1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen-activated protein kinase inhibitory activity |
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| Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, P.O. Box 11562, Cairo, Egypt;2. National Organization for Drug Control And Research (NODCAR), Giza, Egypt;3. Università degli Studi di Firenze, Department NEUROFARBA, Pharmaceutical and Nutraceutical Chemistry Section, University of Florence, via Ugo Schiff 6, I-50019 Sesto Fiorentino, Firenze, Italy;1. DAIS, Alkharj 11942, P.O. Box 217, Saudi Arabia;2. Colorectal Research Chair, Department of Surgery, King Khalid University Hospital, King Saud University College of Medicine, Riyadh 11451, Saudi Arabia;3. Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt;4. Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Alkharj, 11942, Saudi Arabia;5. Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt;6. Pharmaceutical Research Department, Center of Excellence for Advanced Sciences, National Research Centre, P.O. Box 12622, Cairo, Egypt;7. Università degli Studi di Firenze, NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;8. Chemistry Department, Faculty of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt;2. Department of Therapeutical Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt;3. Pharmaceutical Sciences Dept., Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, TX, USA;4. Department of Pharmacology, Faculty of Pharmacy, Al-Azhar University, Egypt;5. Inaya Medical College, Riyadh, Saudi Arabia;1. Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan 475004, China;2. State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, China |
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| Abstract: | Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (CA) enzymes aiming to explore potential dual inhibitors. Results revealed that compounds 3c, 3g, 3h, 4a, 6c and 6d were the most effective derivatives against p38αMAPK (IC50 = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 μM, respectively) compared to sorafenib (IC50 = 1.58 μM) as standard drug. On the other hand, compound 4a revealed the best inhibitory activity against all the tested carbonic anhydrase isoforms CA I, II, IV and IX with Ki values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with Ki values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38αMAPK/CA inhibitor. |
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| Keywords: | Imidazoline-5-ones Sulphonamide derivatives p38αMAPK inhibitors Carbonic anhydrase inhibitors |
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