Development of new HO-1 inhibitors by a thorough scaffold-hopping analysis |
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| Affiliation: | 1. Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy;2. Department of Chemical Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy;1. Department of Chemistry, Karadeniz Technical University, Trabzon, Turkey;2. Department of Biology, Karadeniz Technical University, Trabzon, Turkey;3. Department of Biotechnology, School of Bio-Sciences and Technology, VIT, Vellore 632014, India;1. Department of Chemistry, Abdul Wali Khan University, Mardan 23200, Pakistan;2. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;3. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam 31441, Saudi Arabia;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah, Malaysia;5. Department of Biochemistry, Computational Medicinal Chemistry Laboratory, UCSS, Abdul Wali Khan University, Mardan, Pakistan;6. Department of Pharmacology, Faculty of Medicine, Cyberjaya University College of Medical Sciences, CUCMS, Cyberjaya 63000, Malaysia;7. PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan;1. Institute of Animal Nutrition and Feed, Inner Mongolia Academy of Agriculture and Animal Husbandry Sciences, Hohhot 010031, P. R. China;2. Department of Animal Sciences, University of Illinois, Urbana 61801;3. Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801;1. Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy;2. Department of Drug Sciences, Section of Biochemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy;3. Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand;4. Department of Oncology, Faculty of Medicine, Suez Canal University, Egypt;1. School of Life Science, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116081, China;2. College of Pharmacy, College (Institute) of Integrative Medicine, The National & Local Joint Engineering Research Center for Drug Development of Neurodegenerative Disease, Dalian Medical University, Dalian 116044, China;3. School of Life Science and Biopharmaceutics, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China |
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| Abstract: | HO-1 inhibition is considered a valuable anticancer approach. In fact, up-regulation of HO-1 had been repeatedly reported in many types of human malignancies, and in these clinical cases, poor outcomes are reported. To identify novel HO-1 inhibitors suitable for drug development, a scaffold-hopping strategy calculation was utilized to design novel derivatives. Different parts of the selected molecule were analyzed and the different series of novel compounds were virtually evaluated. The calculation for the linker moiety of the classical HO-1 inhibitors structure led us to compounds 5 and 6. A synthetic pathway for the two molecules was designed and the compounds were synthesized. The biological activity revealed an HO-1 inhibition of 0.9 and 54 μM for molecules 5 and 6 respectively. This study suggested that our scaffold-hopping approach was successful and these results are ongoing for further development. |
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| Keywords: | Heme oxygenase-1 Scaffold-hopping HO-1 imidazole inhibitors |
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