5-Oxo-dihydropyranopyran derivatives as anti-proliferative agents; synthesis, biological evaluation, molecular docking, MD simulation, DFT, and in-silico pharmacokinetic studies.

A series of ethyl 2-amino-7-methyl-5-oxo-4-phenyl-4,5-dihydropyrano[4,3-b]pyran-3-carboxylate derivatives (4a-j) bearing different substitutions on the C4-phenyl ring was synthesized. The anti-proliferative activity of all the synthesized compounds was assessed against two human cancer-cell lines, including SW-480 and MCF-7, by using MTT method. Derivatives 4g, 4i, and 4j, possessing 4-NO2, 4-Cl, and 3,4,5-(OCH3)3 substitutions, were found to be the most potent compounds against both cell lines. The obtained IC50 values for 4g, 4i, and 4j were 34.6, 35.9, and 38.6 µM against SW-480 cells and 42.6, 34.2, and 26.6 µM against MCF-7 cells, respectively. Evaluation of the free radical scavenging potential of the compounds against DPPH radicals showed the highest result for compound 4j with an EC50 value of 580 µM. Molecular docking studies revealed the compounds were well accommodated within the binding site of cyclin-dependent kinase-2 (CDK2) with binding energies comparable to those of DTQ (the co-crystallized inhibitor) and BMS-265246 (a well-known CDK2 inhibitor). Molecular dynamics simulation studies confirmed the interactions and stability of the 4g-CDK2 complex. All derivatives, except 4g, were predicted to comply with the drug-likeness rules. Compound 4j may be proposed as an anti-cancer lead candidate for further studies due to the promising findings from in-silico pharmacokinetic studies, such as high GI absorption, not being a P-gp substrate, and being a P-gp inhibitor. Density functional theory (DFT) analysis was performed at the B3LYP/6-311++G (d,p) level of theory to examine the reactivity or stability descriptors of 4d, 4g, 4i, and 4j derivatives. The highest value of energy gap between HOMO and LUMO and thermochemical parameters were obtained for 4i and 4j.

Trinitroglycerin-loaded chitosan nanogels: Shedding light on cytotoxicity, antioxidativity, and antibacterial activities.

AIM AND BACKGROUND: Trinitroglycerin (TNG) is a remarkable NO-releasing agent. Here, we synthesized TNG based on chitosan Nanogels (Ngs) for ameliorating complications associated with high-dose TNG administration. METHOD: TNG-Ngs fabricated through ionic-gelation technique. Fourier-transformed infrared (FT-IR), zeta-potential, dynamic light scattering (DLS), and electron microscopy techniques evaluated the physicochemical properties of TNG-Ngs. MTT was used to assess the biocompatibility of TNG-Ngs, as the antioxidative properties were determined via lactate dehydrogenase (LDH), reactive oxygen species (ROS), and lipid peroxide (LPO) assays. The antibacterial activity was evaluated against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE). RESULTS: Physicochemical characterization reveals that TNG-Ngs with size diameter (96.2 ± 29 nm), polydispersity index (PDI, 0.732), and negative zeta potential (-1.1 mv) were fabricated. The encapsulation efficacy (EE) and loading capacity (LC) were obtained at 71.1 % and 2.3 %, respectively, with no considerable effect on particle size and morphology. The cytotoxicity assay demonstrated that HepG2 cells exposed to TNG-Ngs showed relative cell viability (RCV) of >80 % for 70 µg/ml compared to the TNG-free drug at the same concentration (P < 0.05). TNG-Ngs showed significant differences with the TNG-free drug for LDH, LPO, and ROS formation at the same concentration (P < 0.001). The antibacterial activity of the TNG-Ngs against S. aureus, E. coli, VRE, and MRSA was higher than the TNG-free drug and Ngs (P < 0.05). CONCLUSION: TNG-Ngs with enhanced antibacterial and antioxidative activity and no obvious cytotoxicity might be afforded as novel nanoformulation for promoting NO-dependent diseases.

Synthesis and cytotoxic activity evaluation of novel imidazopyridine carbohydrazide derivatives.

Two series of novel imidazo[1,2-a]pyridine-2-carbohydrazide derivatives have been designed, synthesized, and evaluated for cytotoxic activity. Target compounds were designed in two series: aryl hydrazone derivatives that were devoid of triazole moiety (7a-e) and aryl triazole bearing group (11a-e). In vitro cytotoxicity screening was carried out using MTT assay against three human cancer cells including breast cancer (MCF-7), colon cancer (HT-29), and leukemia (K562) cell lines as well as a non-cancer cell line (Vero). Compound 7d bearing 4-bromophenyl pendant from aryl hydrazone series exhibited the highest cytotoxic potential with IC50 values of 22.6 µM and 13.4 µM against MCF-7 and HT-29 cells, respectively, while it was not toxic towards non-cancer cells up to the concentration of 100 µM. Cell cycle analysis revealed that 7d increased the number of MCF-7 cells in the G0/G1 phase and also induced apoptosis in these cells as revealed by Hoechst 33,258 staining. The molecular mechanism contributing to the anti-proliferative effect of the most potent compound was investigated in silico using Super Pred software and introduced PDGFRA as a plausible target for 7d. Molecular docking and molecular dynamic studies demonstrated Lys627 and Asp836 as key residues interacting with the active compound. Overall, 7d could serve as a suitable candidate for further modifications as a lead anticancer structure.

Synthesis of 3-hydroxypyridin-4-one derivatives bearing benzyl hydrazide substitutions towards anti-tyrosinase and free radical scavenging activities.

Tyrosinase is a vital enzyme in the biosynthesis of melanin, which has a significant role in skin protection. Due to the importance of the tyrosinase enzyme in the cosmetics and health industries, studies to design new tyrosinase inhibitors have been expanded. In this study, the design and synthesis of 3-dihydroxypyridine-4-one derivatives containing benzo hydrazide groups with different substitutions were carried out, and their antioxidant and anti-tyrosinase activities were also evaluated. The proposed compounds showed tyrosinase inhibitory effects (IC50) in the 25.29 to 64.13 µM range. Among all compounds, 6i showed potent anti-tyrosinase activity with an IC50 = 25.29 µM. Also, the antioxidant activity of derivatives by using DPPH radical scavenging indicates an EC50 value between 0.039 and 0.389 mM. Molecular docking studies were performed to reveal the position and interactions of 6i as the most potent inhibitor within the tyrosinase active site. The results showed that 6i binds well to the proposed binding site and forms a stable complex with the target protein. Furthermore, the physicochemical profiles of the tested compounds indicated drug-like and bioavailability properties. The kinetic assay revealed that 6i acts as a competitive inhibitor. Also, for the estimation of the reactivity of the best compound (6i), the density functional theory (DFT) was performed at the B3LYP/6-31+G**.

Design, synthesis, in silico ADME, DFT, molecular dynamics simulation, anti-tyrosinase, and antioxidant activity of some of the 3-hydroxypyridin-4-one hybrids in combination with acylhydrazone derivatives.

Tyrosinase is the rate-limiting enzyme in synthesizing melanin. Melanin is responsible for changing the color of fruits and vegetables and protecting against skin photo-carcinogenesis. Herein, some of the hybrids of 3-hydroxypyridine-4-one and acylhydrazones were designed and synthesized to study the anti-tyrosinase and antioxidant activities. The diphenolase activity of mushroom tyrosinase using L-DOPA assayed the inhibitory effects, and the antioxidant activity was assessed using DPPH free radical. The synthesized derivatives were confirmed using 1H-NMR, 13C-NMR, IR, and Mass spectroscopy. Among analogs, compound 5h bearing furan ring with IC50=8.94 µM was more potent than kojic acid (IC50=16.68 µM). The pharmacokinetic profile of the compounds showed that the tested compounds had suitable oral bioavailability and drug-likeness properties. The molecular docking studies showed that compound 5h was located in the tyrosinase-binding site. Also, the molecular dynamics simulation was performed on compound 5h, proving the obtained molecular docking results. At the B3LYP/6-31 + G** level of theory, the reactivity descriptors for 5 g and 5h were investigated using DFT calculations. Also, IR frequency was calculated to verify DFT results with experimental data. The electrostatic potential energy of the surface and the HOMO and LUMO molecular orbitals were also studied. It agrees with experimental results that the 5h is a soft molecule and ready for chemical reaction with other interacting molecules.Communicated by Ramaswamy H. Sarma.

Novel quinazoline-1,2,3-triazole hybrids with anticancer and MET kinase targeting properties.

Oncogenic activation of receptor tyrosine kinases (RTKs) such as MET is associated with cancer initiation and progression. We designed and synthesized a new series of quinazoline derivatives bearing 1,2,3-triazole moiety as targeted anticancer agents. The MET inhibitory effect of synthesized compounds was assessed by homogeneous time-resolved fluorescence (HTRF) assay and western blot analysis. Sulforhodamine B assay was conducted to examine the antiproliferative effects of synthetic compounds against 6 cancer cell lines from different origins including MET-dependent AsPC-1, EBC-1 and MKN-45 cells and also Mia-Paca-2, HT-29 and K562 cells. The growth inhibitory effect of compounds in a three-dimensional spheroid culture was examined by acid phosphatase (APH) assay, while apoptosis induction was evaluated by Annexin V/propidium iodide method. Compound 8c bearing p-methyl benzyl moiety on the triazole ring exhibited the highest MET inhibitory capacity among tested agents that was further confirmed by western blot findings. Derivatives 8c and 8h exhibited considerable antiproliferative effects against all tested cell lines, with more inhibitory effects against MET-positive cells with IC50 values as low as 6.1 µM. These two agents also significantly suppressed cell growth in spheroid cultures and induced apoptosis in MET overexpressing AsPC-1 cells. Moreover, among a panel of 24 major oncogenic kinases, the PDGFRA kinase was identified as a target of 8c and 8h compounds. The docking study results of compounds 8c and 8h were in agreement with experimental findings. The results of the present study suggest that quinazoline derivatives bearing 1,2,3-triazole moiety may represent promising targeted anticancer agents.

Discovery of anticancer agents with c-Met inhibitory potential by virtual and experimental screening of a chemical library.

c-Met receptor tyrosine kinase has recently emerged as an important target with therapeutic implications in pancreatic cancer. In this study, we carried out a docking virtual screening on an in-house library of 441 synthesized compounds and selected the compounds with the best interactions with the c-Met protein to be subjected to experimental tests. Ten compounds belonging to 3 different classes of chemical structures were selected for this purpose and their antiproliferative effects were studied against 4 pancreatic ductal adenocarcinoma (PDAC) cell lines including AsPC-1, Suit-2, Panc-1 and Mia-Paca-2 cells, primary PDAC cells and also c-Met amplified EBC-1 cell line by sulforhodamine-B assay. Apoptosis induction was examined by Hoechst 33258 staining and annexin V-FITC/propidium iodide flow cytometric assay. The best compound was also assayed in three-dimensional cultures of AsPC-1 cells and its c-Met inhibitory potential was studied by immunoblotting and a homogenous time resolved fluorescence (HTRF) assay. The compound with a phenanthrotriazine hydrazinyl scaffold bearing nitrophenyl pendant (PhTH) was the most active derivative, with IC50 values in the range of 5-8 µM. This compound exerted antiproliferative effect against AsPC-1 cells also in the presence of hepatocyte growth factor (HGF). PhTH induced apoptosis, dose-dependently inhibited spheroid growth, inhibited c-Met activity in cell-free HTRF assay and also inhibited the phosphorylation of c-Met and its downstream effector ERK1/2 in AsPC-1 cells. Molecular docking and dynamics simulation and MM-PBSA analysis confirmed close interactions of PhTH with c-Met kinase domain. Some of the tested compounds in this study seem to be potential c-Met inhibitors with promising activities against PDAC cells.

Effect of different physical factors on the synthesis of spherical gold nanoparticles towards cost-effective biomedical applications.

Gold nanoparticles (AuNPs) have great potential to contribute to numerous application fields of biomedicine, which are highly dependent on their physicochemical properties, such as size and shape. Due to the final characteristics, nanoparticles (NPs) are primarily affected by different factors of reaction conditions; the present study aimed to evaluate the effects of manipulating the main physical parameters of the Turkevich method to optimise the fabrication of citrated capped AuNPs in a spherical shape, desirable final size, and efficiency. For this purpose, various experiments of citrate-capped spherical AuNPs synthesis were designed to study the roles of a wide range of initial pH values and temperature of reaction, Na3 Cit/HAuCl4 molar ratio, and two order reagent additions, method I and method II, in the final characterisations and reaction efficacy. Prepared NPs synthesised with different experiments were characterised by dynamic light scattering, UV-Visible, and fourier transform infrared spectroscopy. Furthermore, NPs obtained from optimised synthesis conditions were more detailed using UV-Visible, transmission electron microscopy, and XRD. The findings indicated that the final size and synthesis efficacy of citrated capped spherical AuNPs were significantly affected by all studied synthesis parameters and the order addition of reagents. The higher initial reaction temperature and Na3 Cit/HAuCl4 Molar ratio provided a smaller particle size with desirable synthesis efficacy. Besides, final optimised NPs were provided in cubic crystal structures, and each NP's single crystal was obtained. In sum, our findings indicated that optimising synthesis conditions could improve size distribution, morphology, crystallite size, and structures of final NPS, as well as efficiency, which is a principal factor associated with future cost-effective productions on large scales. Further studies are needed in this regard.

Study of the anticancer effect of new quinazolinone hydrazine derivatives as receptor tyrosine kinase inhibitors.

The advent of novel receptor tyrosine kinase inhibitors has provided an important therapeutic tool for cancer patients. In this study, a series of quinazolinone hydrazide triazole derivatives were designed and synthesized as novel MET (c-MET) receptor tyrosine kinase inhibitors. The antiproliferative effect of the synthesized compounds was examined against EBC-1, A549, HT-29 and U-87MG cells by MTT assay. MET kinase inhibitory effect was tested by a Homogenous Time Resolved Fluorescence (HTRF) assay. The antiproliferative effect of compounds in a three-dimensional spheroid culture was studied by acid phosphatase (APH) assay, while apoptosis induction was examined by Hoechst 33258 staining. We found that compound CM9 bearing p-bromo benzyl pendant inhibited MET kinase activity at the concentrations of 10-50 µM (% Inhibition = 37.1-66.3%). Compound CM9 showed antiproliferative effect against cancer cells, in particular lung cancer cells with MET amplification (EBC-1) with an IC50 value of 8.6 µM. Moreover, this derivative inhibited cell growth in spheroid cultures in a dose-dependent manner and induced apoptosis in cancer cells. Assessment of inhibitory effect of CM9 against a panel of 18 different protein kinases demonstrated that this compound also inhibits ALK, AXL, FGFR1, FLT1 (VEGFR1) and FLT4 (VEGFR3) more than 50% at 25 µM. Finally, molecular docking and dynamics simulation corroborated the experimental findings and showed critical structural features for the interactions between CM9 and target kinases. The findings of this study present quinazolinone hydrazide triazole derivatives as kinase inhibitors with considerable anticancer effects.

Ultrasound-assisted synthesis of kojic acid-1,2,3-triazole based dihydropyrano[3,2-b]pyran derivatives using Fe3O4@CQD@CuI as a novel nanomagnetic catalyst.

The magnetic nanoparticles coated with carbon quantum dot and copper (I) iodide (Fe3O4@CQD@CuI) were used as eco-friendly heterogeneous Lewis / Brønsted acid sites and Cu (I) nanocatalysts. In the first step, it was applied in the synthesis of kojic acid-based dihydropyrano[3,2-b]pyran derivatives in a three-component reaction and in the second step, as a recyclable catalyst for the synthesis of kojic acid-1,2,3-triazole based dihydropyrano[3,2-b]pyran derivatives in the CuI-catalyzed azide/alkyne cycloaddition (CuAAC) reaction. The catalyst was characterized fully by using the different techniques including fourier transform infrared spectroscopy (FT-IR), elemental mapping analysis, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), X-ray spectroscopy (EDX), transmission electron microscopy (TEM), thermal gravimetric (TG) and value-stream mapping (VSM) methods. The final synthesized derivatives were identified by 1H- and 13C-NMR spectroscopy.

Design, synthesis, spectroscopic characterization, in vitro tyrosinase inhibition, antioxidant evaluation, in silico and kinetic studies of substituted indole-carbohydrazides.

In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC50 values in the range of 0.070 to > 100 µM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC50 = 0.070 µM), 8f (R = 4-OH, IC50 = 0.072 µM), and 19e (IC50 = 0.19 µM) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 µM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.

Rational Design, Synthesis, in Vitro, and in Silico Studies of Chlorophenylquinazolin-4(3H)-One Containing Different Aryl Acetohydrazides as Tyrosinase Inhibitors.

Tyrosinase plays a pivotal role in the hyperpigmentation and enzymatic browning of fruit and vegetable. Therefore, tyrosinase inhibitors can be of interest in industries as depigmentation compounds as well as anti-browning agents. In the present study, a series of chlorophenylquinazolin-4(3H)-one derivative were rationally designed and synthesized. The formation of target compounds was confirmed by spectral characterization techniques such as IR, 1 H-NMR, 13 C-NMR, and elemental analysis. Among the synthesized derivatives, compound 8l was proved to be the most potent inhibitor with an IC50 value of 25.48±1.19 µM. Furthermore, the results of the molecular docking study showed that this compound fitted well in the active site of tyrosinase with the binding score of -10.72.

Evaluating the effects of disubstituted 3-hydroxy-1H-pyrrol-2(5H)-one analog as novel tyrosinase inhibitors.

In the present study, a series of 3-hydroxy-1H-pyrrol-2(5H)-one derivative were rationally designed and synthesized. The structure of targeted compounds was confirmed by IR, 1H NMR, 13C NMR, and elemental analysis. Next, all derivatives were evaluated as tyrosinase inhibitors, and among the synthesized derivatives, compound 6a was proved to be the most potent inhibitor with an IC50 value of 6.98 ± 1.05 µM. Kinetic study of compound 6a confirmed the mixed type of inhibitory activity towards tyrosinase. Furthermore, the results of the molecular docking study showed that this compound fitted well in the active site of tyrosinase and exhibited interaction with important residues of the binding site.

5-Oxo-hexahydroquinoline and 5-oxo-tetrahydrocyclopentapyridine derivatives as promising antiproliferative agents with potential apoptosis-inducing capacity.

Discovery of novel anticancer agents is of crucial importance to expand the therapeutic options for cancer patients. In this study, a series of 49 5-oxo-hexahydroquinoline and 5-oxo-tetrahydrocyclopentapyridine analogs, containing different pyridine alkyl carboxylates at C3 and various aliphatic, aromatic, and heteroaromatic substitutions at the C4 position of the central core, were synthesized. The target compounds were tested for antiproliferative effect against three human cancer cell lines including MOLT-4 (acute lymphoblastic leukemia), K562 (chronic myelogenous leukemia), and MCF-7 (breast adenocarcinoma) by MTT assay, and the effect of the most potent derivatives on cell cycle was evaluated by RNase/propidium iodide (PI) flow cytometric assay. Generally, 5-oxo-hexahydroquinoline derivatives (E series) possessed superior antiproliferative activities compared to their 5-oxo-tetrahydrocyclopentapyridine counterparts (F series). 5-Oxo-hexahydroquinoline compounds bearing 2-pyridyl propyl carboxylate (group D) and 3-pyridyl propyl carboxylate (group E) were better antiproliferative agents than those bearing other pyridyl alkyl carboxylates. Five best compounds with IC50 values in the range of 9.5-22.9 µM against MOLT-4 cells were selected for cell-cycle analysis, which revealed that derivatives D5, E3, and E5 with 2,3-dichlorophenyl, 3-nitrophenyl, and 2-nitrophenyl substitutions at C4 position, respectively, may induce apoptosis in MOLT-4 cells. Molecular docking analysis, which was employed to make some predictions on the interaction of the most active derivatives with the binding site of Bcl-2 and Bcl-xL proteins, suggested that the compounds may be well accommodated within the binding sites of these anti-apoptotic proteins via hydrogen-bonding and hydrophobic interactions. The findings of this study present 5-oxo-hexahydroquinoline derivatives as antiproliferative agents with potential apoptosis-inducing ability in cancer cells.

Novel Cytotoxic Phenanthro-triazine-3-thiol Derivatives as Potential DNA Intercalators and Bcl-2 Inhibitors.

Novel phenanthro-triazine-3-thiol derivatives were designed as potential DNA intercalators and Bcl-2 inhibitors. After being synthesized, the compounds were evaluated for their cytotoxic activity against MOLT-4 (human acute lymphoblastic leukemia) and MCF-7 (human breast adenocarcinoma) cells by MTT assay. P1 (bearing hydrogen substitution) was the most potent derivative against MOLT-4 with an IC50 value of 7.1 ± 1.1 µM, whereas P11 (bearing phenyl substitution) demonstrated considerable cytotoxicity against MCF-7 with an IC50 value of 15.4 ± 2.9 µM. Compounds P7, P8, P14 and P15 exhibited moderate cytotoxic effects. Furthermore, to confirm the potential DNA intercalation and Bcl-2 inhibitory activities of phenanthro-triazine scaffolds, molecular docking analysis was performed. Molecular docking studies indicated that these compounds not only bind to DNA by intercalation mainly through stacking interactions but also are well accommodated in the active site of Bcl-2. Therefore, P1 and P11 having phenanthro-triazine-3-thiol scaffold could be presented as cytotoxic agents with dual DNA intercalation and Bcl-2 inhibitory activities.

Phenanthrotriazine Derivatives Containing Arylidine Hydrazone Moieties as Novel Potential c-Met Inhibitors with Anticancer Effect.

Cancer is the second cause of death in the world and the discovery of novel anticancer agents is of vital importance to provide better therapeutic options for cancer patients. In this study, a new series of 12 arylidene hydrazone phenanthrotriazine derivatives were designed, synthesized, and tested in-vitro for antiproliferative activity against three cancer cell lines including colorectal cancer (HT-29), breast cancer (MCF-7) and leukemia (MOLT-4) cells and also against Vero normal cells. The effect of derivatives on cell cycle and apoptosis induction were studied by flow cytometric propidium iodide/RNase assay and Hoechst 33258 staining, respectively, while docking analysis was used to investigate the interactions of synthesized derivatives with the c-Met receptor kinase domain. Some compounds showed considerable antiproliferative activity against tested cancer cells. The most potent derivative was 9k bearing pyrrole moiety with IC50 values of 14.3, 4.7 and 1.7 µM against HT-29, MCF-7 and MOLT-4 cells, respectively, while it showed negligible activity against Vero normal cells (IC50: 95.4 µM). Derivatives bearing 2-nitrophenyl (9g), 4-cyanophenyl (9j), pyrrole (9k), and thiophene (9l) moieties induced G0/G1 cell cycle arrest and also apoptosis at higher doses in MCF-7 cells. Docking study showed that the phenanthrotriazine backbone form H-bond interactions with Asn1209, while phenyl moieties of the pendants generate different hydrophobic interactions with the Asp1164 and Asp1231 residues of c-Met. In conclusion, phenanthrene 1,2,4-triazines, especially the ones with less influence on normal cells, may constitute promising compounds for the discovery of antiproliferative agents with potential c-Met inhibitory capacity.

Design, synthesis, and biological evaluation of symmetrical azine derivatives as novel tyrosinase inhibitors.

A series of symmetrical azine derivatives containing different substituted benzyl moieties were designed, synthesized, and evaluated for their inhibitory activity against tyrosinase. The results showed that compounds 3e, 3f, 3h, 3i, 3j, and 3k possess effective tyrosinase inhibition with IC50 values ranging from 7.30 µM to 62.60 µM. Particularly, compounds 3f displayed around three-fold improvement in the potency (IC50 = 7.30 ± 1.15 µM) compared to that of kojic acid (IC50 = 20.24 ± 2.28 µM) as the positive control. Kinetic study of compound 3f confirmed uncompetitive inhibitory activity towards tyrosinase indicating that it can bind to enzyme-substrate complex. Next, molecular docking analysis was performed to study the interactions and binding mode of the most potent compound 3f in the tyrosinase active site. Besides, the cytotoxicity of 3f, as well as its potency to reduce the melanin content were also measured on invasive melanoma B16F10 cell line. Also, 3f exhibited above 82% cell viability in the A375 cell line at 10 µM. Consequently, compounds 3f could be introduced as a potent tyrosinase inhibitor that might be a promising candidate in the cosmetics, medicine, and food industry.

Viral 3CLpro as a Target for Antiviral Intervention Using Milk-Derived Bioactive Peptides.

Viruses of the picornavirus-like supercluster mainly achieve cleavage of polyproteins into mature proteins through viral 3-chymotrypsin proteases (3Cpro) or 3-chymotrypsin-like proteases (3CLpro). Due to the essential role in processing viral polyproteins, 3Cpro/3CLpro is a drug target for treating viral infections. The 3CLpro is considered the main protease (Mpro) of coronaviruses. In the current study, the SARS-CoV-2 Mpro inhibitory activity of di- and tri-peptides (DTPs) resulted from the proteolysis of bovine milk proteins was evaluated. A set of 326 DTPs were obtained from virtual digestion of bovine milk major proteins. The resulted DTPs were screened using molecular docking. Twenty peptides (P1-P20) showed the best binding energies (ΔG b < - 7.0 kcal/mol). Among these 20 peptides, the top five ligands, namely P1 (RVY), P3 (QSW), P17 (DAY), P18 (QSA), and P20 (RNA), based on the highest binding affinity and the highest number of interactions with residues in the active site of Mpro were selected for further characterization by ADME/Tox analyses. For further validation of our results, molecular dynamics simulation was carried out for P3 as one of the most favorable candidates for up to 100 ns. In comparison to N3, a peptidomimetic control inhibitor, high stability was observed as supported by the calculated binding energy of the Mpro-P3 complex (- 59.48 ± 4.87 kcal/mol). Strong interactions between P3 and the Mpro active site, including four major hydrogen bonds to HIS41, ASN142, GLU166, GLN189 residues, and many hydrophobic interactions from which the interaction with CYS145 as a catalytic residue is worth mentioning. Conclusively, milk-derived bioactive peptides, especially the top five selected peptides P1, P3, P17, P18, and P20, show promise as an antiviral lead compound. Supplementary Information: The online version contains supplementary material available at 10.1007/s10989-021-10284-y.

Benzylidene-6-hydroxy-3,4-dihydronaphthalenone chalconoids as potent tyrosinase inhibitors.

BACKGROUND AND PURPOSE: Tyrosinase enzyme has a key role in melanin biosynthesis by converting tyrosine into dopaquinone. It also participates in the enzymatic browning of vegetables by polyphenol oxidation. Therefore, tyrosinase inhibitors are useful in the fields of medicine, cosmetics, and agriculture. Many tyrosinase inhibitors having drawbacks have been reported to date; so, finding new inhibitors is a great need. EXPERIMENTAL APPROACH: A variety of 6-hydroxy-3,4-dihydronaphthalenone chalcone-like analogs (C1-C10) have been synthesized by aldol condensation of 6-hydroxy tetralone and differently substituted benzaldehydes. The compounds were evaluated for their inhibitory effect on mushroom tyrosinase by a spectrophotometric method. Moreover, the inhibition manner of the most active compound was determined by Lineweaver-Burk plots. Docking study was done using AutoDock 4.2. The drug-likeness scores and ADME features of the active derivatives were also predicted. RESULTS/FINDINGS: Most of the compounds showed remarkable inhibitory activity against the tyrosinase enzyme. 6-Hydroxy-2-(3,4,5-trimethoxybenzylidene)-3,4-dihydronaphthalen-1(2H)-one (C2) was the most potent derivative amongst the series with an IC50 value of 8.8 µM which was slightly more favorable to that of the reference kojic acid (IC50 = 9.7 µM). Inhibitory kinetic studies revealed that C2 behaves as a competitive inhibitor. According to the docking results, compound C2 formed the most stable enzyme-inhibitor complex, mainly via establishing interactions with the two copper ions in the active site. In silico drug-likeness and pharmacokinetics predictions for the proposed tyrosinase inhibitors revealed that most of the compounds including C2 have proper drug-likeness scores and pharmacokinetic properties. CONCLUSION AND IMPLICATIONS: Therefore, C2 could be suggested as a promising tyrosinase inhibitor that might be a good lead compound in medicine, cosmetics, and the food industry, and further drug development of this compound might be of great interest.

Anti-melanogenesis and anti-tyrosinase properties of aryl-substituted acetamides of phenoxy methyl triazole conjugated with thiosemicarbazide: Design, synthesis and biological evaluations.

A series of aryl phenoxy methyl triazole conjugated with thiosemicarbazides were designed, synthesized, and evaluated for their tyrosinase inhibitory activities in the presence of l-dopa and l-tyrosine as substrates. All the compounds showed tyrosinase inhibition in the sub-micromolar concentration. Among the derivatives, compound 9j bearing benzyl displayed exceptionally high potency against tyrosinase with IC50 value of 0.11 µM and 0.17 µM in the presence of l-tyrosine and l-dopa as substrates which is significantly lower than that of kojic acid as the positive control with an IC50 value of 9.28 µM for l-tyrosine and 9.30 µM for l-dopa. According to Lineweaver-Burk plot, 9j demonstrated an uncompetitive type of inhibition in the kinetic assay. Also, in vitro antioxidant activities determined by DPPH assay recorded an IC50 value of 68.43 µM for 9i. The melanin content of 9j was determined on B16F10 melanoma human cells which demonstrated a significant reduction of the melanin content. Moreover, the binding energies corresponding to the same ligand as well as computer-aided drug-likeness and pharmacokinetic studies were also carried out. Compound 9j also possessed metal chelation potential correlated to its high anti-TYR activity.