title: Design, synthesis, molecular docking and biological evaluation of thiophen-2-iminothiazolidine derivatives for use against Trypanosoma cruzi.
abstract: 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.
authors.affiliation: Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil.
authors.forename: E F
authors.initials: EF
authors.lastname: Silva-Júnior
authors.affiliation: Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil.
authors.forename: E P S
authors.initials: EPS
authors.lastname: Silva
authors.affiliation: Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil.
authors.forename: P H B
authors.initials: PHB
authors.lastname: França
authors.affiliation: Cell Biology Laboratory, Federal University of Alagoas, Maceio, Brazil.
authors.forename: J P N
authors.initials: JPN
authors.lastname: Silva
authors.affiliation: Cell Biology Laboratory, Federal University of Alagoas, Maceio, Brazil.
authors.forename: E O
authors.initials: EO
authors.lastname: Barreto
authors.affiliation: Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: E B
authors.initials: EB
authors.lastname: Silva
authors.affiliation: Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: R S
authors.initials: RS
authors.lastname: Ferreira
authors.affiliation: Inorganic Synthesis and Crystallography Laboratory, Institute of Chemistry, University of Brasilia, Federal District, Brazil.
authors.forename: C C
authors.initials: CC
authors.lastname: Gatto
authors.affiliation: Tissue Engineering and Immunopharmacology Laboratory, Oswaldo Cruz Foundation, Salvador, Bahia, Brazil.
authors.forename: D R M
authors.initials: DRM
authors.lastname: Moreira
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, California, San Diego La Jolla, United States.
authors.forename: J L
authors.initials: JL
authors.lastname: Siqueira-Neto
authors.affiliation: Laboratory of Drug Synthesis and Delivery, Biological Sciences Department, State University of Paraiba, Campus V, João Pessoa, Brazil.
authors.forename: F J B
authors.initials: FJB
authors.lastname: Mendonça-Júnior
authors.affiliation: Drug Design and Synthesis Laboratory, National Science and Technology Institute for Pharmaceutical Innovation, Federal University of Pernambuco, Recife, Brazil.
authors.forename: M C A
authors.initials: MCA
authors.lastname: Lima
authors.affiliation: Catalysis and Chemical Reactivity Group (GCaR), Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio, Brazil.
authors.forename: J H
authors.initials: JH
authors.lastname: Bortoluzzi
authors.affiliation: Laboratory of Drug Synthesis and Delivery, Biological Sciences Department, State University of Paraiba, Campus V, João Pessoa, Brazil.
authors.forename: M T
authors.initials: MT
authors.lastname: Scotti
authors.affiliation: Laboratory of Drug Synthesis and Delivery, Biological Sciences Department, State University of Paraiba, Campus V, João Pessoa, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Scotti
authors.affiliation: Catalysis and Chemical Reactivity Group (GCaR), Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceio, Brazil.
authors.forename: M R
authors.initials: MR
authors.lastname: Meneghetti
authors.affiliation: Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil. Electronic address: thiago.aquino@iqb.ufal.br.
authors.forename: T M
authors.initials: TM
authors.lastname: Aquino
authors.affiliation: Medicinal Chemistry Laboratory, Pharmacy and Nursing School, Federal University of Alagoas, Maceio, Brazil.
authors.forename: J X
authors.initials: JX
authors.lastname: Araújo-Júnior
mesh_terms: D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D005998:Glycine / Q000737:chemistry; D051379:Mice; D062105:Molecular Docking Simulation; D017830:Octoxynol; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors; D053778:Thiazolidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D013890:Thiourea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D015800:Protozoan Proteins; D053778:Thiazolidines; D013876:Thiophenes; D014344:Trypanocidal Agents; C000621437:ethyl 2-((3-allyl-4-phenylthiazol-2(3H)-ylidene)amino)-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylate; D017830:Octoxynol; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi; D013890:Thiourea; D005998:Glycine
keywords: Chagas disease; Docking; T. cruzi; Thiazolidine; Thiophene