Synthesis, tyrosinase inhibition and transportation behavior of novel β-enamino thiosemicarbazide derivatives by human serum albumin

The novel β-enamino thiosemicarbazide derivatives (Z)-2-(3-(phenethylamino)-but-2-enoyl)-hydrazine carbothioamide (ETS1) and (Z)-N-methyl-2-(3-(phenethylamino)-but-2-enoyl)-hydrazine carbothioamide (ETS2) as well as their β-enamino ester precursor (Z)-ethyl-3-(phenethylamino)-but-2-enoate (ENE) were...

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Bibliographic Details
Published in:	Journal of molecular liquids Vol. 254; pp. 280 - 290
Main Authors:	Chaves, Otávio Augusto, de Lima Santos, Margareth Rose, de Oliveira, Márcia C.C., Sant'Anna, Carlos Mauricio R., Ferreira, Romulo Correia, Echevarria, Aurea, Netto-Ferreira, José Carlos
Format:	Journal Article
Language:	English
Published:	Elsevier B.V 15-03-2018
Subjects:	Human serum albumin Molecular docking Spectroscopy Synthesis Tyrosinase Human serum albumin Spectroscopy Synthesis Tyrosinase Molecular docking
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Summary:	The novel β-enamino thiosemicarbazide derivatives (Z)-2-(3-(phenethylamino)-but-2-enoyl)-hydrazine carbothioamide (ETS1) and (Z)-N-methyl-2-(3-(phenethylamino)-but-2-enoyl)-hydrazine carbothioamide (ETS2) as well as their β-enamino ester precursor (Z)-ethyl-3-(phenethylamino)-but-2-enoate (ENE) were synthesized and characterized. The synthetic compounds were tested against tyrosinase activity and ETS1 was the only compound showing high inhibition percentage (89%) through an uncompetitive inhibitory mechanism and with IC50 = 49 μM. Quantum chemical calculations showed a clear relationship between the HOMO and sulfur electrostatic values of ETS1 and its efficiency as tyrosinase inhibitor. Molecular docking results suggest that ETS1 can be better accommodated than ENE and ETS2 inside the active tyrosinase site. ETS1 is able to interact with the amino acid residues His-47, Asn-152, His-155 and Phe-156. The transportation behavior of human serum albumin (HSA) towards ETS1 was evaluated by spectroscopic methods (steady state, time-resolved, synchronous and 3D fluorescence, and circular dichroism), zeta potential and theoretical calculations (molecular docking). Studies on the interaction HSA:ETS1 revealed the existence of a moderate and spontaneous association between them in the ground state. Besides, it has been shown that hydrogen bonding played an important role in the transportation of ETS1. Competitive binding studies indicated Sudlow's site I as the main binding site for ETS1 and molecular docking results suggested that the amino acid residues Trp-214, Val-343, Asp-450, Leu-452, Ser-453, Leu-456 and Leu-480 can interact via hydrogen bond and hydrophobic forces with ETS1. Overall, the experimental parameters indicated that ETS1 could be effectively stored and carried by HSA. [Display omitted] •β-Enamino ester and two thiosemicarbazide derivatives were synthesized and tested on tyrosinase activity.•ETS1 is a potential tyrosinase inhibitor, with IC50 = 49 μM and uncompetitive inhibitory mechanism.•For the best tyrosinase inhibitor (ETS1) the interaction with human serum albumin was evaluated.•ETS1 showed a moderate binding and weak perturbation on the secondary structure of the albumin.•The main binding site is Sudlow's site I and the presence of ETS1 can change the polarity around Trp-214 residue.
ISSN:	0167-7322 1873-3166
DOI:	10.1016/j.molliq.2018.01.083