N-substituted noscapine derivatives as new antiprotozoal agents: Synthesis,antiparasitic activity and molecular docking study |
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| Institution: | 1. Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, 1983963113 Tehran, Iran;2. Swiss Tropical and Public Health Institute, Basel, Switzerland;3. University of Basel, Basel, Switzerland;4. Department of Chemistry, Shahid Beheshti University, G. C., Evin, 1983963113 Tehran, Iran;5. National and Medical Sciences Research Center, University of Nizwa, P.O. Box 33, Birkat Al-Mauz, Nizwa 611, Oman;1. Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), CNRS, Univ Paris Sud, Université Paris-Saclay, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France;2. Chimiothérapie antiparasitaire, UMR 8076 BioCis, CNRS, Univ Paris Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290 Châtenay-Malabry, France;3. Center of Biochemistry of Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany;1. Faculty of Science, Ontario Tech University, 2000 Simcoe St North, Oshawa, Ontario L1G 0C5, Canada;2. Purdue Pharma Canada, 575 Granite Court, Pickering, Ontario L1W 3W8, Canada;1. Department of Chemistry and Biochemistry, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA;2. Department of Biology, Georgia State University, Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA;3. Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai 400076, India;4. Advinus Therapeutics Limited, Bangalore, Karnataka, India;5. Department of Chemistry, University of Delhi, India;6. Special Centre of Molecular Medicine, Jawaharlal Nehru University, Delhi, India;1. Department of Chemistry, Faculty of Science, The University of Zanjan, Postal Code 45371-38791, Zanjan, Iran;2. Department of Chemistry, Payame Noor University (PNU), P.O. Box 19395-4697, Tehran, Iran;1. Institute of Biochemistry and Genetics Russian Academy of Science (IBG RAS), Ufa Scientific Centre, Ufa 450054, Russia;2. Department of Chemistry and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119992, Russia;3. Bashkir State Medical University, Ministry of Health of Russia, Ufa 450008, Russia;4. Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo 143026, Russia;5. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 142290, Russia;6. InterBioScreen ltd, Chernogolovka 142432, Russia;7. The Federal State Unitary Enterprise Dukhov Automatics Research Institute, Moscow 127055, Russia;8. Department of Chemistry, Lomonosov Moscow State University, Moscow 119234, Russia |
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| Abstract: | Novel N-substituted noscapine derivatives were synthesized by a three-component Strecker reaction of cyclic ether of N-nornoscapine with varied aldehydes, in the presence of cyanide ion. Moreover, the corresponding amides were synthesized by the oxidation of cyanide moieties in good yields. The in vitro antiprotozoal activity of the products was also investigated. Interestingly, some analogues did put on display promising antiparasitic activity against Trypanosoma brucei rhodesiense with IC50 values between 2.5 and 10.0 µM and selectivity index (SI) ranged from 0.8 to 13.2. Eight compounds exhibited activity against Plasmodium falciparum K1 strain with IC50 ranging 1.7–6.4 µM, and SI values between 2.8 and 10.5 against L6 rat myoblast cell lines. Molecular docking was carried out on trypanothione reductase (TbTR, PDB ID: 2WOW) and UDP-galactose 4′ epimerase (TbUDPGE PDB: 1GY8) as targets for studying the envisaged mechanism of action. Compounds 6j2 and 6b2 displayed excellent docking scores with −8.59 and −8.86 kcal/mol for TbTR and TbUDPGE, respectively. |
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| Keywords: | Noscapine Strecker reaction Molecular docking Induced fit docking |
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