Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi.

Autor: Silva-Júnior EF; Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil., Silva EPS; Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil., França PHB; Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil., Silva JPN; Cell Biology Laboratory, Federal University of Alagoas, Maceio, Brazil., Barreto EO; Cell Biology Laboratory, Federal University of Alagoas, Maceio, Brazil., Silva EB; Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil., Ferreira RS; Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil., Gatto CC; Inorganic Synthesis and Crystallography Laboratory, Institute of Chemistry, University of Brasilia, Federal District, Brazil., Moreira DRM; Tissue Engineering and Immunopharmacology Laboratory, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil., Siqueira-Neto JL; Skaggs School of Pharmacy and Pharmaceutical Sciences, California, San Diego La Jolla, United States., Mendonça-Júnior FJB; Laboratory of Drug Synthesis and Delivery, Biological Sciences Department, State University of Paraiba, Campus V, João Pessoa, Brazil., Lima MCA; Drug Design and Synthesis Laboratory, National Science and Technology Institute for Pharmaceutical Innovation, Federal University of Pernambuco, Recife, Brazil., Bortoluzzi JH; Catalysis and Chemical Reactivity Group (GCaR), Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio, Brazil., Scotti MT; Laboratory of Drug Synthesis and Delivery, Biological Sciences Department, State University of Paraiba, Campus V, João Pessoa, Brazil., Scotti L; Laboratory of Drug Synthesis and Delivery, Biological Sciences Department, State University of Paraiba, Campus V, João Pessoa, Brazil., Meneghetti MR; Catalysis and Chemical Reactivity Group (GCaR), Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio, Brazil., Aquino TM; Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil. Electronic address: thiago.aquino@iqb.ufal.br., Araújo-Júnior JX; Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2016 Sep 15; Vol. 24 (18), pp. 4228-4240. Date of Electronic Publication: 2016 Jul 20.
DOI: 10.1016/j.bmc.2016.07.013
Abstrakt: In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03μM. The 8c derivative showed the highest potency against cruzain (IC50=2.4μM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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