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Bioorg Chem. 2019 Oct;91:103116. doi: 10.1016/j.bioorg.2019.103116. Epub 2019 Jul 11.

N-substituted noscapine derivatives as new antiprotozoal agents: Synthesis, antiparasitic activity and molecular docking study.

Author information

1
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, 1983963113 Tehran, Iran.
2
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, G. C., Evin, 1983963113 Tehran, Iran. Electronic address: p-salehi@sbu.ac.ir.
3
Swiss Tropical and Public Health Institute, Basel, Switzerland; 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.

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.

KEYWORDS:

Induced fit docking; Molecular docking; Noscapine; Plasmodium falciparum; Strecker reaction; Trypanosoma brucei

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