Design and synthesis of 5-(substituted benzylidene)thiazolidine-2,4-dione derivatives as novel tyrosinase inhibitors.
ABSTRACT In continuing our search for novel tyrosinase inhibitors, a series of 5-(substituted benzylidene)thiazolidine-2,4-diones were rationally designed and synthesized, and their inhibitory effects on mushroom tyrosinase activity were evaluated. Twelve target compounds 2a-2l were designed and synthesized based on the structural characteristics of N-phenylthiourea, a tyrosinase inhibitor, and tyrosine and L-DOPA, the natural substrates of tyrosinase. Among them, (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (2a) and (Z)-5-(3-hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (2f) exhibited much higher tyrosinase inhibitory activities, with IC(50) values of 13.36 and 9.87 μM, respectively, than kojic acid (IC(50) = 24.72 μM). Kinetic analysis of tyrosinase inhibition revealed that 2a and 2f are competitive inhibitors of mushroom tyrosinase. In addition, through prediction of the potato catechol oxidase tertiary structure and simulation of docking with compounds 2a and 2f using DOCK6, we found that these inhibitors likely bind to the active site of the enzyme. Docking simulation results suggested that 2a and 2f have high binding affinities with potato catechol oxidase. In addition, compounds 2a and 2f effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-melanocyte-stimulating hormone (α-MSH). These data strongly suggest that compounds 2a and 2f suppress the production of melanin via the inhibition of tyrosinase activity.
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ABSTRACT: Here a new class of hydroxy- or methoxy-substituted 5-benzylidene(thio)barbiturates were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that several compounds had more potent tyrosinase inhibitory activities than the widely used tyrosinase inhibitor kojic acid (IC50=18.25μM). In particular, 3',4'-dihydroxylated 1e was found to be the most potent inhibitor with IC50 value of 1.52μM. The inhibition mechanism analysis revealed that the potential compounds 1e and 2e exhibited such inhibitory effects on tyrosinase by acting as the irreversible inhibitors. Structure-activity relationships' (SARs) analysis also suggested that further development of such compounds might be of interest.Bioorganic & Medicinal Chemistry 05/2014; · 2.95 Impact Factor
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ABSTRACT: Urea transporter (UT) proteins, including UT-A in kidney tubule epithelia and UT-B in vasa recta microvessels, facilitate urinary concentrating function. A screen for UT-A inhibitors was developed in MDCK cells expressing UT-A1, water channel aquaporin-1, and YFP-H148Q/V163S. An inwardly directed urea gradient produces cell shrinking followed by UT-A1-dependent swelling, which was monitored by YFP-H148Q/V163S fluorescence. Screening of ∼90,000 synthetic small molecules yielded four classes of UT-A1 inhibitors with low micromolar half-maximal inhibitory concentration that fully and reversibly inhibited urea transport by a noncompetitive mechanism. Structure-activity analysis of >400 analogs revealed UT-A1-selective and UT-A1/UT-B nonselective inhibitors. Docking computations based on homology models of UT-A1 suggested inhibitor binding sites. UT-A inhibitors may be useful as diuretics ("urearetics") with a mechanism of action that may be effective in fluid-retaining conditions in which conventional salt transport-blocking diuretics have limited efficacy.Chemistry & biology 09/2013; · 6.52 Impact Factor
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ABSTRACT: The efficient synthesis of sixteen 5-arylidene-2,4-thiazolidinediones by aldol condensation reaction of 2,4-thiazolidinedione, mono- and di-substituted arenealdehydes and KOH using ultrasound irradiation is reported. The desired compounds were obtained in a few min (10-30min) with moderate to good yields (25-81%).Ultrasonics Sonochemistry 04/2014; · 3.82 Impact Factor