between ligand and macromolecule. AutoDock is one of the most commonly used methodology, shows the efficiency of scoring function ligand that bound to its active site [3]. So that, it can be used to understand about interaction between phenytoin and cimetidine in CYP2C9. Crystal structure of CYP2C9 complexed with flurbiprofen (PDB ID: 1R90) has resolution 2.00 A. This structure, used in this experiment, has the closed conformational structure and complexed with S-warfarin. Three dimensional structure of phenytoin and cimetidine were minimized, charge were added for docking preparation. Binding of substrate phenytoin in CYP2C9 is stabilized by hidrogen bonds, interaction with cationic residue Argl08, hydrophobic interaction particularly with Phel 14. On the other side, binding of cimetidine inhibitor in CYP2C9 is stabilized by hydrogen bonds with some amino acid residues, including Glu300 which has role as anionic residue, also the exist of hydrophobic interaction. Cimetidine being competitive inhibitor of CYP2C9 at the substrate recognition site of phenytoin. "

"Pendahuluan: Artesunat amodiakuin (AS-AQ) merupakan artemisinin-based combination therapy (ACT) yang digunakan sebagai lini pertama di berbagai daerah endemik di Indonesia. Studi sebelumnya pada pasien malaria falsiparum tanpa komplikasi di Sumba Indonesia menunjukkan gagal terapi sebesar 11,1%. Diduga salah satu penyebab kegagalan terapi adalah polimorfisme gen sitokrom P450 2C8 (CYP2C8), CYP1A1 dan CYP1B1. Penelitian ini bertujuan untuk mempelajari peran polimorfisme pada gen pemetabolisme artesunat amodiakuin terhadap kegagalan terapi amodiakuin. Metodologi: Analisis polimorfisme CYP2C8*2, CYP2C8*3, CYP1A1*2, CYP1B1*2 dan CYP1B1*3 dilakukan pada pasien malaria falsiparum yang mendapatkan AS-AQ di Sumba Indonesia (N=110). Single nucleotide polymorphisms (SNPs) dianalisis menggunakan polymerase chain reaction (PCR) dilanjutkan dengan retriction-fragment length polymorphism (RFLP) dan sekuensing. Hasil: Tidak ditemukan alel CYP2C8*2 dan alel CYP2C8*3 pada sampel penelitian (N=110). Frekuensi alel CYP1A1*2, CYP1B1*2 dan CYP1B1*3 berturut-turut sebanyak 5%, 23,6% dan 4,1%. Tidak ditemukan kemaknaan pada analisis haplotipe CYP1B1*2 (p=0,13, 95% CI: 0,11 – 1,34) dan CYP1B1*3 (p=0,34, 95% CI: 0,44 – 11,34). Hanya ditemukan tipe heterozigot pada alel CYP1A1*2 dan CYP1B1*3. Kesimpulan: Tidak ditemukan hubungan antara alel CYP2C8*2, CYP2C8*3, CYP1A1*2, CYP1B1*2 dan CYP1B1*3 dengan kegagalan terapi amodiakuin di Sumba, Indonesia.

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Introduction: Artesunate amodiaquine (AS-AQ) is one of the ACT used in many endemic areas in Indonesia. Previous study in Sumba showed that there were 11,1% treatment failure with AS-AQ in uncomplicated malaria falciparum patients. Polymorphisms in cytochrome P450 2C8 (CYP2C8), CYP1A1 and CYP1B1 genes are thought to be the major factors in the treatment failure of amodiaquine. The aim of this study was to analyze the role of polymorphisms in the genes encoding amodiaquine metabolizing enzymes (CYP2C8, CYP1A1, CYP1B1) in the treatment failure of amodiaquine.

Methodology: Polymorphisms of CYP2C8*2, CYP2C8*3, CYP1A1*2, CYP1B1*2 and CYP1B1*3 were studied in patients with malaria falciparum treated with AS-AQ in Sumba Indonesia (N=110). Single nucleotide polymorphisms (SNPs) were analyzed using polymerase chain reaction (PCR) continued with restriction-fragment length polymorphism (RFLP) and sequencing.

Results: There were no CYP2C8*2 and CYP2C8*3 alleles found in the samples (N=110). The frequency of CYP1A1*2, CYP1B1*2 and CYP1B1*3 alleles were 5%, 23,6% and 4,1%, respectively. There were no significant difference in haplotype analysis of CYP1B1*2 (p value=0,13, 95% confidence interval=0,11 – 1,34) and CYP1B1*3 (p value=0,34, 95% confidence interval=0,44 – 11,34). Heterozygote types were found in CYP1A1*2 and CYP1B1*3 alleles.

Conclusions: There were no associations between CYP2C8*2, CYP2C8*3, CYP1A1*2, CYP1B1*2 and CYP1B1*3 alleles with treatment failure of amodiaquine in Sumba, Indonesia."

"Beberapa penelitian terakhir melaporkan bahwa karotenoid memiliki kemampuan untuk memodulasi sistem metabolisme xenobiotik. Beberapa penelitian tersebut terutama dipicu oleh studi CARET dan ATBC, yang melaporkan bahwa suplementasi beta karoten dalam dosis besar pada perokok dapat meningkatkan risiko terjadinya kanker paru. Efek beta karoten ini diduga terjadi melalui induksi enzim metabolisme yang berhubungan dengan senyawa karsinogenik, terutama enzim sitokrom P450. Selain beta karoten, karotenoid lain yang sampai saat ini telah diketahui mempengaruhi sistem enzim sitokrom P450 adalahkantaxantin, astaxantin dan beta apo-8-karotenal. Di samping itu, likopen, salah satu anggota karotenoid non-provitamin A, dilaporkan merniliki efek inhibisi in vitro pada CYP2E1, salah satu isoform sitokrom P450 yang berperan dalam konversi xenobiotik tertentu menjadi karsinogen. Likopen merupakan salah satu senyawa yang akhir-akhir inibanyak diteliti karena sifat antioksidan dan antiproliferatifnya yang kuat.Penelitian ini dirancang untuk menyelidiki pengaruh likopen in vivo terhadap enzim sitokrom P450 total, CYP1A2 dan CYP2E1 mikrosom hati. Fraksi mikrosom diisolasi dengan metode sentrifugasi diferensial yang dikombinasi dengan agregasi mikrosom menggunakan ion kalsium. Kadar sitokrom P450 total, aktivitas CYPIAZ (asetanilid-4-hidroksilase) dan CYP2E1 (p-nitrofenol hidroksilase) dipelajari pada mikrosom hati tikus Sprague Dawley jantan. Untuk mempelajari efek induksi, hewan coba diberi likopen dalam dosis 0 mg/kgBB/hari, 25 mg/kgBB/hari, 50 mg/kgBB/hari atau 100 mg/kgBB/hari per oralselama 14 hari, sedangkan efek inhibisi likopen dipelajari dengan pemberian likopen dosis tunggal 0 mg/kgBB atau 100 mg/kgBB.Aktivitas sitokrom P450 total dan asetanilid-4-hidroksilase tidak dipengaruhi oleh semua perlakuan. CYP2E1 (p-nitrofenol hidroksilase) menurun secara bermakna oleh pemberian likopen dosis tunggal 100 mg/kgBB maupun dengan pemberian likopen 100 mg/kgBB/hari selama 14 hari.Hasil penelitian ini menunjukkan bahwa likopen tidak mempengaruhi kadar sitokrom P450 total dan aktivitas CYPIA2 (asetanilid-4-hidroksilase), namun memiliki efek inhibisi pada aktivitas CYP2E1 (p-nitrofenol hidroksilase)."

"Latar belakang: Penyakit hati imbas obat akibat penggunaan obat anti tuberkulosis OAT merupakan salah satu faktor risiko yang telah dilaporkan Faktor kerentanan individu dalam memetabolisme dan detoksifikasi setiap obat yang dipengaruhi oleh faktor faktor genetik juga mempengaruhi kejadian penyakit hati imbas obat. Penelitian ini bertujuan untuk meneliti status asetilator enzim N Acetylator Transferase 2 NAT2 dan polimorfisme sitokrom P450 CYP 2E1 terhadap kejadian penyakit hati imbas obat. Metode: Studi kasus kontrol pada 50 pasien tuberkulosis di Rumah Sakit Cipto Mangunkusumo dan klinik paru PPTI yang dikelompokkan menjadi grup kasus n 25 dan grup kontrol n 25. Hasil: Dari 50 subyek penelitian didapatkan bahwa karakteristik subyek penelitian terbanyak berjenis kelamin perempuan 62 berusia 45 tahun 56 normoweight 66. Pada analisis bivariat terhadap faktor risiko kejadian penyakit hati imbas obat yang diinduksi oleh OAT hanya ditemukan faktor risiko status asetilator lambat enzim NAT2 yang signifikan dengan crude OR 1 563 95 KI 1 165 2 097 dengan p 0 002 sedangkan pada faktor risiko polimorfisme CYP 2E1 tidak ditemukan hasil yang bermakna secara statistik. Kesimpulan: Faktor risiko status asetilator lambat enzim NAT2 merupakan faktor risiko kejadian penyakit hati imbas obat yang diinduksi oleh OAT.

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Background: Antituberculous agents is one of a drug induced liver injury's risk factors Individual susceptibility in drug metabolism and detoxification due to genetic factors was also reported lately. Among the individual susceptibility factors we would like to identify the genotype of N acetylator 2 enzyme status and polymorphism of cytochrome P450 2E1 as a risks factors of antituberculous agent induced liver injury.

Methods: This is a case control study in 50 tuberculous rsquo patient at Cipto Mangunkusumo hospital and PPTI clinics which were divided in control group n 25 and case group n 25.

Results: From 50 subjects the baseline charactersitic were mostly female 62 age 45 years old 56 normoweight 66 Bivariate analysis were performed to identify the risk factors and only slow acetylator status of NAT2 enzymes was found significant with crude OR 1 563 95 CI 1 165 ndash 2 097 p 0 002 but not in a CYP 2E1 polymorphism status.

Conclusions: Slow acetylator status of NAT2 enzymes was a risk factor for antituberculous agents ndash induced liver injury."

"Diabetes melitus tipe 2 dapat dikontrol dengan menghambat kerja enzim α-glukosidase. Sulokrin merupakan salah satu senyawa yang mempunyai potensi sebagai penghambat α-glukosidase. Senyawa sulokrin-I dan sulokrin-125I telah disintesa serta dipelajari ikatannya dengan metode Radioligand Binding Assay (RBA) dan penambatan molekuler. Sulokrin-I disintesa dengan rumus molekul C17H15O7I dan berat molekul 457,9940. Senyawa sulokrin-125I disintesa dari sulokrin-I menggunakan metode pertukaran isotop. Sulokrin-125I diperoleh dengan kemurnian radiokimia sebesar 82,3%. Dari hasil pengujian dengan metode RBA diperoleh Kd dan Bmax secara berturut turut 83,33 pM dan 1,2 x 10-6 pmol/mg reseptor. Penambatan molekuler sulokrin-I dilakukan terhadap α-glukosidase Saccharomyces cerevisiae dan α-glukosidase manusia. Sulokrin-I yang digunakan dalam proses penambatan molekuler adalah metil 2-(2,6-dihidroksi-3-iodo-4-metilbenzoil)-5-hidroksi-3-metoksibenzoat [A] dan metil 2-(2,6-dihidroksi-5-iodo-4-metilbenzoil)-5-hidroksi-3-metoksibenzoat [B]. Model senyawa A dan B berinteraksi dengan α-glukosidase Saccharomyces cerevisiae melalui pembentukan ikatan hidrogen dengan residu Arg213, Asp215, Glu277, Asp352. Nilai ΔG dan Ki yang diperoleh adalah -6,71 kkal/mol dan 12,03 µM untuk senyawa A, -5,82 kkal/mol dan 54,39 µM untuk senyawa B. Interaksi senyawa A, senyawa B dengan α-glukosidase manusia menghasilkan ΔG dan Ki sebesar -6,81 kkal/mol dan 10,3 µM untuk senyawa A, senyawa B mempunyai ΔG dan Ki sebesar -6,27 kkal/mol dan 25,4 µM.;Treatment type 2 diabetes melitus can be done by inhibiting α-glucosidase.

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Sulochrin is one of the potential α-glucosidase inhibitor compound. Sulochrin-I and sulochrin-125I were synthesized and their binding were studied using Radioligand Binding Assay and molecular docking method. Sulochrin-I has been synthesized with molecular formula C17H15O7I and molecular weight 457.9940. Sulochrin-125I was synthesized from sulochrin-I by isotope exchange method. sulochrin-125I radiochemical purity was 82.3%. From the RBA method, Kd and Bmax were obtained 83.33 pM and 1.2 x 10-6 pmol / mg receptor respectively. Molecular docking of sulochrin-I was done in two macromolecules, Saccharomyces cerevisiae α-glucosidase and human α-glucosidase. Two ligands were used in this research, they are methyl 2 - (2,6-dihydroxy-3-iodo-4-methylbenzoil)-5-hydroxy-3-methoxibenzoate [A] and methyl 2 - (2,6-dihydroxy-5-iodo-4-methylbenzoil)-5-hydroxy-3-methoxybenzoat [B]. Compound A and B showed interaction with Saccharomyces cerevisiae α-glucosidase and showed hydrogen bound with Arg213, Asp215, Glu277, Asp352. ΔG and Ki values for compound A are -6.71 kcal / mol and 12.03 µM, whereas for compound B are - 5.82 kcal/mol and 54.39 µM respectively. Interaction study with human α-glucosidase gave ΔG -6.81 kcal/mol and Ki 10.3 µM for compound A, whereas compound B gave ΔG and Ki -6.27 kcal/mol and 25.4 µM respectively."

"Research through a metabolomics approach is carried out withoutisolating a single active compound responsible for an activity. Empirically the root, stem, and leaf preparations of Rhinachantus nasutus (L.) Kurz have long been used in traditional medicine such as the treatment of diabetes, eczema, pulmonary tuberculosis, herpes, hepatitis, and hypertension. This dissertation aims to evaluate compounds that have antioxidant and antidiabetic activity through inhibition of alpha-glucosidase activity of plant R. Nasutus metabolomics and molecular tethering based liquid chromatography very high performance mass spectrometry/mass spectrometry (KCKST SM/SM). The stages of research carried out include: (1) Extraction of leaves, flowers, and bark using 70% ethanol with ultrasonic wave-assisted extraction method. (2) Fractionation of selected extracts using centrifugation partition chromatography (PPP). (3) Testing of antidiabetic activity through the mechanism of alpha-glucosidase inhibition of selected extracts and their PPP fractions in vitro. (4) Testing of antioxidant activity by 1,1-diphenyl-2-picrylhydrazil (DPPH) method; ferric reducing antioxidant power (FRAP); cupric ion reducing antioxidant capacity (CUPRAC) in vitro against extracts and PPP fractions whose alpha-glucosidase inhibitory activity is very active and/or active. (5) Determination of metabolite profiles using KCKST SM/SM Q-Orbitrap on PPP fractions whose alpha-glucosidase inhibitory activity is very active and/or active. (6) Chemometric analysis with multivariate data analysis using SIMCA software against metabolite area area data and bioactivity data. (7) Verification of compounds that contribute significantly as inhibitors of alpha-glucosidase activity resulting from metabolomics by molecular tethering. This study obtained 10 active compounds in the inhibition of alpha-glucosidase in the KPS fraction of R. nasutus, namely compounds (5) bis(2-ethylhexyl) amines, (6) choline, (7) leu gly, (8) N-methyltanolamine phosphate, (11) N-methyldioctylamine, (14) dodesiltrimethethlammonium, (15) austalida J, (17) DL-β-leucine, (22) cemilicoisoflavone B, and (26) licoflavone B. In addition, 6 compounds (compounds 5, 8, 11, 14, 15, and 22) contributed significantly as alpha-glucosidase inhibitors as well as very strong antioxidants with the FRAP method and 3 compounds (compounds 5, 11, and 15) with the CRAPC method.

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In the metabolomics approach, research is done without isolating any active compounds that cause activity. Empirically, preparations of the roots, stems, and leaves of Rhinachantus nasutus (L.) Kurz have long been used in traditional medicine for such purposes as the treatment of diabetes, eczema, pulmonary tuberculosis, herpes, hepatitis, and hypertension. This dissertation aims to evaluate compounds with antioxidant and anti-diabetic activity by inhibiting the alpha-glucosidase activity of the plant R. nasutus using a metabolomics approach and molecular docking based on ultra-high performance liquid chromatography mass spectrometry/mass spectrometry (UHPL MS/MS). The stages of the research included: (1) extraction of leaves, flowers, and stem bark using 70% ethanol using an ultrasound-assisted extraction (UAE) method. (2) Fractionation of selected extracts using centrifugation partition chromatography (CPC). (3) In vitro testing of antidiabetic activity through the mechanism of alpha-glucosidase inhibition of selected extracts and their CPC fractions. (4) Testing the antioxidant activity with the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method, ferric reducing antioxidant power (FRAP), and cupric ion reducing antioxidant capacity (CUPRAC) in vitro against extracts and CPC fractions with highly active, active, or slightly active alpha-glucosidase inhibitory activity. (5) Determination of metabolite profiles using KCKST SM/SM Q-Orbitrap on CPC fractions with highly active or slightly active alpha-glucosidase inhibitory activity. (6) Chemometric analysis in the form of multivariate data analysis using SIMCA software on metabolite area data and bioactivity data. (7) Verification of compounds that contribute significantly as inhibitors of alpha-glucosidase activity in metabolomics by molecular docking.This study obtained 10 active compounds in alpha-glucosidase inhibition in the R. nasutus CPC fraction, namely compounds (5) bis(2-ethylhexyl) amine, (6) choline, (7) leugly, (8) N-methylethanolamine phosphate, (11) N-methyldioctylamine, (14) dodecyltrimethylammonium, (15) austalide J, (17) DL-β-Leucine, (22) semilicoisoflavone B, and (26) licoflavone B. In addition, it was also found that six compounds (compounds 5, 8, 11, 14, 15, and 22) significantly contributed as alpha-glucosidase inhibitors as well as very strong antioxidants with the FRAP method and three compounds (compounds 5, 11, and 15) with the CUPRAC method."