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Abstract Objectives The objective of this meta-analysis was to investigate the association between plasma bilirubin levels and the incidence of metabolic syndrome and diabetes mellitus across all populations. Methods Several databases were searched, including PubMed (Medline), Scopus, Web of Science, and Embase (Elsevier), to identify relevant cohort studies. All cohort studies that reported the risk ratio along with a 95% confidence interval were included. The association between bilirubin levels and metabolic syndrome or diabetes was reported as a pooled RR with a 95% CI in the forest plot. All analyses were conducted using STATA version 17, with a significance level of 0.05. Results Out of the 10 studies included in the analysis, four investigated the effect of hyperbilirubinemia on the incidence of type 2 diabetes. When these four studies were combined, the pooled RR was 0.78 (95% CI: 0.73, 0.83; I2: 88.61%; P heterogeneity

Abstract In the present study, new structural variants of 4-hydroxyquinolinone-hydrazones were designed and synthesized. The structure elucidation of the synthetic derivatives 6a–o was carried out using different spectroscopic techniques including FTIR, 1H-NMR, 13C-NMR, and elemental analysis, and their α-glucosidase inhibitory activity was also determined. The synthetic molecules 6a–o exhibited good α-glucosidase inhibition with IC50 values ranging between 93.5 ± 0.6 to 575.6 ± 0.4 µM as compared to the standard acarbose (IC50 = 752.0 ± 2.0 µM). Structure–activity relationships of this series were established which is mainly based on the position and nature of the substituent on the benzylidene ring. A kinetic study of the active compounds 6l and 6m as the most potent derivatives were also carried out to confirm the mode of inhibition. The binding interactions of the most active compounds within the active site of the enzyme were determined by molecular docking and molecular dynamic simulations.

Abstract: Articles 454 and 455 of the Civil Code are ambiguous in terms of the examples of the "right of rescission", the examples of "the implied condition of prohibition of the customer in the assignment" and the meaning of the word "void"; however, the supreme court decision as a unified judicial precedent No. 810 dated 24/06/2021is also vague and outside the scope of the lawsuits. A court has described the option of violation of the payment of installments and the delivery of the goods upon rescission as an implicit prohibition of the customer's assignment, and has ruled on the invalidity of the possessions and eviction. But in similar lawsuits, another court, from the terms of the same contract, did not describe such a concept, and with a different interpretation of the law, ruled against the seller. The supreme court emphasized the intent of the contracting parties in the case of the right to rescind the contract and return of goods sold, by commenting on an implicit matter, and did not comment on the legal status of the possession of the seller, and believes that the owner's right of priority does not invalidate the condition and the right of rescission against the return of the goods. While, according to the opinion of the majority of late and contemporary jurisprudents, deduced from Articles 454 and 455 of the Civil Code, the customer's right of assignment in the contractual right of rescission is dependent null. Thus, since the implicit matter of the return of goods sold and the request for eviction is based on the request for the cancellation of the assignment, the decision of the court is logically voidable.

Abstract Solanum nigrum L. (Black nightshade), is one of the most troublesome weeds of summer crops such as corn, soybean, sunflower, etc. To study the effect of combined Castor oil as an adjuvant with different doses of Lumax (Mesotrion + S-metolacholor + Terbuthylazine) on the physiological behavior of Solanum nigrum L., a greenhouse experiment was conducted in randomized complete block design with four replications in agricultural faculty of the University of Tabriz in 2021. A foliar application of Lumax increased proline, malondialdehyde, and hydrogen peroxide concentrations and superoxide dismutase, catalase, and peroxidase activity. The content of protein and photosynthetic pigments (Chlorophyll a, b, and carotenoids) also decreased significantly by using Lumax herbicide. Applying castor oil in combination with Lumax intensifies oxidative stress and lipid peroxidation. Results showed that by increasing the herbicide doses in comparison with control (non-herbicide), Area, Fm, Fv, Fv/Fm, Fv/F0, Sm, Sm/Tfm, and Fv/F0 decreased 48.32%, 19.52%, 27.95%, 10.47%, 50.90%, 28.34%, 79.38%, and 50.90%, respectively and F0, F0/Fm increased 46.76% and 82.38%, respectively. Castor oil showed a synergistic effect on Lumax herbicide and enhanced its efficacy on Solanum nigrum. The presented results supported the view that by evaluating chlorophyll a fluorescence parameters, we would realize herbicide (alone or mixed with any adjacent) efficacy before the visual symptoms appear in the plant.

Abstract Understanding the fracture patterns of hydrocarbon reservoirs is vital in the Zagros area of southwest of Iran as they are strongly affected by the collision of the Arabian and Iranian plates. It is essential to evaluate both primary and secondary (fracture) porosity and permeability to understand the fluid dynamics of the reservoirs. In this study, we adopted an integrated workflow to assess the influence of various fracture sets on the heterogeneous carbonate reservoir rocks of the Cenomanian–Santonian Bangestan group, including Ilam and upper Sarvak Formations. For this purpose, a combination of field data was used including seismic data, core data, open-hole well-logs, petrophysical interpretations, and reservoir dynamic data. FMI interpretation revealed that a substantial amount of secondary porosity exists in the Ilam and Sarvak Formations. The upper interval of Sarvak 1-2 (3491 m to 3510 m), Sarvak 1-3 (3530 m to 3550 m), and the base of Sarvak 2-1 are the most fractured intervals in the formation. The dominant stress regime in the study area is a combination of compressional and strike-slip system featuring reverse faults with a NW–SE orientation. From the depositional setting point of view, mid-ramp and inner-ramp show a higher concentration of fractures compared to open marine environment. Fracture permeability was modeled iteratively to establish a realistic match with production log data. The results indicate that secondary permeability has a significant influence on the productivity of wells in the study area.

linking of futures studies with the tourism industry can create a suitable position for research in the field of urban tourism. The present study is seeking to analyze of key affecting propellants on the development of tourism in Rasht city with future studies approach. The present study in terms of purpose is qualitative and in terms of data collection method and final results is applied. To conduct this research, 34 factors were extracted as the main factors in 5 dimensions (environmental, socio-cultural, planning-institutional, infrastructure-welfare, economic) and Then the propellants factors were identified by using the Delphi method. For data analysis, the interaction analysis method was used in MICMAC software. The results of the study indicate that due to the distribution of variables, tourism development in the Rasht metropolis is unstable. Then the key factors were ranked that the variables of development of relations with neighbors, animal life, the existence of shopping centers, were ranked first to third, respectively. According to the studies conducted in this field, so far no study has been conducted in relation of tourism development futures studies in the studied area. Finally, four scenarios were presented for the future studies of the tourism industry in the Rasht metropolis.

The over-exploitation of groundwater has led to many problems in the country. Since groundwater level is a variable that varies over the time and place, it can be considered as a spatio-temporal dataset. The purpose of this study is to investigate the spatial-temporal variation of the groundwater level in Jask plain from 1997 to 2013 to determine the spatial trend of groundwater changes. First, interpolation was carried out based on the Kriging and the Radial Basis Functions (RBF), and then accuracy was evaluated using MBE, MAE and RMSE statistics. The findings suggested that, compared with RBF, Kriging can estimate groundwater levels more accurately in the study area. Consequently, for each time in the study period, a groundwater level map was produced based of the method. To identify the spatial variability of the groundwater level, R2 and Man-Kendall test were used. The results of the R2 statistics indicated a significant variation in the water level. Similarly, the results of the Man-Kendall test showed a decreasing trend in the north-to-northwest margin with a high intensity of nearly -1. Generally, in different parts of the study area, the process of change has a specific and meaningful pattern.

The terahertz frequency band becomes a growth platform of various applications from medical imaging to indoor communications. Emerging new materials such as graphene and developing reliable models paved the design way for graphene-based microstructures. This paper proposes a relatively comprehensive design methodology for graphene-based multi-layers structures. The procedure includes forming device geometry, finding graphene patterns, material types, and optimizing control parameters. In this way, a reconfigurable THz wave absorber is introduced. Exploiting a multi bias scheme for a single graphene layer provide opportunity to affect device reaction via bias itself and patterns period simultaneously which increase adjustability of device response. Also using two different graphene patterns turns the device complex regarding design optimizations and simulations. So a well-known and simple circuit representation is used to design the proposed methodology and the proposed device. Knowing equivalent circuit models for the device elements triggers developing an evolutionary algorithm to search for a desirable response. In this context, the paper suggests using a weighted binary matrix in the design process. The matrix determines bias schemes for each layer. Then an evolutionary algorithm optimizes whole biases values. The expectation is more in-depth control over the device behavior via biases values. This is verified by exploited circuit model formulations and Finite Element Method (FEM) as numerical simulation for a unique three layers device.

In order to evaluate the effects of bentazon and nicosulfuron on the photosynthetic apparatus of X. strumarium in greenhouse condition, chlorophyll a fluorescence (ChlF) method was studied at 1, 2, 3, and 4 days after herbicide treatment (DAHT). Bentazon in comparison to nicosulfuron, dramatically affect ChlF parameters and the shape of polyphasic OJIP curves at 1 DAHT. Bentazon significantly decreased photosystem II activity via increasing minimum fluorescence (Fo) and maximum quantum yield of basal non-photochemical energy losses (Fo/FM) and decreasing maximum fluorescence (Fm), variable fluorescence (Fv), time to reach maximum fluorescence (Tfm), size of the plastoquinone pool on the reducing side of photosystem II (Area), maximum efficiency of water-splitting complex on the donor side of the photosystem II (Fv/Fo), maximum quantum efficiency of photosystem II (Fv/Fm), trapping flux leading to QA reduction per RC (TRo/RC), electron transport flux further than QA– per RC (ETo/RC), and electron flux reducing end electron acceptors at the photosystem I acceptor side per RC (REo/RC). In most cases, the inhibitory effects of bentazon on photosystem II activity were observed at 1 DAHT but, those inhibitory effects were delayed by nicosulfuron application. It was concluded that ChlF is a rapid method for studding herbicide mode of action as photosystem II activity considered primary sites of action in bentazon and secondary sites of action in nicosulfuron.

The effects of mulches on weeds and cucumber (Cucumis sativus L.) yield, examined by field experiment at Research Station of Tabriz University in 2012, based on randomized complete block designed with four replications. Treatments included four kinds of mulches such as transparent plastic, black plastic, wheat straw, paper and control (mulch free). Results showed that black plastic was the most successful in weeds control, so that up to one month after sowing time (the first time sampling), some weeds were controled 100 percent, and all traits were reduced in some others. Two monthes after sowing time (the second sampling time), also all traits of weeds presented under black plastic significantly were reduced. After block plastic, paper was very important in weed control. At bigening of the growth season, transparent plastic caused increases in weed growth, but increasing of temperature under this kind of mulch, during season, weeds were bleached. The effects of wheat straw on weeds control was not significant. Cucumber yield in mulch treatments significantly was increased, so that from 21.25 t/h in control were reached to 57.4, 47.7, and 36.65 t/h in transparent plastic, black plastic and paper, respectively. The results of this experiment showed that using of suitable mulch, by controlling of weeds improved cucumber performance.

Introduction: In the near future, retinopathy of prematurity (ROP) will be the most significant cause of blindness in upper and middle-income countries. Due to the increasing survival chances for premature and low birth weight infants and the importance of the diagnosis and treatment of ROP, this study was aimed at determining the prevalence of ROP and its related factors in Sanandaj, Iran, in 2014. Methods: This cross-sectional study was performed on 47 preterm infants, weighing less than 2000 g or with a gestational age of less than of 34 weeks. The sampling method was census. From the first examination to 1 to 4 weeks later, until retinal vascularization completion, examinations were performed by the same ophthalmologist. Data were analyzed using SPSS version 20 and frequency, mean, SD and Chi-square tests. Results: The prevalence of ROP in the infants was 10.6%. Prevalence among girls was 16% and among boys it was 4.5%. The results showed that 23.5% of infants with ROP needed mechanical ventilation. The difference between the two groups was statistically significant (p = 0.031). Conclusion: In this study, the prevalence of ROP in the NICU and neonatal ward of Besat Hospital in Sanandaj was low. However, due to serious consequences of the disease in premature infants, timely screening, determination, and control of risk factors provided necessary support to manage the disease.

The effect of seven herbicides (U-46 Combi Fluid, Cruz, MR, Basagran Bromicide, Lumax, and Gramoxone) on Xanthium strumarium plants was studied. Chlorophyll content and fluorescence, leaf temperature, and stomatal conductance were evaluated at 12 h, 36 h, 60 h, and 84 h after herbicides application. U46 Combi Fluid, Cruz, and MR did not have a significant effect on chlorophyll fluorescence induction curves as compared to the control treatment. However, Basagran, Bromicide, Lumax, and Gramoxone showed significant changes in the shape of polyphasic fluorescence transients (OJIP transients). Variations in chlorophyll content index, leaf temperature, and stomatal conductance parameters were dependent on the type of applied herbicide. Our study revealed that the specific impact of the applied herbicides on the photosynthetic efficiency of plants is related to their chemical groups and their mechanism of action.

This research aims at comparing the effectiveness of training skills of parents in problem solving and expressiveness on the social adaptation and educational progress of their children.This study was conducted randomly on 24 high school boys in Somehsara. The research method was semi- experimental proper to dimentions. The means of research were questionnaires relating to social adjustment of high school students (AISS) (Sinha and Sink, 1993). (b) the average of the lessons of these students in grade one in high school to analyze the achieved data, first the averages and standard deviations were used and then for testing hypothesis analysis of the variance of a few variables was used. The research results showed that the program of parents' expressing skill has had influence on the increasing of the social adaptation and educational achievement of their students. Problem solving skill has had influence on children's social adaptation, but it hasn't had any influence on their educational achievement. The Findings of this research can be applied to students` educational progress, growth and advancement of social adaptation

This research aims at comparing the effectiveness of training skills of parents in problem solving and expressiveness on the social adaptation and educational progress of their children.This study was conducted randomly on 24 high school boys in Somehsara. The research method was semi- experimental proper to dimentions. The means of research were questionnaires relating to social adjustment of high school students (AISS) (Sinha and Sink, 1993). (b) the average of the lessons of these students in grade one in high school to analyze the achieved data, first the averages and standard deviations were used and then for testing hypothesis analysis of the variance of a few variables was used. The research results showed that the program of parents' expressing skill has had influence on the increasing of the social adaptation and educational achievement of their students. Problem solving skill has had influence on children's social adaptation, but it hasn't had any influence on their educational achievement. The Findings of this research can be applied to students` educational progress, growth and advancement of social adaptation

The process of the surface urban heat island (SUHI) varies with latitude, climate, topography and meteorological conditions. This study investigated the seasonal variability of SUHI in the Tehran metropolitan area, Iran, with respect to selected surface biophysical variables. Terra Moderate Resolution Imaging Spectroradiometer (MODIS) Land Surface Temperature (LST) was retrieved as nighttime LST data, while daytime LST was retrieved from Landsat 8 Thermal Infrared Sensor (TIRS) using the split-window algorithm. Both data covered the time period from September 2013 to September 2015. To assess SUHI intensity, we employed three SUHI indicators, i.e., the LST difference of urban-rural, that of urban-agriculture and that of urban-water. Physical and biophysical surface variables, including land use and land cover (LULC), elevation, impervious surface (IS), fractional vegetation cover (FVC) and albedo, were selected to estimate the relationship between LST seasonal variability and the surface properties. Results show that an inversion of the SUHI phenomenon (i.e., surface urban cool island) existed at daytime with the maximal value of urban-rural LST difference of −4 K in March; whereas the maximal value of SUHI at nighttime yielded 3.9 K in May. When using the indicators of urban-agriculture and urban-water LST differences, the maximal value of SUHI was found to be 8.2 K and 15.5 K, respectively. Both results were observed at daytime, suggesting the role of bare soils in the inversion of the SUHI phenomenon with the urban-rural indicator. Maximal correlation was observed in the relationship between night LST and elevation in spring (coefficient: −0.76), night LST and IS in spring (0.60), night LST and albedo in winter (−0.53) and day LST with fractional vegetation cover in summer (−0.41). The relationship between all surface properties with LST possessed large seasonal variations, and thus, using these relationships for SUHI modeling may not be effective. The only exception existed in the correlation between elevation and IS, which may be useful to simulate the SUHI at night. This study suggests that in semi-arid cities, such as Tehran, with the urban-rural indicator, a surface urban cool island may be observed in daytime while SUHI at nighttime; with other indicators, SUHI can be observed in both day and night. Thus, SUHI studies require the acquisition of remote sensing image data at both daytime and nighttime and careful selection of SUHI indicators.

Background: Multiple Sclerosis (MS) is a chronic autoimmune, inflammatory neurological disease of the CNS. Riluzole and dimethyl fumarate (DMF) are two FDA-approved drugs to treat amyotrophic lateral sclerosis (ALS) and MS. Riluzole (a benzothiazole derivative) inhibits glutamate release from nerve terminals by antagonizing the N-Methyl-D-Aspartate (NMDA) receptor, and DMF upregulates anti-oxidative pathways., Objectives: Herein, using molecular hybridization strategy, we synthesized some new hybrid structures of Riluzole and DMF through some common successive synthetic pathways for evaluating their potential activity for remyelination in MS treatment., Methods: Molecular docking experiments assessed the binding affinity of proposed structures to the NMDA active site. The designed structures were synthesized and purified based on well-known chemical synthesis procedures. Afterward, in vivo evaluation for their activity was done in the C57Bl/6 Cuprizone-induced demyelination MS model., Results and Conclusion: The proposed derivatives were recognized to be potent enough based on docking studies (ΔG bind of all derivatives were -7.2 to -7.52 compare to the Ifenprodil (-6.98) and Riluzole (-4.42)). The correct structures of desired derivatives were confirmed using spectroscopic methods. Based on in vivo studies, D4 and D6 derivatives exhibited the best pharmacological results, although only D6 showed a statistically significant difference compared to the control. Also, for D4 and D6 derivatives, myelin staining confirmed reduced degeneration in the corpus callosum. Consequently, D4 and D6 derivatives are promising candidates for developing new NMDA antagonists with therapeutic value against MS disorders., Competing Interests: Declarations Conflict of interest There are no conflicts of interest declared by the authors., (© 2024. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

KDM4A-F enzymes are a subfamily of histone demethylases containing the Jumonji C domain (JmjC) using Fe(II) and 2-oxoglutarate for their catalytic function. Overexpression or deregulation of KDM4 enzymes is associated with various cancers, altering chromatin structure and causing transcriptional dysfunction. As KDM4 enzymes have been associated with malignancy, they may represent novel targets for developing innovative therapeutic tools to treat different solid and blood tumors. KDM4A is the isozyme most frequently associated with aggressive phenotypes of these tumors. To this aim, industrial and academic medicinal chemistry efforts have identified different KDM4 inhibitors. Industrial and academic efforts in medicinal chemistry have identified numerous KDM4 inhibitors, primarily pan-KDM4 inhibitors, though they often lack selectivity against other Jumonji family members. The pharmacophoric features of the inhibitors frequently include a chelating group capable of coordinating the catalytic iron within the active site of the KDM4 enzyme. Nonetheless, non-chelating compounds have also demonstrated promising inhibitory activity, suggesting potential flexibility in the drug design. Several natural products, containing monovalent or bivalent chelators, have been identified as KDM4 inhibitors, albeit with a micromolar inhibition potency. This highlights the potential for leveraging them as templates for the design and synthesis of new derivatives, exploiting nature's chemical diversity to pursue more potent and selective KDM4 inhibitors., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Background and Purpose: The seventh most common type of cancer with increasing diagnosis rates around the world is head and neck squamous cell carcinoma (HNSCC). Specificity proteins (SPs) have been known for their role in the regulation of cellular division, growth, and apoptotic pathways in various cancers. In this work, we analyzed the expression levels of SPs in HNSCC to assess their diagnostic and prognostic biomarker potential., Experimental Approach: Differential gene expression and correlation analysis methods were used to determine the top dysregulated genes in HNSCC. Functional enrichment and protein-protein interaction analyses were done with the DAVID database and Cytoscape software to understand their function and biological processes. Receiver operating test, logistic regression, and Cox regression analyses were performed to check SP genes' diagnostic and prognostic potential., Findings/results: SP1 (LogFC = -0.27, P = 0.0013) and SP2 (LogFC = -0.20, P = 0.0019) genes were upregulated in HNSCC samples, while SP8 (LogFC = 2.57, P < 0.001) and SP9 (LogFC = 2.57, P < 0.001) genes were downregulated in cancer samples. A moderate positive correlation was observed among the expression levels of SP1, SP2, and SP3 genes. The SP8 and SP9 genes with AUC values of 0.79 and 0.75 demonstrated diagnostic potential which increased to 0.84 when both genes were assessed by logistic regression test. Also, the SP1 gene held a marginally significant prognostic potential., Conclusion and Implications: Our findings clarify the potential of SP transcription factors as candidate diagnostic and prognostic biomarkers for early screening and treatment of HNSCC., Competing Interests: All authors declared no conflict of interest in this study., (Copyright: © 2024 Research in Pharmaceutical Sciences.)

Background: The cholinergic hypothesis posits a robust correlation between the onset of Alzheimer's disease and a pronounced deficit in acetylcholine, a pivotal neurotransmitter crucial for the central cholinergic nervous system's function, pivotal for memory and learning. Diterpene alkaloids exhibit intricate and distinctive chemical structures that facilitate their passage through the blood-brain barrier. Moreover, their potent pharmacological attributes render them promising candidates for addressing central nervous system disorders., Objectives: This investigation aims to scrutinize the alkaloidal composition of Delphinium cyphoplectrum (Ranunculaceae) roots, further exploring their anticholinesterase inhibitory activity and mode of inhibition., Method: Innovative chromatography techniques were repetitively employed to purify the alkaloids. Acetylcholinesterase (AChE) inhibition assays were conducted using Ellman's tests. The mode of inhibition was meticulously characterized through Michaelis-Menten, and Lineweaver-Burk plots. Conducting molecular docking studies, we employed the AUTO DOCK 4.2 software package., Results: Eight alkaloids were identified including five C19-diterpene alkaloids (6,14,16,18-tetramethoxy-1,7,8-trihydroxy-4-methylaconitane (1), 6,16,18-trimethoxy-1,7,8,14-tetrahydroxy-4-methylaconitane (2), 6,8,16,18-tetramethoxy-1,7,14-trihydroxy-4-methylaconitane (3), 6,14,16-trimethoxy-1,7,8,18-tetrahydroxy-4-methylaconitane (4), and 14-O-acetyl-8,16-dimethoxy-1,6,7,18-tetrahydroxy-4-methylaconitane (5)), an epoxy C18-diterpene alkaloid (6,8,16-trimethoxy-1,7,14-trihydroxy-3,4-epoxyaconitane (6)), a known (pyrrolidin-2-one (7) and an undescribed amide alkaloid (1-(2'-hydroxylethylamine)-3,5,5,-trimethyl-1,5-dihydro-2H-pyrrol-2-one (8). All diterpene alkaloids underwent assessment for acetylcholinesterase (AChE) inhibition assay and displayed noteworthy AChE activity, surpassing that of the reference drug (with IC 50 values of 13.7, 21.8, 23.4, 28.2, 40.4, and 23.9 for compounds 1-6, respectively, in comparison to 98.4 for Rivastigmine). Analysis of Michaelis-Menten and Lineweaver-Burk plots represents an uncompetitive mode of inhibition for compound 1 on AChE. Notably, computational docking simulations indicated that all diterpene alkaloids were accommodated within the same enzymatic cleft as the reference ligand, and displaying superior free binding energy values (from - 10.32 to -8.59 Kcal.mol -1 ) in contrast to Rivastigmine (-6.31 Kcal.mol -1 )., Conclusion: The phytochemical analysis conducted on the roots of Delphinium cyphoplectrum yielded the identification of eight alkaloidal compounds including one C18-diterpene, five C19-diterpene, one pyrrolidine and one amide alkaloids. AChE inhibition assay and molecular simulations unveiled remarkable significant potency attributed to the C19-diterpene alkaloids by the order of 1 > 2 > 3,6 > 4 > 5. Presence of hydroxyl group on C-1, C-7, C-8, C-14, and C-18 increased the effect. The best in vitro activity was recorded for compound 1 able to bind to Asp 72 in the narrow region of PAS, while interacting by pi-sigma with Phe 330 at the hydrophobic region of the gorge involving the acyl and choline binding site. This observation underscores the substantial promise of this category of natural products in the realm of drug discovery for Alzheimer's Disease, offering a compelling avenue for further research and therapeutic development., (© 2024. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

Hypoxia-inducible factors (HIFs) are the main regulatory factors implicated in the adaptation of cancer cells to hypoxic stress, which has provoked much interest as an attractive target for the design of promising chemotherapeutic agents. Since indirect HIF inhibitors (HIFIs) lead to the occurrence of various side effects, the need of the hour is to develop direct HIFIs, physically interacting with important functional domains within the HIF protein structure. Accordingly, in the present study, it was attempted to develop an exhaustive structure-based virtual screening (VS) process coupled with molecular docking, molecular dynamic (MD) simulation, and MM-GBSA calculations for the identification of novel direct inhibitors against the HIF-2α subunit. For this purpose, a focused library of over 200,000 compounds from the NCI database was used for VS against the PAS-B domain of the target protein, HIF-2α. This domain was suggested to be a possible ligand-binding site, which is characterized by a large internal hydrophobic cavity, unique to the HIF-2α subunit. The top-ranked compounds, NSC106416, NSC217021, NSC217026, NSC215639, and NSC277811 with the best docking scores were taken up for the subsequent in silico ADME properties and PAINS filtration. The selected drug-like hits were employed for carrying out MD simulation which was followed by MM-GBSA calculations to retrieve the candidates showing the highest in silico binding affinity towards the PAS-B domain of HIF-2α. The analysis of results indicated that all molecules, except the NSC277811, fulfilled necessary drug-likeness properties. Four selected drug-like candidates, NSC106416, NSC217021, NSC217026, and NSC215639 were found to expose the stability profiles within the cavity located inside the PAS-B domain of HIF-2α over simulation time. Finally, the results of the MM-GBSA rescoring method were indicative of the highest binding affinity of NSC217026 for the binding site of the HIF-2α PAS-B domain among selected final hits. Consequently, the hit NSC217026 could serve as a promising scaffold for further optimization toward the design of direct HIF-2α inhibitors for cancer therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

One of the chief pathways to regulate p53 levels is MDM2 protein, which negatively controls p53 by direct inhibition. Many cancers overproduce MDM2 protein to interrupt p53 functions. Therefore, impeding MDM2's binding to p53 can reactivate p53 in tumor cells may suggest an effective approach for tumor therapy. Here, some Monastrol derivatives were designed in silico as MDM2 inhibitors, and their initial cytotoxicity was evaluated in vitro on MFC-7 and MDA-MB-231 cells. A small library of Monastrol derivatives was created, and virtual screening (VS) was performed on them. The first-ranked compound, which was extracted from VS, and the other six compounds 5a-5f were selected to carry out the single-docking and docking with explicit waters. The compound with the best average results was then subjected to molecular dynamic (MD) simulation. Compounds 5a-5f were chemically synthesized and evaluated in vitro for their initial cytotoxicity on MFC-7 and MDA-MB-231 cells by MTT assay. The best compound was compound 5d with ΔG ave  = -10.35 kcal/mol. MD simulation revealed a median potency in comparison with Nutlin-3a. The MTT assay confirmed the docking and MD experiments. 5d has an IC 50 of 60.09 μM on MCF-7 cells. We attempted to use Monastrol scaffold as a potent inhibitor of MDM2 rather than an Eg5 inhibitor using in silico modification. The results obtained from the in silico and in vitro evaluations were noteworthy and warranted much more effort in the future., (© 2023 John Wiley & Sons Ltd.)

Since the emergence of SARS-CoV-2, many genetic variations within its genome have been identified, but only a few mutations have been found in nonstructural proteins (NSPs). Among this class of viral proteins, NSP3 is a multidomain protein with 16 different domains, and its largest domain is known as the macrodomain or Mac1 domain. In this study, we present a virtual screening campaign in which we computationally evaluated the NCI anticancer library against the NSP3 Mac1 domain, using Molegro Virtual Docker. The top hits with the best MolDock and Re-Rank scores were selected. The physicochemical analysis and drug-like potential of the top hits were analyzed using the SwissADME data server. The binding stability and affinity of the top NSC compounds against the NSP3 Mac1 domain were analyzed using molecular dynamics (MD) simulation, using Desmond software, and their interaction energies were analyzed using the MM/GBSA method. In particular, by applying subsequent computational filters, we identified 10 compounds as possible NSP3 Mac1 domain inhibitors. Among them, after the assessment of binding energies (ΔG bind ) on the whole MD trajectories, we identified the four most interesting compounds that acted as strong binders of the NSP3 Mac1 domain (NSC-358078, NSC-287067, NSC-123472, and NSC-142843), and, remarkably, it could be further characterized for developing innovative antivirals against SARS-CoV-2.

Background and Purpose: Acyl-CoA synthetase (ACS) enzymes play an important role in the activation of fatty acids. While many studies have found correlations between the expression levels of ACS enzymes with the progression, growth, and survival of cancer cells, their role and expression patterns in colon adenocarcinoma are still greatly unknown and demand further investigation., Experimental Approach: The expression data of colon adenocarcinoma samples were downloaded from the Cancer Genome Atlas (TCGA) database. Normalization and differential expression analysis were performed to identify differentially expressed genes (DEGs). Gene set enrichment analysis was applied to identify top enriched genes from ACS enzymes in cancer samples. Gene ontology and protein-protein interaction analyses were performed for the prediction of molecular functions and interactions. Survival analysis and receiver operating characteristic test (ROC) were performed to find potential prognostic and diagnostic biomarkers., Findings/results: ACSL6 and ACSM5 genes demonstrated more significant differential expression and LogFC value compared to other ACS enzymes and also achieved the highest enrichment scores. Gene ontology analysis predicted the involvement of top DEGs in fatty acids metabolism, while protein-protein interaction network analysis presented strong interactions between ACSLs, ACSSs, ACSMs, and ACSBG enzymes with each other. Survival analysis suggested ACSM3 and ACSM5 as potential prognostic biomarkers, while the ROC test predicted stronger diagnostic potential for ACSM5, ACSS2, and ACSF2 genes., Conclusion and Implications: Our findings revealed the expression patterns, prognostic, and diagnostic biomarker potential of ACS enzymes in colon adenocarcinoma. ACSM3, ACSM5, ACSS2, and ACSF2 genes are suggested as possible prognostic and diagnostic biomarkers., Competing Interests: All authors declared no conflict of interest in this study., (Copyright: © 2023 Research in Pharmaceutical Sciences.)

In this paper, we present the development of a computer-based repurposing approach to identify FDA-approved drugs that are potentially able to interfere with irisin dimerization. It has been established that altered levels of irisin dimers are a pure hallmark of lipodystrophy (LD) syndromes. Accordingly, the identification of compounds capable of slowing down or precluding the irisin dimers' formation could represent a valuable therapeutic strategy in LD. Combining several computational techniques, we identified five FDA-approved drugs with satisfactory computational scores (iohexol, XP score = -7.70 kcal/mol, SP score = -5.5 kcal/mol, ΔG bind = -61.47 kcal/mol, ΔG bind (average) = -60.71 kcal/mol; paromomycin, XP score = -7.23 kcal/mol, SP score = -6.18 kcal/mol, ΔG bind = -50.14 kcal/mol, ΔG bind (average) = -49.13 kcal/mol; zoledronate, XP score = -6.33 kcal/mol, SP score = -5.53 kcal/mol, ΔG bind = -32.38 kcal/mol, ΔG bind (average) = -29.42 kcal/mol; setmelanotide, XP score = -6.10 kcal/mol, SP score = -7.24 kcal/mol, ΔG bind = -56.87 kcal/mol, ΔG bind (average) = -62.41 kcal/mol; and theophylline, XP score = -5.17 kcal/mol, SP score = -5.55 kcal/mol, ΔG bind = -33.25 kcal/mol, ΔG bind (average) = -35.29 kcal/mol) that are potentially able to disrupt the dimerization of irisin. For this reason, they deserve further investigation to characterize them as irisin disruptors. Remarkably, the identification of drugs targeting this process can offer novel therapeutic opportunities for the treatment of LD. Furthermore, the identified drugs could provide a starting point for a repositioning approach, synthesizing novel analogs with improved efficacy and selectivity against the irisin dimerization process.

Aim: In this study, novel hybrid structures of pyrimido-indole-oxadiazole were developed as MDM2 inhibitors for restoring the regular function of the p53. Materials & methods: A multistep chemical pathway was used to synthesize the derivatives. Nutlin-3a was used as a standard lead in molecular docking and molecular dynamics simulations. Finally, cytotoxicity was evaluated against MCF-7 cancer cells versus Doxorubicin. Results: The most promising candidate was 12c , which had an NO 2 group in the para position of the oxadiazole ring (IC 50 : 1.1 μM). A satisfactory result was obtained with the combined application of 12c and Doxorubicin (IC 50 decreased to 0.63 μM), which could be potentially attributed to MDM2 inhibition. Conclusion: These hybrid structures can be further investigated as potential MDM2 inhibitors.

Background and Purpose: Precise structures of macromolecules are important for structure-based drug design. Due to the limited resolution of some structures obtained from X-ray diffraction crystallography, differentiation between the NH and O atoms can be difficult. Sometimes a number of amino acids are missing from the protein structure. In this research, we intend to introduce a small database that we have prepared for providing the corrected 3D structure files of proteins frequently used in structure-based drug design protocols., Experimental Approach: 3454 soluble proteins belonging to the cancer signaling pathways were collected from the PDB database from which a dataset of 1001 was obtained. All were subjected to corrections in the protein preparation step. 896 protein structures out of 1001 were corrected successfully and the decision on the remained 105 proposed twelve for homology modeling to correct the missing residues. Three of them were subjected to molecular dynamics simulation for 30 ns., Findings / Results: 896 corrected proteins were perfect and homology modeling on 12 proteins with missing residues in the backbone resulted in acceptable models according to Ramachandran, z-score, and DOPE energy plots. RMSD, RMSF, and Rg values verified the stability of the models after 30 ns molecular dynamics simulation., Conclusion and Implication: A collection of 1001 proteins were modified for some defects such as adjustment of the bond orders and formal charges, and addition of missing side chains of residues. Homology modeling corrected the amino missing backbone residues. This database will be completed for quite a lot of water-soluble proteins to be uploaded to the internet., Competing Interests: The authors declared no conflicts of interest in this study., (Copyright: © 2022 Research in Pharmaceutical Sciences.)

Background and Purpose: Histone deacetylation is one of the essential cellular pathways in the growth and spread of cancer, so the design of histone deacetylase (HDAC) inhibitors as anticancer agents is of great importance in pharmaceutical chemistry. Here, a series of indole acylhydrazone derivatives of 4-pyridone have been introduced as potential histone deacetylase inhibitors., Experimental Approach: Seven indole-acylhydrazone-pyridinone derivatives were synthesized via simple, straightforward chemical procedures. The molecular docking studies were accomplished on HDAC2 compared to panobinostat. The cytotoxicity of all derivatives was studied on MCF-7 and MDA-MB-231 breast cancer cell lines by MTT assay., Findings / Results: Molecular docking studies supported excellent fitting to the HADC2 active site with binding energies in the range of -10 Kcal/mol for all derivatives. All compounds were tested for their cytotoxicity against MCF-7 and MDA-MB-231 cell lines; derivatives A, B, F, and G were the best candidates. The half-maximal inhibitory concentration (IC 50 ) values on MCF-7 were below 25 mg/mL and much lower than those obtained on the MDA-MB-231 cell line., Conclusion and Implications: The derivatives showed selectivity toward the MCF-7 cell line, probably due to the higher HDAC expression in the MCF-7 cell line. In this regard, debenzylated derivatives F and G showed slightly better cytotoxicity, which should be more studied in the future. Derivatives A, B, F, and G were promising for future enzymatic studies., Competing Interests: The authors declared no conflicts of interest in this study., (Copyright: © 2022 Research in Pharmaceutical Sciences.)

Background and Purpose: Hypoxia-inducible factors (HIFs) are transcription factors that get activated and stabilized in the heterodimerized form under hypoxic conditions. many studies have reported the importance of the HIF-1α and HIF-2α activity in biological pathways of hypoxic cancer cells. However, the importance of HIF-3α in a variety of cancers remains unknown., Experimental Approach: The expression profile of 13 different types of cancer samples from the Cancer Genome Atlas (TCGA) database were subjected to normalization, and differential gene expression analysis was performed using computational algorithms by R programming. Receiver operating characteristic tests and survival analyses were carried out for HIF-α subunits in different cancers., Findings / Results: The expression status of HIF-3α was notably less in all cancer samples in contrast to their adjacent normal tissues. The expression degree of HIF-1α varied among distinct types of cancer and the expression degree of HIF-2α was lower in nearly all types of cancers. HIF-3α had very weak diagnostic potential, while HIF-2α had better diagnostic potential in most types of cancers compared to HIF-1α. Patients who had a higher level of HIF-3α had better survival, while the higher expression level of HIF-1α and HIF-2α were associated with worse survival in many types of cancers., Conclusion and Implications: Our findings showed that each HIF-α subunit had a unique heterogeneous expression pattern in different classes of cancers. The expression level of each HIF-α subunit correlated differently with the stages, tumor sizes, and survival rate of patients from different classes of TCGA cancers., Competing Interests: All authors declared no conflict of interest in this study., (Copyright: © 2022 Research in Pharmaceutical Sciences.)

Histone deacetylases (HDACs) as an important family of epigenetic regulatory enzymes are implicated in the onset and progression of carcinomas. As a result, HDAC inhibition has been proven as a compelling strategy for reversing the aberrant epigenetic changes associated with cancer. However, non-selective profile of most developed HDAC inhibitors (HDACIs) leads to the occurrence of various side effects, limiting their clinical utility. This evidence provides a solid ground for ongoing research aimed at identifying isoform-selective inhibitors. Among the isoforms, HDAC1 have particularly gained increased attention as a preferred target for the design of selective HDACIs. Accordingly, in this paper, we have developed a reliable virtual screening process, combining different ligand- and structure-based methods, to identify novel benzamide-based analogs with potential HDAC1 inhibitory activity. For this purpose, a focused library of 736,160 compounds from PubChem database was first compiled based on 80% structural similarity with four known benzamide-based HDAC1 inhibitors, Mocetinostat, Entinostat, Tacedinaline, and Chidamide. Our inclusive in-house 3D-QSAR model, derived from pharmacophore-based alignment, was then employed as a 3D-query to discriminate hits with the highest predicted HDAC1 inhibitory activity. The selected hits were subjected to subsequent structure-based approaches (induced-fit docking (IFD), MM-GBSA calculations and molecular dynamics (MD) simulation) to retrieve potential compounds with the highest binding affinity for HDAC1 active site. Additionally, in silico ADMET properties and PAINS filtration were also considered for selecting an enriched set of the best drug-like molecules. Finally, six top-ranked hit molecules, CID&#95;38265326, CID&#95;56064109, CID&#95;8136932, CID&#95;55802151, CID&#95;133901641 and CID&#95;18150975 were identified to expose the best stability profiles and binding mode in the HDAC1 active site. The IFD and MD results cooperatively confirmed the interactions of the promising selected hits with critical residues within HDAC1 active site. In summary, the presented computational approach can provide a set of guidelines for the further development of improved benzamide-based derivatives targeting HDAC1 isoform., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In the central nervous system (CNS), extra virgin olive oil (EVOO) produces interesting effects against neurodegenerative disorders including Alzheimer's disease (AD). The valuable properties of EVOO are largely ascribed to oleuropein aglycone (OA), its most abundant phenolic constituent. In particular, it has been demonstrated that in AD, OA produces strong neuroprotective effects being able to reduce amyloid β (Aβ) aggregates, thereby diminishing the related cytotoxicity and inflammation. OA prevents Aβ aggregation, but more importantly OA was able to disrupt the preformed Aβ fibrils. Herein, we describe a comprehensive computational investigation of the mechanism of action of OA as an Aβ fibril disruptor at the molecular level. We employed extensive molecular docking calculations and long-time molecular dynamics simulation for mimicking the system of OA/Aβ fibrils. The results showed that OA is able to move in depth within the Aβ fibrils targeting a key motif in Aβ peptide, known to be relevant for stabilizing the assembled fibrils. OA causes a structural instability of preformed Aβ fibrils, determining the effective Aβ fibril disaggregation. Accordingly, this study highlighted the role of OA as a potent anti-amyloidogenic drug. On the other hand, our work has relevant implications for rationally designing potent multifunctional compounds acting as disease modifying anti-Alzheimer's drugs for the development of innovative anti-AD therapeutics.

Background and Purpose: Cancer is the leading cause of death in today's world, therefore the efforts to achieve anticancer drugs with higher potency and fewer side effects have always been conducted by researchers in the field of pharmaceutical chemistry.Monastrol, a cytotoxic small molecule, from dihydropyrimidinone scaffold, is an inhibitor of the kinesin-5 protein. So, efforts to identify more derivatives of this molecule have been of interest., Experimental Approach: Some of monastrol's analogs as Eg5 inhibitors with different substitution patterns were analyzed, synthesized, and their cytotoxic effects were evaluated on MCF-7 and HeLa cancerous cells in vitro using the MTT assay. The structure-activity relationship (SAR) was studied in silico by molecular docking., Findings / Results: Among all proposed structures, in ducking study, those with hydrophobic moieties on the C2-N3 region, those with a hydroxyl group on the phenyl on C4 position, and those with a carboxylic group on C5 were the best candidates. In vitro studies, on the other side, emphasized that monastrol still was the most potent derivative. Another finding was the more moderate activity of synthesized compounds on the HeLa cell compared to the MCF-7 cell line. During different challenges for substitution at 5-position, some earlier reports around the dihydropyrimidinone reactions were questioned. It seems that the change at the position 5 is not merely accessible, as earlier reports claimed. Also, we could not achieve any better cell cytotoxicity by the larger group in the thiourea region or position 5; nonetheless, it seems that the introduction of a methylene group at this position could be beneficial., Conclusion and Implications: The initial results of this study were valuable in terms of design and synthesis and will be useful for future investigations., Competing Interests: The authors declare no conflicts of interest for this study., (Copyright: © 2020 Research in Pharmaceutical Sciences.)

Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R 2 = 0.958) and a satisfactory predictive power (Q 2 = 0.822; Q 2 F3 = 0.894). The model was validated (r 2 ext&#95;ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner-Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity.

The p53 protein, also called guardian of the genome, plays a critical role in the cell cycle regulation and apoptosis. This protein is frequently inactivated in several types of human cancer by abnormally high levels of its negative regulator, mouse double minute 2 (MDM2). As a result, restoration of p53 function by inhibiting p53-MDM2 protein-protein interaction has been pursued as a compelling strategy for cancer therapy. To date, a limited number of small-molecules have been reported as effective p53-MDM2 inhibitors. X-ray structures of MDM2 in complex with some ligands are available in Protein Data Bank and herein, these data have been exploited to efficiently identify new p53-MDM2 interaction antagonists through a hierarchical virtual screening strategy. For this purpose, the first step was aimed at compiling a focused library of 686,630 structurally suitable compounds, from PubChem database, similar to two known effective inhibitors, Nutlin-3a and DP222669. These compounds were subjected to the subsequent structure-based approaches (quantum polarized ligand docking and molecular dynamics simulation) to select potential compounds with highest binding affinity for MDM2 protein. Additionally, ligand binding energy, ADMET properties and PAINS analysis were also considered as filtering criteria for selecting the most promising drug-like molecules. On the basis of these analyses, three top-ranked hit molecules, CID&#95;118439641, CID&#95;60452010 and CID&#95;3106907, were found to have acceptable pharmacokinetics properties along with superior in silico inhibitory ability towards the p53-MDM2 interaction compared to known inhibitors. Molecular docking and molecular dynamics results well confirmed the interactions of the final selected compounds with critical residues within p53 binding site on the MDM2 hydrophobic clefts with satisfactory thermodynamics stability. Consequently, the new final scaffolds identified by the presented computational approach could offer a set of guidelines for designing promising anti-cancer agents targeting p53-MDM2 interaction., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an in silico structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed in vitro for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the in vitro tests along with no toxicity. Among them HPCAR-28 represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline HPCAR-28 as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN.

Background: Despite the progress in the discovery of antiretroviral compounds for treating HIV-1 infection by targeting HIV integrase (IN), a promising and well-known drug target against HIV-1, there is a growing need to increase the armamentarium against HIV, for avoiding the drug resistance issue., Objective: To develop novel HIV-1 IN inhibitors, a series of 3-hydroxy-pyrane-4-one (HP) and 3- hydroxy-pyridine-4-one (HPO) derivatives have been rationally designed and synthesized., Methods: To provide a significant characterization of the novel compounds, in-depth computational analysis was performed using a novel HIV-1 IN/DNA binary 3D-model for investigating the binding mode of the newly conceived molecules in complex with IN. The 3D-model was generated using the proto-type foamy virus (PFV) DNA as a structural template, positioning the viral polydesoxyribonucleic chain into the HIV-1 IN homology model. Moreover, a series of in vitro tests were performed including HIV-1 activity inhibition, HIV-1 IN activity inhibition, HIV-1 IN strand transfer activity inhibition and cellular toxicity., Results: Bioassay results indicated that most of HP analogues including HPa, HPb, HPc, HPd, HPe and HPg, showed favorable inhibitory activities against HIV-1-IN in the low micromolar range. Particularly halogenated derivatives (HPb and HPd) offered the best biological activities in terms of reduced toxicity and optimum inhibitory activities against HIV-1 IN and HIV-1 in cell culture., Conclusion: Halogenated derivatives, HPb and HPd, displayed the most promising anti-HIV profile, paving the way to the optimization of the presented scaffolds for developing new effective antiviral agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Tyrosinase is a key enzyme in pigment synthesis. Overproduction of melanin in parts of the skin results in hyperpigmentation diseases. This enzyme is also responsible for the enzymatic browning in fruits and vegetables. Thus, its inhibitors are of great importance in the medical, cosmetic and agricultural fields., Materials and Methods: A series of twelve kojic acid derivatives were designed to be evaluated as tyrosinase activity inhibitors. The potential inhibitory activity of these compounds was investigated in silico using molecular docking simulation method. Four compounds with a range of predicted tyrosinase inhibitory activities were prepared and their inhibitory effect on tyrosinase activity was evaluated. The antioxidant properties of these compounds were also investigated by in vitro DPPH (2,2-diphenyl-1-picrylhydrazyl) and hydrogen peroxide scavenging assays., Results: Compound IIId exhibited the highest tyrosinase inhibitory activity with an IC50 value of 0.216 ± 0.009 mM which was in accordance with the in silico ΔGbind results (-13.24 Kcal/mol)., Conclusion: Based on the docking studies, from the twelve compounds studied, one (IIId) appeared to have the highest inhibition on tyrosinase activity. This was confirmed by enzyme activity measurements. Compound IIId has an NO2 group which binds to both of Cu(2+) ions located inside the active site of the enzyme. This compound appeared to be even stronger than kojic acid in inhibiting tyrosinase activity. The DPPH free radical scavenging ability of all the studied compounds was more than that of BHT. However, they were not as strong as BHT or gallic acid in scavenging hydrogen peroxide.