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Investigation of 1,2,4-Triazole Derivatives as Potantial Anti-Diabetic Agents: In vitro Enzyme Inhibition and In silico Pharmacokinetic Studies

Year 2023, , 345 - 356, 31.08.2023

Fulya Öz Tuncay , Ümmühan Çakmak

https://doi.org/10.18185/erzifbed.1216717

Abstract

Diabetes Mellitus (DM), kan glukoz seviyesinin yükseldiği, postprandiyal hiperglisemiye neden olan, böbrek yetmezliği, körlük, kardiyovasküler hastalıklar ve sinir hasarı gibi pek çok sekonder probleme neden olan metabolik bir hastalıktır. α-Amilaz ve α-glukozidaz doğrudan tip II DM ile ilgilidir ve bu enzimlerin inhibitörleri nişasta sindirimini inhibe edebildiğinden DM tedavisinde yaygın olarak kullanılmaktadır. Bu çalışmada flor içeren 1,2,4-triazol-5-on türevlerinin (4a-d, 6a-b, 7a-b, 8a-b) α-amilaz ve α-glukozidaza karşı inhibisyon potansiyelleri araştırıldı. Tüm moleküller, akarboz standardı kontrolü altında (IC50 = 411,3 ± 6,4 uM) 185,2 ± 3,4 ila 535,6 ± 5,5 μM arasında değişen farklı oranlarda α-amilaz inhibisyonu sergiledi; α-glukozidaz varlığında ise, pozitif kontrol akarboza kıyasla IC50 değerleri 205,0 ± 3,8 ila 803,2 ± 10,3 μM arasında değişim gösterdi (IC50 = 252,0 ± 4,8 μM). 10 farklı inhibitör molekülü arasında 4c'nin her iki durumda da mükemmel inhibe edici potansiyele sahip olduğu tespit edildi ve a-amilaz ve a-glukozidazın inhibisyon türü kinetik çalışmalarla değerlendirildi. Ayrıca SwissADME yazılımı kullanılarak 4c molekülünün fizikokimyasal ve farmakokinetik özellikleri hesaplandı. Mevcut araştırmanın sonuçları, tip II DM'nin tedavisi için umut vaat eden bir aday olarak 4c molekülünün potansiyelini desteklemektedir.

Keywords

α-Amylase α-glucosidase inhibition kinetics pharmacokinetics triazoles

References

  • [1] Lotter, N., Chivandi, E., Lembede, B.W., Ndhlala, A.R., Nyakudya, T.T., Erlwanger, K., (2019) Anti-oxidant activity, alpha-amylase inhibition and toxicity of leaf extracts of cultivated Rapanea melanophloeos (L.) Mez (cape beech), South African Journal of Botany, 126 261-264.
  • [2] Duhan, M., Kumar, P., Sindhu, J., Singh, R., Devi, M., Kumar, A., Kumar, R., Lal, S., (2021) Exploring biological efficacy of novel benzothiazole linked 2,5-disubstituted-1,3,4-oxadiazole hybrids as efficient α-amylase inhibitors: Synthesis, characterization, inhibition, molecular docking, molecular dynamics and Monte Carlo based QSAR studies, Computers in Biology and Medicine, 138 104876.
  • [3] Siahbalaei, R., Kavoosi, G., Noroozi, M., (2021) Protein nutritional quality, amino acid profile, anti-amylase and anti-glucosidase properties of microalgae: Inhibition and mechanisms of action through in vitro and in silico studies, LWT, 150 112023.
  • [4] Shamim, S., Khalid, M.K., Ullah, N., Sridevi, C., Wadood, A., Rehman, A.U., Ali, M., Salar, U., Alhowail, A., Taha, M., (2020) Synthesis and screening of (E)-3-(2-benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazine analogs as novel dual inhibitors of α-amylase and α-glucosidase, Bioorganic Chemistry, 101 103979.
  • [5] Toumi, A., Boudriga, S., Hamden, K., Sobeh, M., Cheurfa, M., Askri, M., Knorr, M., Carsten, S., Brieger, L., (2021) Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel α-amylase inhibitors, Bioorganic Chemistry, 106 104507.
  • [6] Kelishadi, R., (2007) Childhood overweight, obesity and the metabolic syndrome in developing countries, Epidemiologic Reviews, 29 62-76.
  • [7] Mehmood, H., Haroon, M., Akhtar, T., Woodward, S., Andleeb, H., (2022) Synthesis and molecular docking studies of 5-acetyl-2-(arylidenehydrazin-1-yl)-4-methyl-1,3-thiazoles as α-amylase inhibitors, Journal of Molecular Structure, 1250 131807.
  • [8] Aljabi, H.R., Pawelzik, E., (2022) Influence of weather conditions on the activity and properties of alpha-amylase in maize grains, Journal of Cereal Science, 103 103403.
  • [9] Hosseini, A., Ramezani, S., Tabibiazar, M., Mohammadi, M., Golchinfar, Z., Mahmoudzadeh, M., Jahanban-Esfahlan, A., (2022) Immobilization of α-amylase in ethylcellulose electrospun fibers using emulsion-electrospinning method, Carbohydrate Polymers, 278 118919.
  • [10] Proença, C., Freitas, M., Ribeiro, D., Oliveira, E.F.T., Sousa, J.L.C., Tomé, S.M., Ramos, M.J., Silva, A.M.S., Fernandes, P.A., Fernandes, E., (2017) α-Glucosidase inhibition by flavonoids: An in vitro and in silico structure–activity relationship study, Journal of Enzyme Inhibition and Medicinal Chemistry, 32 1216-1228.
  • [11] Hajlaoui, A., Laajimi, M., Znati, M., Jannet, H.B., Romdhane, A., (2021) Novel pyrano-triazolo-pyrimidine derivatives as anti α-amylase agents: Synthesis, molecular docking investigations and computational analysis, Journal of Molecular Structure, 1237 130346.
  • [12] Taha, M., Alrashedy, A.S., Almandil, N.B., Iqbal, N., Anouar, E.H., Nawaz, M., Uddin, N., Sridevi, C., Wadood, A., Rahim, F., Das, S., Venugopal, V., Nawaz, F., Khan, K.M., (2021) Synthesis of indole derivatives as diabetics II inhibitors and enzymatic kinetics study of α-glucosidase and α-amylase along with their in-silico study, International Journal of Biological Macromolecules, 190 301-318.
  • [13] Abbasi, I., Nadeem, H., Saeed, A., Kharl, H.A.A., Tahir, M.N., Naseer, M.M., (2021) Isatin-hydrazide conjugates as potent α-amylase and α-glucosidase inhibitors: Synthesis, structure and in vitro evaluations, Bioorganic Chemistry, 116 105385.
  • [14] Yeye,E.O., Khan, K.M., Chigurupati, S., Wadood, A., Rehman, A.U., Perveen, S., Maharajan, M.K., Shamim, S., Hameed, S., Aboaba, S.A., Taha, M., (2020) Syntheses, in vitro α-amylase and α-glucosidase dual inhibitory activities of 4-amino-1, 2, 4-triazole derivatives their molecular docking and kinetic studies, Bioorganic and Medicinal Chemistry, 28 115467-115475.
  • [15] Kumari, M., Tahlan, S., Narasimhan, B., Ramasamy, K., Lim, S.M., Shah, S.A.A., Mani, V., Kakkar, S. (2021) Synthesis and biological evaluation of heterocyclic 1,2,4-triazole scaffolds as promising pharmacological agents, BMC Chemistry, 15 1-16.
  • [16] Balba, M., El-Hady, N.A., Taha, N., Rezk, N., El Ashry el, S.H. (2011) Inhibition of α-glucosidase and α-amylase by diaryl derivatives of imidazole-thione and 1,2,4-triazole-thiol. European Journal of Medicinal Chemistry, 46 2596-601.
  • [17] Channar, P.A., Saeed, A., Larik, F.A., Sajid Rashid, S., Iqbal, Q., Rozi, M., Younis, S., Mahar, J. (2017) Design and synthesis of 2,6-di(substituted phenyl)thiazolo[3,2-b]-1,2,4-triazoles as a-glucosidase and a-amylase inhibitors, co-relative Pharmacokinetics and 3D QSAR and risk analysis, Biomedicine and Pharmacotherapy, 94 499-513.
  • [18] H. El Sayed, M.M., Farahat, L.F., Awad, M., Balbaa, H., Yusef, M.E., Badawy, M.N., Abd Al Moaty (2022) New 4-(arylidene) amino-1,2,4-traizole-5-thiol derivatives and their acyclo thioglycosides as α-glucosidase and α-amylase inhibitors: design, synthesis, and molecular modelling studies, Journal of Molecular Structure, 1259 132733.
  • [19] Bekircan, O., Baltaş, N., Menteşe, E., Gültekin, E., (2016) Synthesis of new fluorine-containing 1,2,4-triazole-5-on derivatives with their anti-urease, anti-xanthine oxidase and antioxidant activities. Revue Roumaine de Chimie, 61 733-746.
  • [20] Taha, M., Baharudin, M.S., Ismail, N.H., Imran, S., Khan, M.N., Rahim, F., Selvaraj, M., Chigurupati, S., Nawaz, M., Qureshi, F., Vijayabalan, S., (2018) Synthesis, α-amylase inhibitory potential and molecular docking study of indole derivatives, Bioorganic Chemistry, 80 36-42.
  • [21] Quan, N.V., Xuan, T.D., Tran, H.-D., Thuy, N.T.D., Trang, L.T., Huong, C.T., Andriana, Y., Tuyen, P.T., (2019) Antioxidant, α-amylase and α-glucosidase inhibitory activities and potential constituents of canarium tramdenum bark, Molecules, 24 605.
  • [22] Kicel, A., Owczarek, A., Kapusta, P., Kolodziejczyk-Czepas, J., Olszewska, M.A., (2020) Contribution of individual polyphenols to antioxidant activity of Cotoneaster bullatus and Cotoneaster zabelii leaves-structural relationships, synergy effects and application for quality control, Antioxidants, 9 69. [23] http://www.swissadme.ch/, (Accessed on 15 Nov 2022)
  • [24] Küҫüküzel, S.G., Ҫikla-Süzgün, P., (2015) Recent advances bioactive 1,2,4-triazole-3-thiones, European Journal of Medicinal Chemistry, 97 830-870.
  • [25] Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J., (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced Drug Delivery Reviews, 23 3-25.
  • [26] Al Azzam, K.M., Negim, E.S., Aboul-Enein, H.Y., (2022) ADME studies of TUG-770 (a GPR-40 inhibitor agonist) for the treatment of type 2 diabetes using SwissADME predictor: In silico study, Journal of Applied Pharmaceutical Science, 12 (04) 159-169.
  • [27] Cakmak, U., Oz Tuncay, F., (2022) Antityrosinase activities and in silico adme properties of fluorine-containing 1,2,4-triazole-5-on derivatives, Hacettepe Journal of Biology and Chemistry, 50 (4) 319-324.
  • [28] Sicak, Y., (2021) Design and antiproliferative and antioxidant activities of furan-based thiosemicarbazides and 1,2,4-triazoles: their structure-activity relationship and SwissADME predictions, Medicinal Chemistry Research, 30 1557-1568.
  • [29] Mahanthesh, M., Ranjith, D., Yaligar, R., Jyothi, R., Narappa, G., Ravi, M., (2020) Swiss ADME prediction of phytochemicals present in Butea monosperma (Lam.) Taub., Journal of Pharmacognnosy and Phytochemistry, 9 1799-1809.
  • [30] Martin, Y.C., (2015) A bioavailability score, Journal of Medicinal Chemistry, 48 3164-3170.

Year 2023, , 345 - 356, 31.08.2023

Fulya Öz Tuncay , Ümmühan Çakmak

https://doi.org/10.18185/erzifbed.1216717

Abstract

Keywords

α-Amylase α-glucosidase inhibition kinetics pharmacokinetics triazoles

References

  • [1] Lotter, N., Chivandi, E., Lembede, B.W., Ndhlala, A.R., Nyakudya, T.T., Erlwanger, K., (2019) Anti-oxidant activity, alpha-amylase inhibition and toxicity of leaf extracts of cultivated Rapanea melanophloeos (L.) Mez (cape beech), South African Journal of Botany, 126 261-264.
  • [2] Duhan, M., Kumar, P., Sindhu, J., Singh, R., Devi, M., Kumar, A., Kumar, R., Lal, S., (2021) Exploring biological efficacy of novel benzothiazole linked 2,5-disubstituted-1,3,4-oxadiazole hybrids as efficient α-amylase inhibitors: Synthesis, characterization, inhibition, molecular docking, molecular dynamics and Monte Carlo based QSAR studies, Computers in Biology and Medicine, 138 104876.
  • [3] Siahbalaei, R., Kavoosi, G., Noroozi, M., (2021) Protein nutritional quality, amino acid profile, anti-amylase and anti-glucosidase properties of microalgae: Inhibition and mechanisms of action through in vitro and in silico studies, LWT, 150 112023.
  • [4] Shamim, S., Khalid, M.K., Ullah, N., Sridevi, C., Wadood, A., Rehman, A.U., Ali, M., Salar, U., Alhowail, A., Taha, M., (2020) Synthesis and screening of (E)-3-(2-benzylidenehydrazinyl)-5,6-diphenyl-1,2,4-triazine analogs as novel dual inhibitors of α-amylase and α-glucosidase, Bioorganic Chemistry, 101 103979.
  • [5] Toumi, A., Boudriga, S., Hamden, K., Sobeh, M., Cheurfa, M., Askri, M., Knorr, M., Carsten, S., Brieger, L., (2021) Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel α-amylase inhibitors, Bioorganic Chemistry, 106 104507.
  • [6] Kelishadi, R., (2007) Childhood overweight, obesity and the metabolic syndrome in developing countries, Epidemiologic Reviews, 29 62-76.
  • [7] Mehmood, H., Haroon, M., Akhtar, T., Woodward, S., Andleeb, H., (2022) Synthesis and molecular docking studies of 5-acetyl-2-(arylidenehydrazin-1-yl)-4-methyl-1,3-thiazoles as α-amylase inhibitors, Journal of Molecular Structure, 1250 131807.
  • [8] Aljabi, H.R., Pawelzik, E., (2022) Influence of weather conditions on the activity and properties of alpha-amylase in maize grains, Journal of Cereal Science, 103 103403.
  • [9] Hosseini, A., Ramezani, S., Tabibiazar, M., Mohammadi, M., Golchinfar, Z., Mahmoudzadeh, M., Jahanban-Esfahlan, A., (2022) Immobilization of α-amylase in ethylcellulose electrospun fibers using emulsion-electrospinning method, Carbohydrate Polymers, 278 118919.
  • [10] Proença, C., Freitas, M., Ribeiro, D., Oliveira, E.F.T., Sousa, J.L.C., Tomé, S.M., Ramos, M.J., Silva, A.M.S., Fernandes, P.A., Fernandes, E., (2017) α-Glucosidase inhibition by flavonoids: An in vitro and in silico structure–activity relationship study, Journal of Enzyme Inhibition and Medicinal Chemistry, 32 1216-1228.
  • [11] Hajlaoui, A., Laajimi, M., Znati, M., Jannet, H.B., Romdhane, A., (2021) Novel pyrano-triazolo-pyrimidine derivatives as anti α-amylase agents: Synthesis, molecular docking investigations and computational analysis, Journal of Molecular Structure, 1237 130346.
  • [12] Taha, M., Alrashedy, A.S., Almandil, N.B., Iqbal, N., Anouar, E.H., Nawaz, M., Uddin, N., Sridevi, C., Wadood, A., Rahim, F., Das, S., Venugopal, V., Nawaz, F., Khan, K.M., (2021) Synthesis of indole derivatives as diabetics II inhibitors and enzymatic kinetics study of α-glucosidase and α-amylase along with their in-silico study, International Journal of Biological Macromolecules, 190 301-318.
  • [13] Abbasi, I., Nadeem, H., Saeed, A., Kharl, H.A.A., Tahir, M.N., Naseer, M.M., (2021) Isatin-hydrazide conjugates as potent α-amylase and α-glucosidase inhibitors: Synthesis, structure and in vitro evaluations, Bioorganic Chemistry, 116 105385.
  • [14] Yeye,E.O., Khan, K.M., Chigurupati, S., Wadood, A., Rehman, A.U., Perveen, S., Maharajan, M.K., Shamim, S., Hameed, S., Aboaba, S.A., Taha, M., (2020) Syntheses, in vitro α-amylase and α-glucosidase dual inhibitory activities of 4-amino-1, 2, 4-triazole derivatives their molecular docking and kinetic studies, Bioorganic and Medicinal Chemistry, 28 115467-115475.
  • [15] Kumari, M., Tahlan, S., Narasimhan, B., Ramasamy, K., Lim, S.M., Shah, S.A.A., Mani, V., Kakkar, S. (2021) Synthesis and biological evaluation of heterocyclic 1,2,4-triazole scaffolds as promising pharmacological agents, BMC Chemistry, 15 1-16.
  • [16] Balba, M., El-Hady, N.A., Taha, N., Rezk, N., El Ashry el, S.H. (2011) Inhibition of α-glucosidase and α-amylase by diaryl derivatives of imidazole-thione and 1,2,4-triazole-thiol. European Journal of Medicinal Chemistry, 46 2596-601.
  • [17] Channar, P.A., Saeed, A., Larik, F.A., Sajid Rashid, S., Iqbal, Q., Rozi, M., Younis, S., Mahar, J. (2017) Design and synthesis of 2,6-di(substituted phenyl)thiazolo[3,2-b]-1,2,4-triazoles as a-glucosidase and a-amylase inhibitors, co-relative Pharmacokinetics and 3D QSAR and risk analysis, Biomedicine and Pharmacotherapy, 94 499-513.
  • [18] H. El Sayed, M.M., Farahat, L.F., Awad, M., Balbaa, H., Yusef, M.E., Badawy, M.N., Abd Al Moaty (2022) New 4-(arylidene) amino-1,2,4-traizole-5-thiol derivatives and their acyclo thioglycosides as α-glucosidase and α-amylase inhibitors: design, synthesis, and molecular modelling studies, Journal of Molecular Structure, 1259 132733.
  • [19] Bekircan, O., Baltaş, N., Menteşe, E., Gültekin, E., (2016) Synthesis of new fluorine-containing 1,2,4-triazole-5-on derivatives with their anti-urease, anti-xanthine oxidase and antioxidant activities. Revue Roumaine de Chimie, 61 733-746.
  • [20] Taha, M., Baharudin, M.S., Ismail, N.H., Imran, S., Khan, M.N., Rahim, F., Selvaraj, M., Chigurupati, S., Nawaz, M., Qureshi, F., Vijayabalan, S., (2018) Synthesis, α-amylase inhibitory potential and molecular docking study of indole derivatives, Bioorganic Chemistry, 80 36-42.
  • [21] Quan, N.V., Xuan, T.D., Tran, H.-D., Thuy, N.T.D., Trang, L.T., Huong, C.T., Andriana, Y., Tuyen, P.T., (2019) Antioxidant, α-amylase and α-glucosidase inhibitory activities and potential constituents of canarium tramdenum bark, Molecules, 24 605.
  • [22] Kicel, A., Owczarek, A., Kapusta, P., Kolodziejczyk-Czepas, J., Olszewska, M.A., (2020) Contribution of individual polyphenols to antioxidant activity of Cotoneaster bullatus and Cotoneaster zabelii leaves-structural relationships, synergy effects and application for quality control, Antioxidants, 9 69. [23] http://www.swissadme.ch/, (Accessed on 15 Nov 2022)
  • [24] Küҫüküzel, S.G., Ҫikla-Süzgün, P., (2015) Recent advances bioactive 1,2,4-triazole-3-thiones, European Journal of Medicinal Chemistry, 97 830-870.
  • [25] Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J., (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced Drug Delivery Reviews, 23 3-25.
  • [26] Al Azzam, K.M., Negim, E.S., Aboul-Enein, H.Y., (2022) ADME studies of TUG-770 (a GPR-40 inhibitor agonist) for the treatment of type 2 diabetes using SwissADME predictor: In silico study, Journal of Applied Pharmaceutical Science, 12 (04) 159-169.
  • [27] Cakmak, U., Oz Tuncay, F., (2022) Antityrosinase activities and in silico adme properties of fluorine-containing 1,2,4-triazole-5-on derivatives, Hacettepe Journal of Biology and Chemistry, 50 (4) 319-324.
  • [28] Sicak, Y., (2021) Design and antiproliferative and antioxidant activities of furan-based thiosemicarbazides and 1,2,4-triazoles: their structure-activity relationship and SwissADME predictions, Medicinal Chemistry Research, 30 1557-1568.
  • [29] Mahanthesh, M., Ranjith, D., Yaligar, R., Jyothi, R., Narappa, G., Ravi, M., (2020) Swiss ADME prediction of phytochemicals present in Butea monosperma (Lam.) Taub., Journal of Pharmacognnosy and Phytochemistry, 9 1799-1809.
  • [30] Martin, Y.C., (2015) A bioavailability score, Journal of Medicinal Chemistry, 48 3164-3170.
There are 29 citations in total.

Details

Primary Language English
Subjects Engineering
Journal Section Makaleler
Authors

Fulya Öz Tuncay 0000-0003-3185-4933

Ümmühan Çakmak 0000-0001-8719-2436

Early Pub Date August 24, 2023
Publication Date August 31, 2023
Published in Issue Year 2023

Cite

APA Öz Tuncay, F., & Çakmak, Ü. (2023). Investigation of 1,2,4-Triazole Derivatives as Potantial Anti-Diabetic Agents: In vitro Enzyme Inhibition and In silico Pharmacokinetic Studies. Erzincan University Journal of Science and Technology, 16(2), 345-356. https://doi.org/10.18185/erzifbed.1216717