Design, Synthesis, and Structural Characterization of Thioflavones and Thioflavonols as Potential Tyrosinase Inhibitors: In Vitro and In Silico Studies.

To find new potential tyrosinase inhibitors, a diverse range of 2-arylchromone-4-thione derivatives (2a-2p) were designed and synthesized by employing a multistep strategy, and the newly synthesized compounds, for the first time, were screened in vitro for their tyrosinase inhibitory activity. In this context, the newly synthesized compounds (2a-2p) were characterized using a combination of several spectroscopic techniques including Fourier transform infrared, UV-vis, 1H NMR, and 13C NMR spectroscopies and electron ionization-mass spectrometry. All the target compounds were potent against tyrosinase as compared to the standard inhibitor kojic acid (half-maximal inhibitory concentration (IC50) = 12.6 ± 0.6 µM). The compounds (2a-2p) produced IC50 values in the range from 1.12 ± 0.04 to 5.68 ± 0.13 µM. Among the synthesized 4-thioflavones and 4-thioflavonols, the compound 2n exhibited excellent tyrosinase inhibitory activity with the lowest IC50 of 1.12 ± 0.04 µM that could be recommended as potential lead candidates to cure tyrosinase-mediated hyperpigmentation in the future. A kinetic study of compound 2n revealed that compound 2n inhibited tyrosinase in a competitive mode. Furthermore, the nontoxic performance of the most beneficial compounds ranging from 1 to 25 g/mL was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test method for A375 human melanoma cells for the highly efficient target compounds (2m, 2n, 2o, and 2p). Moreover, a molecular modeling study was performed against tyrosinase enzyme (2Y9X) to check the binding interactions of the synthesized compounds (2a-2p) against the target protein. Furthermore, quantitative structure-activity relationship studies were conducted based on an antityrosinase assay. The value of the correlation coefficient (R 2) 0.9997 shows that there was a good correlation between (2a-2p) structures and selected properties. The geometry optimization of all complexes was performed by using Gaussian 09. Additionally, a drug-likeness research was used to establish the potent analogues' positive action as a new antityrosinase agent (2n, 2o, and 2p).

Biological potential of copper complexes: a review.

This review comprises the inorganic compounds particularly metal coordinated complexes, as drugs play a relevant role in medicinal chemistry. It has been observed that copper complexes are potentially attractive as medicinal importance. In this review, the most remarkable achievements of copper complexes undertaken over the past few decades as antimicrobial, antioxidant, enzyme inhibition activity, and anti-cancer agents are discussed. This work was motivated by the observation that no comprehensive surveys of the diversity of biological activities of copper complexes were available in the literature.

Structure-based designing and synthesis of 2-phenylchromone derivatives as potent tyrosinase inhibitors: In vitro and in silico studies.

The present study describes the discovery of novel inhibitors of mushroom tyrosinase enzyme. For that purpose, a series of varyingly substituted 2-phenylchromone analogues 1-28 were synthesized and characterized in detail by various spectroscopic techniques (UV-Vis, FTIR, 1H NMR, 13C NMR) and mass spectrometry. All the derivatives (1-28) were screened in vitro for their inhibitory potential against mushroom tyrosinase enzyme. Interestingly, all the synthetic compounds displayed good to excellent inhibitory activity with IC50 values ranging from 0.093 ± 0.003 µg/ml to 23.58 ± 0.94 µg/ml for brominated 3-hydroxy-2-phenylchromones and 0.22 ± 0.017 µg/ml to 22.22 ± 1.1 µg/ml for brominated 2-phenylchromones against tyrosinase in comparison to the standard kojic acid (IC50 = 1.79 ± 0.64 µg/ml). Remarkably, the bromine atoms attached on ring A attribute to increases the inhibitory potential of 2-phenylchromone moiety and anti-tyrosinase assay demonstrated that compound 10 (IC50 = 0.093 ± 0.003 µg/ml) was found almost nineteenfold, 11 (IC50 = 0.126 ± 0.015 µg/ml) fourteenfold and 26 (IC50 = 0.22 ± 0.017 µg/ml) about eightfold more active than the positive control. Notably, among the already literature reported tyrosinase inhibitors, these analogues have been found the most active inhibitors of mushroom tyrosinase with the lowest possible IC50 values. To design and develop novel tyrosinase inhibitors using 2-phenylchromone as a structural motif in the future, a limited structure-activity relationship was established. Moreover, in silico studies were carried out to rationalize the binding mode of interactions of all the targeted compounds (1-28) with the active site of enzymes. The experimental and theoretical results are in parallel with one another. In addition, molecular description was performed with the drug-likeness and bioactivity scores. Computational analysis predicted that few compounds are in a linear correlation with Lipinski's RO5 indicating superb drug-likeness and bioactivity score for drug targets.

2-Benzylidenebenzofuran-3(2H)-ones as a new class of alkaline phosphatase inhibitors: synthesis, SAR analysis, enzyme inhibitory kinetics and computational studies.

The excelling role of organic chemistry in the medicinal field continues to be one of the main leads in the drug development process. Particularly, this industry requires organic chemists to discover small molecular structures with powerful pharmacological potential. Herein, a diverse range of chalcone (1-11) and aurone (12-22) derivatives was designed and synthesized and for the first time, and both motifs were evaluated as potent inhibitors of alkaline phosphatases (APs). Structural identification of the target compounds (1-22) was accomplished using common spectroscopic techniques. The effect of the nature and position of the substituent was interestingly observed and justified based on the detailed structure-activity relationship (SAR) of the target compounds against AP. It was concluded from the obtained results that all the newly synthesized compounds exhibit high inhibitory potential against the AP enzyme. Among them, compounds 12 (IC50 = 2.163 ± 0.048 µM), 15 (IC50 = 2.146 ± 0.056 µM), 16 (IC50 = 2.132 ± 0.034 µM), 18 (IC50 = 1.154 ± 0.043 µM), 20 (IC50 = 1.055 ± 0.029 µM) and 21 (IC50 = 2.326 ± 0.059 µM) exhibited excellent inhibitory activity against AP, and even better/more active than KH2PO4 (standard) (IC50 = 2.80 ± 0.065 µM). Remarkably, compound 20 (IC50 = 1.055 ± 0.029 µM) may serve as a lead structure to design more potent inhibitors of alkaline phosphatase. To the best of our knowledge, these synthetic compounds are the most potent AP inhibitors with minimum IC50 values reported to date. Furthermore, a molecular modeling study was performed against the AP enzyme (1EW2) to check the binding interaction of the synthesized compounds 1-22 against the target protein. The Lineweaver-Burk plots demonstrated that most potential derivative 20 inhibited h-IAP via a non-competitive pathway. Finally, molecular dynamic (MD) simulations were performed to evaluate the dynamic behavior, stability of the protein-ligand complex, and binding affinity of the compounds, resulting in the identification of compound 20 as a potential inhibitor of AP. Accordingly, excellent correlation was observed between the experimental and theoretical results. The pharmacological studies revealed that the synthesized analogs 1-22 obey Lipinski's rule. The assessment of the ADMET parameters showed that these compounds possess considerable lead-like characteristics with low toxicity and can serve as templates in drug design.

Exploring 3-hydroxyflavone scaffolds as mushroom tyrosinase inhibitors: synthesis, X-ray crystallography, antimicrobial, fluorescence behaviour, structure-activity relationship and molecular modelling studies.

To explore new scaffolds as tyrosinase enzyme inhibitors remain an interesting goal in the drug discovery and development. In due course and our approach to synthesize bioactive compounds, a series of varyingly substituted 3-hydroxyflavone derivatives (1-23) were synthesized in one-pot reaction and screened for in vitro against mushroom tyrosinase enzyme. The structures of newly synthesized compounds were unambiguously corroborated by usual spectroscopic techniques (FTIR, UV-Vis, 1H-, 13C-NMR) and mass spectrometry (EI-MS). The structure of compound 15 was also characterized by X-ray diffraction analysis. Furthermore, the synthesized compounds (1-23) were evaluated for their antimicrobial potential. Biological studies exhibit pretty good activity against most of the bacterial-fungal strains and their activity is comparable to those of commercially available antibiotics i.e. Cefixime and Clotrimazole. Amongst the series, the compounds 2, 4, 5, 6, 7, 10, 11, 14 and 22 exhibited excellent inhibitory activity against tyrosinase, even better than standard compound. Remarkably, the compound 2 (IC50 = 0.280 ± 0.010 µg/ml) was found almost sixfold and derivative 5 (IC50 = 0.230 ± 0.020 µg/ml) about sevenfold more active as compared to standard Kojic acid (IC50 =1.79 ± 0.6 µg/ml). Moreover, these synthetic compounds (1-23) displayed good to moderate activities against tested bacterial and fungal strains. Their emission behavior was also investigated in order to know their potential as fluorescent probes. The molecular modelling simulations were also performed to explore their binding interactions with active sites of the tyrosinase enzyme. Limited structure-activity relationship was established to design and develop new tyrosinase inhibitors by employing 2-arylchromone as a structural core in the future. Communicated by Ramaswamy H. Sarma.

Flavonols and 4-thioflavonols as potential acetylcholinesterase and butyrylcholinesterase inhibitors: Synthesis, structure-activity relationship and molecular docking studies.

To explore new scaffolds for the treat of Alzheimer's disease appears to be an inspiring goal. In this context, a series of varyingly substituted flavonols and 4-thioflavonols have been designed and synthesized efficiently. All the newly synthesized compounds were characterized unambiguously by common spectroscopic techniques (IR, 1H-, 13C NMR) and mass spectrometry (EI-MS). All the derivatives (1-24) were evaluated in vitro for their inhibitory potential against cholinesterase enzymes. The results exhibited that these derivatives were potent selective inhibitors of acetylcholinesterase (AChE), except the compound 11 which was selective inhibitor of butyrylcholinesterase (BChE), with varying degree of IC50 values. Remarkably, the compounds 20 and 23 have been found the most potent almost dual inhibitors of AChE and BChE amongst the series with IC50 values even less than the standard drug. The experimental results in silico were further validated by molecular docking studies in order to find their binding modes with the active pockets of AChE and BChE enzymes.