mehdi khoshneviszadeh

Tyrosinase is an essential enzyme in melanin production, which plays an important role in the browning of plants and vegetables and skin diseases in humans. Therefore, the design and synthesis of tyrosinase inhibitors are important in the food industry and in treating melanin-related skin diseases. In this study, the tyrosinase inhibitory activity and the antioxidant capacity of a series of 3-hydroxypyridin-4-one derivatives that have been synthesized in the Department of Medicinal Chemistry at the Faculty of Pharmacy, Shiraz University of Medical Sciences, were assessed. The antioxidant activities were evaluated using the 1,1-diphenyl-2-picrylhydrazine (DPPH) radical scavenging method. The biological results indicated that these derivatives exhibit mild anti-tyrosinase and antioxidant properties. Docking studies were also conducted, and the results showed that the compounds have suitable binding free energy and interactions with the active site of the tyrosinase enzyme, which were not consistent with the biological results. Finally, the investigation of the pharmacokinetic characteristics and drug-likeness of the derivatives showed that they have the potential for oral bioavailability.

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.

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.

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.

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.

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.

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.

Melanogenesis is a process of melanin synthesize, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin formation, natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti-tyrosinase agents. Therefore its inhibition may be an efficient way for the development of depigmenting agents. A novel series of 2-arylidine-1H-indene-1,3(2H)-dione analogs were designed, synthesized and screened for their in vitro tyrosinase inhibitory activity. 3d derivative bearing nitrothiophene revealed excellent anti-tyrosinase activity with an IC50 value of 3.55 μM comparable to kojic acid as a positive control. 3d as the most potent inhibitor and 3f as the least active derivative were subjected to in silico evaluations considering the 3D conformations, ΔGb of bindings and interactions within the active site of tyrosinase.

The aim of this study was to evaluate the in vitro and in vivo anti-Toxoplasma gondii (T. gondii) effect of 5-oxo-hexahydroquinoline compounds. Moreover, molecular docking study of the compounds into the active site of enoyl-acyl carrier protein reductase (ENR) as a necessary enzyme for the vitality of apicoplast was carried out.

A number of 5-oxo-hexahydoquinoline derivatives (Z1-Z4) were synthesized. The T. gondii tachyzoites of RH strain were treated by different concentrations (1-64 μg/mL) of the compounds. The viability of the encountered parasites with compounds was assessed using flow cytometry and propidium iodide (PI) staining. Due to the high mortality effect of Z3 and Z4 in vitro, their chemotherapy effect was assessed by inoculation of tachyzoites to four BALB/c mice groups (n = 5), followed by the gavage of various concentrations of the compounds to the mice. Molecular docking was done to study the binding affinity of the synthesized 5-oxo-hexahydroquinolines into ENR enzyme active site byusing AutoDock Vina® software. Docking was performed by a Lamarckian Genetic Algorithm with 100 runs.

Flow cytometry assay results indicated compounds Z3 and Z4 had relevant mortality effect on parasite tachyzoites. Besides, in vivo experiments were also performed and a partial increase of mice longevity between control and experiment groups was recorded. Molecular docking of Z3 and Z4 in the binding site of ENR enzyme indicated that the compounds were well accommodated within the binding site. Therefore, it could be suggested that these compounds may exert their anti-T. gondii activity through the inhibition of the ENR enzyme.

Compounds Z3 and Z4 are good leads in order to develop better anti-T. gondii agents as they demonstrated both in vitro and in vivo inhibitory effects on tachyzoites viability and infection. Further studies on altering the route of administration along with additional pharmacokinetics evaluations are needed to improve the anti-T. gondii impacts of 5-oxo-hexahydroquinoline compounds.

Among Recent advances in the identification of anti-inflammation agents, anti-cytokines (like Interleukin-1), related to p38 MAPK families play an important role; Here in we designed new effective and low toxic anti-cytokine agents based on 1-Hydroxy-2,4,5-triaryl imidazole derivatives. The reaction of oximoinoketone intermediate with ten different aromatic aldehyde and ammonium acetate in refluxing acetic acid condition give imidazole derived product, the IL-1β inhibitory assay were performed on Human PBMCs (peripheral blood mononuclear cells) using an enzyme-linked immunosorbent assay (ELISA) kit and then in computational part the binding mode of the best compound was accomplished  by docking in Crystal structure of p38 MAP kinase (PDB ID: 1A9U) compared with SB202190 as standard drug. All compounds were synthesized and evaluated in biological assay showing the inhibitory activity from 28% to 82% compared to SB202190 and binding mode analysis revealed that the hydrogen-bond interactions with residues (Met109, Val30) were key point in inhibitor binding. Compound 5g clearly proved the best inhibitory action and could be further utilized for designing newer anti-cytokine agents and p38α MAP kinase potentially inhibitory action.

Given the importance of Stachys genus in Iran and their significant biological activity, we collected three species of this plant: St. aucheri Benth., Stachys benthamiana Boiss and St. inflata Benth. from different regions of Iran. We examined the free radical scavenging potential, total phenol content and tyrosinase inhibitory activity of their methanol, methanol 80% and dichloromethane extracts.

Antioxidant activity and total phenol content of the mentioned extracts were assessed using DPPH and FolinCiocalteu reagent, respectively. The inhibitory activity of the extracts on tyrosinase was also investigated.

Total phenol content of different extracts was high in the extracts as 98.5-139.7 mg eq. gallic acid/g in methanol 80% extract, 36.8-54.7 mg eq. gallic acid/g in methanol extract and 17.9-44.9 mg eq. gallic acid/g  in dichloromethane extract. Furthermore, their antioxidant activity was correlated with total phenol content of the extracts. Methanol 80% extract had the highest total phenol content and antioxidant activity. Evaluation of the tyrosinase inhibitory potential of the extracts revealed that St.inflata exhibited a considerable inhibitory potential (IC50= 5.4 ± 0.6 µM).

It can be concluded that tyrosinase inhibitory activity of Stachys genus might be due to the less polar compounds and these compounds are mostly present in the dichloromethane extract of St. inflatai over St. aucheri and St. benthamiana

Dipeptidyl peptidase IV (DPP-4) is a serine protease that plays a crucial role in glucose metabolism; hence, it is a significant target for type II diabetes mellitus treatment. DPP-4 inhibitors decrease glucose concentrations in such patients by preventing the rapid degradation and thereby lengthening the physiological actions of hypoglycemic incretin hormones. In this study, a structure-based virtual screening strategy was applied to search for novel natural DPP4 inhibitors. From the Supernatural database, 1856 natural structures were picked up and were subjected to molecular docking analysis. Thirteen of them were identified to form more stable complexes than the co-crystallized ligand with the DPP-4 protein. The drug-likeness and pharmacokinetic properties of the top five compounds were also predicted. It was proved that the compounds were compliant with the drug-likeness rules and possess favorable pharmacokinetic properties. The proposed natural compounds can be introduced as potential DPP-4 inhibitors that might be promising leads for further drug development.

Mammalian target of rapamycin (mTOR) is a phosphoinositide 3-kinase-related protein kinase which controls cell growth and is frequently deregulated in many cancers. Therefore, mTOR inhibitors are used as antineoplastic agents for cancer treatment. In this study, 1,2,4-triazine derivatives containing different arylidene-hydrazinyl moieties were designed and synthesized. Cytotoxicity of the compounds was evaluated on HL-60 and MCF-7 cell lines by MTT assay. S1, S2 and S3 exhibited good cytotoxic activity on both cell lines with an IC50 range of 6.42 - 20.20 μM. In general, substitution of a five-membered heterocyclic ring containing NO2, such as 5-nitrofuran-2-yl, resulted in the best potency. Molecular docking analysis was performed to study the possible interactions and binding modes of all the triazine derivatives with mTOR receptor. The most promising compound, S1, was well accommodated within the active site and had the least estimated free energy of binding (even less than the inherent ligand of the protein, PDB ID: 4JT6). It is concluded from both MTT assay and docking studies that the arylidene moiety linked to the hydrazinyl part of the structure had a prominent role in cytotoxicity and mTOR inhibitory activity.

The IL-1β play a major role in inflammatory disorders and IL-1β production inhibitors can be used in the treatment of inflammatory and related diseases. In this study, quantitative relationships between the structures of 46 pyridazine derivatives (inhibitors of IL-1β production) and their activities were investigated by Multiple Linear Regression (MLR) technique Stepwise Regression Method (ES-SWR). The genetic algorithm (GA) has been proposed for improvement of the performance of the MLR modeling by choosing the most relevant descriptors. The results show that eight descriptors are able to describe about 83.70% of the variance in the experimental activity of the molecules in the training set. The physical meaning of the selected descriptors is discussed in detail. Power predictions of the QSAR models developed were evaluated using cross-validation, and validation through an external prediction set. The results showed satisfactory goodness-of-fit, robustness and perfect external predictive performance. The applicability domain was used to define the area of reliable predictions. Furthermore, the in silico screening technique was applied in order to predict the structure and potency of new compounds of this type using the proposed QSAR model.

Apoptosis is critical for tissue homeostasis and for the physiological removal of abnormal cells. Bcl-2 family proteins are important regulators of apoptosis. It’s observed that antiapototic Bcl-2 family members are generally over expressed in many cancer cells. As a result, it has stimulated a growing interest in the discovery of small molecules targeting such proteins as potential anticancer therapeutics. With the aim of designing and virtual screening of new phenanthrene based Bcl-2 inhibitors, we performed a cross-docking study. This study is done for different available Bcl-2 X-ray crystal structures in order to find the most appropriate PDB code of this enzyme. After analytical analyses, we found a PDB code for the enzyme. Designed library of phenanthrene triazine containing different hydrazone moieties was further screened using selected crystal structure. It identifies the ligand which interacts the target with lower binding energy. As a conclusion, cross docking study could be a validated strategy for finding the most appropriate crystal structure for docking study. Our designed library of phenanthrene triazine-based derivatives containing hydrazone pendant could be served as potential candidates for Bcl-2 inhibition.

Dichloroacetate (DCA) is a pyruvate mimetic compound that stimulates the activity of the enzyme pyruvate dehydrogenase (PDH) through inhibition of the enzyme pyruvate dehydrogenase kinases (PDK1-4). DCA works by turning on the apoptosis which is suppressed in tumor cells, hence let them to die on their own. Here, in this paper a series of DCA analogues were applied to quantitative structure–activity relationship (QSAR) analysis. A collection of chemometrics methods such as multiple linear regression (MLR), factor analysis–based multiple linear regression (FA-MLR), principal component regression (PCR), simple Free-Wilson analysis (FWA) and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were conducted to make relations between structural features and cytotoxic activities of a variety of DCA derivatives. The best multiple linear regression equation obtained from genetic algorithms partial least squares which predict 91% of variances. On the basis of the produced model, an in silico-screening study was also employed and new potent lead compounds based on new structural patterns were suggested. Docking studies of these compounds were also investigated and promising results were obtained. The docking results were also conducted to protein ligand interaction fingerprints (PLIF) studies using self-organizing map (SOM) in order to evaluate the predictive ability in suggesting new potent compounds and some compounds were introduced as a good candidates for synthesis.

Some N-substituted piperidine structures were synthesized and evaluated for cytotoxic activity against four different cell lines using the standard MTT assay method and Doxorubicin was used as the reference drug. The result of cytotoxic activity as a measurement of IC50 values revealed that three of the synthesized compounds were active against breast cancer cell line. Compound 6a bearing hydroxyl at para position of piperidine ring was the most active compound within this series. The N-subtituted piperidine with propene substructure could be considered as a lead structure for further studies of structure activity relationship to develop more potent compounds in future.

The complex metabolic syndrome, diabetes mellitus, is a major human health concern in the world and is estimated to affect 300 million people by the year 2025. Several drugs such as sulfonylureas and biguanides are presently available to reduce hyperglycemia in diabetes mellitus. These drugs have side effects and thus searching for a new class of compounds is essential to overcome this problems. A series of seven novel N-(4-phenylthiazol-2-yl)benzenesulfonamides derivatives were synthesized and assayed in-vivo to investigate their antidiabetic activities by streptozotocin-induced model in rat. These derivatives showed considerable biological efficacy when compared to glibenclamide, a potent and well-known antidiabetic agent, as a reference drug. Four of the compounds were effective, amongst which 13 show more prominent activity at 100 mg/Kg p.o. The experimental results are statistically significant at p < 0.05 level.