Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose reductase inhibition: Synthesis,biological screening and molecular docking study |
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| Institution: | 1. Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistan;2. Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan;3. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;4. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan;5. Institute of Chemistry, University of Punjab, Lahore, Pakistan;6. School of Fundamental Science, Universiti Malaysia Terengganu, 21030 Kuala Terengganu, Terengganu, Malaysia;1. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;2. Center for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;3. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;4. Institute of Chemistry, The University of the Punjab, Lahore 54000, Pakistan;1. Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China;2. Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, PR China;1. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;2. Centre for Advanced Drug Research, COMSATS University Islamabad, Abbottabad Campus, Abbottabad 22060, Pakistan;3. H.E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75720 Pakistan;4. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia;5. Département de microbiologie-infectiologie et d''immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada;6. Centre de Recherche du CHU de Québec – Université Laval, Québec, QC G1V 4G2, Canada;1. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;2. COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Karachi, Pakistan;4. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan;5. Department of Chemistry, Science and Arts College, Rabigh Campus, King Abdulaziz University, Jeddah, Saudi Arabia;6. School of Fundamental Science, Universiti Malaysia Terengganu, 21030 kuala Terengganu, Terengganu, Malaysia;1. Pharmaceutical Department, 251 General Air Force Hospital, 11525 Athens, Greece;2. Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54214 Thessaloniki, Greece;3. Department of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Athens, Greece;4. Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska Cesta 9, 841 04 Bratislava, Slovakia |
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| Abstract: | Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ± 0.04 and 0.19 ± 0.03 μM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ± 0.02 μM). |
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| Keywords: | Aldose reductase Benzoxazinone Thiosemicarbazones Molecular docking |
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