Design, synthesis, and cytotoxicity evaluation of novel indole-acylhydrazone derivatives of 4-pyridinone as potential histone deacetylase-2 inhibitors.

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 (IC50) 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.

Sb(V) Kaempferol and Quercetin Derivative Complexes: Synthesis, Characterization and Antileishmanial Activities.

Background: Recent studies on Leishmaniasis treatment have confirmed the antiparasitic effects of flavonols and organic antimony pentavalent [(Sb(V)] complexes. Objectives: This study aimed to identify new Sb(V) complexes by combining the benefits of antimonials and flavonols as well as by optimizing their properties. Methods: Kaempferol and quercetin peracetate were prepared using acetic anhydride in pyridine. By performing regioselective synthesis, 7-O-paramethylbenzyl as an electron-donating group and 7-O-paranitrobenzyl as an electron-withdrawing group were added to quercetin, and, then, the synthesis of Sb(V) kaempferol and quercetin derivative complexes were performed using SbCl5 solution in glacial acetic acid. The structures were confirmed by UV, ESI mass, IR, 1H-, and 13C-NMR spectral data, and the Stoichiometry of the ligand-metal complex by the mole ratio method. Computational molecular modeling was conducted using the Gaussian program. Results: The structures were confirmed based on the results from UV, nuclear magnetic resonance (NMR), and electrospray ionization (ESI) mass analyses (3-12). Among the produced compounds, 11 and 12 as newly described, and other compounds as pre-defined compounds were identified. According to the results from biological test, kaempferol triacetate with more lipophilicity showed the highest anti-promastigote activity with an IC50 value of 14.93 ± 2.21 µM. As for anti-amastigote activity, despite the differences, all antimony complexes showed anti-amastigote effects in vitro with IC50 values of 0.52 to 14.50 µM. Conclusions: All flavonol Sb(V) complexes showed higher activity compared to meglumine antimonate in anti-amastigote effect. Inside the host macrophages, by breaking down the complex into antimony and quercetin or kaempferol analogs, the observed antiparasitic effects may have been related to both Sb(V)/Sb(III) conversion and flavonoid antileishmanial activities.

Design, synthesis, biological evaluation, and molecular modeling studies of pyrazole-benzofuran hybrids as new α-glucosidase inhibitor.

In this work, new derivatives of biphenyl pyrazole-benzofuran hybrids were designed, synthesized and evaluated in vitro through enzymatic assay for inhibitory effect against α-glucosidase activity. Newly identified inhibitors were found to be four to eighteen folds more active with IC50 values in the range of 40.6 ± 0.2-164.3 ± 1.8 µM, as compared to the standard drug acarbose (IC50 = 750.0 ± 10.0 µM). Limited Structure-activity relationship was established. A kinetic binding study indicated that most active compound 8e acted as the competitive inhibitors of α-glucosidase with Ki = 38 µM. Molecular docking has also been performed to find the interaction modes responsible for the desired inhibitory activity. As expected, all pharmacophoric features, used in the design of the hybrid, are involved in the interaction with the active site of the enzyme. In addition, molecular dynamic simulations showed compound 8e oriented vertically into the active site from mouth to the bottom and stabilized the enzyme domains by interacting with the interface of domain A and domain B and the back side of the active site while acarbose formed non-binding interaction with the residue belong to the domain A of the enzyme.

Synthesis and Antiplatelet Activity Evaluation of a Group of Novel Ethyl Acetoacetate Phenylhydrazone Derivatives.

A group of Novel phenylhydrazone derivatives of ethyl acetoacetate was synthesized and evaluated for their antiplatelet activities. Fourteen ethyl acetoacetate phenylhydrazone derivatives were synthesized using the diazonium salt of various aromatic primary amines with good yields and purity. The structure of the final compounds was confirmed and approved by spectroscopic techniques such as 1HNMR, FTIR, and ESI-Mass. We examined the antiplatelet activity of the derivatives against Arachidonic Acid (AA) and Adenosine Diphosphate (ADP) as platelet aggregation inducers. The final results indicated the acceptable potency for different derivatives. In this regard, the para-hydroxyphenylhydrazine derivative of ethyl acetoacetate has the best activity among all derivatives, both on AA and ADP pathways. It seems that the derivatives with electron-releasing substituents (hydroxyl, methoxy, and methyl group) have better inhibition activities against the aggregation induced by AA. In contrast, those with an electron-withdrawing group showed a significant decrease in their potency. Based on the results of this study, we would proceed with further assessments both in-vitro and in-vivo to get success in introducing some new antiplatelet agents to the clinic.

Design and synthesis of novel quinazolinone-pyrazole derivatives as potential α-glucosidase inhibitors: Structure-activity relationship, molecular modeling and kinetic study.

In this study, a new series of quinazolinone-pyrazole hybrids were designed, synthesized and screened for their α-glucosidase inhibitory activity. The results of the in vitro screening indicated that all the molecular hybrids exhibited more inhibitory activity (IC50 values ranging from 60.5 ± 0.3 µM-186.6 ± 20 µM) in comparison to standard acarbose (IC50 = 750.0 ± 10.0 µM). Limited structure-activity relationship suggested that the variation in the inhibitory activities of the compounds affected by different substitutions on phenyl rings of diphenyl pyrazole moiety. The enzyme kinetic studies of the most potent compound 9i revealed that it inhibited α-glucosidase in a competitive mode with a Ki of 56 µM. Molecular docking study was performed to predict the putative binding interaction. As expected, all pharmacophoric moieties used in the initial structure design playing a pivotal role in the interaction with the binding site of the enzyme. In addition, by performing molecular dynamic investigation and MM-GBSA calculation, we investigated the difference in structural perturbation and dynamic behavior that is observed over α-glycosidase in complex with the most active compound and acarbose relative to unbound α-glycosidase enzyme.

Synthesis, antioxidant activity, and density functional theory study of some novel 4-[(benzo[d]thiazol-2-ylimino)methyl]phenol derivatives: a comparative approach for the explanation of their radical scavenging activities.

BACKGROUND AND PURPOSE: Radicals produced by Fenton and Haber-Weiss reactions play detrimental roles in our body. Some oxidized proteins as toxic configurations are identified in amyloid-ß deposits. These deposits mostly occur in conditions, such as Alzheimer's disease. Here, we report the synthesis, evaluation of the antioxidant activity, and implementation of density functional theory (DFT) calculations of some4- [(benzo[d]thiazol-2-ylimino) methyl]phenol derivatives. The aim of this study was to provide a comparative theoretical-experimental approach to explain the antioxidant activities of the compounds. EXPERIMENTAL APPROACH: Compounds were synthesized by the reaction between para hydroxybenzaldehyde and aminobenzothiazole derivatives. The scavenging activity of the compounds was evaluated. Various electronic and energetic descriptors such as high occupied molecular orbital and low unoccupied molecular orbital energy gaps, bonding dissociation enthalpy of OH bond, ionization potential, electron affinity, hardness, softness, and spin density of the radical and neutral species were calculated. DFT calculations with B3LYP hybrid functional and 6-311++ G** basis set in the polarizable continuum model were utilized to obtain these descriptors. FINDINGS/RESULTS: Ascorbic acid showed the best DPPH scavenging activity. However, 4d and 4c showed promising antioxidant activity. The values of EHOMO for 4c and 4d were closer to zero, thus, they showed the best scavenging activities. The computational results were in accordance with the experimental ones. The energetic descriptors indicated that the sequential proton loss-electron transfer mechanism is preferred over other mechanisms. CONCLUSION AND IMPLICATION: Antioxidant activity of 4-[(Benzo[d]thiazol-2-ylimino) methyl]phenol derivatives confirmed by experimental and theoretical documents proves them as novel antioxidants against amyloid-ß based disease.

Design and synthesis of novel pyrazole-phenyl semicarbazone derivatives as potential α-glucosidase inhibitor: Kinetics and molecular dynamics simulation study.

A series of novel pyrazole-phenyl semicarbazone derivatives were designed, synthesized, and screened for in vitro α-glucosidase inhibitory activity. Given the importance of hydrogen bonding in promoting the α-glucosidase inhibitory activity, pharmacophore modification was established. The docking results rationalized the idea of the design. All newly synthesized compounds exhibited excellent in vitro yeast α-glucosidase inhibition (IC50 values in the range of 65.1-695.0 µM) even much more potent than standard drug acarbose (IC50 = 750.0 µM). Among them, compounds 8o displayed the most potent α-glucosidase inhibitory activity (IC50 = 65.1 ± 0.3 µM). Kinetic study of compound 8o revealed that it inhibited α-glucosidase in a competitive mode (Ki = 87.0 µM). Limited SAR suggested that electronic properties of substitutions have little effect on inhibitory potential of compounds. Cytotoxic studies demonstrated that the active compounds (8o, 8k, 8p, 8l, 8i, and 8a) compounds are also non-cytotoxic. The binding modes of the most potent compounds 8o, 8k, 8p, 8l and 8i was studied through in silico docking studies. Molecular dynamic simulations have been performed in order to explain the dynamic behavior and structural changes of the systems by the calculation of the root mean square deviation (RMSD) and root mean square fluctuation (RMSF).

Pharmacophore Modeling, Synthesis, Scaffold Hopping and Biological ß- Hematin Inhibition Interaction Studies for Anti-malaria Compounds.

Backgound: Exploring potent compounds is critical to generating multi-target drug discovery. Hematin crystallization is an important mechanism of malaria. METHODS: A series of chloroquine analogues were designed using a repositioning approach to develop new anticancer compounds. Protein-ligand interaction fingerprints and ADMET descriptors were used to assess docking performance in virtual screenings to design chloroquine hybrid ß-hematin inhibitors. A PLS algorithm was applied to correlate the molecular descriptors to IC50 values. The modeling presented excellent predictive power with correlation coefficients for calibration and cross-validation of r2 = 0.93 and q2 = 0.72. Using the model, a series of 4-aminoquinlin hybrids were synthesized and evaluated for their biological activity as an external test series. These compounds were evaluated for cytotoxic cell lines and ß-hematin inhibition. RESULTS: The target compounds exhibited high ß-hematin inhibition activity and were 3-9 times more active than the positive control. Furthermore, all the compounds exhibited moderate to high cytotoxic activity. The most potent compound in the dataset was docked with hemoglobin and its pharmacophore features were generated. These features were used as input to the Pharmit server for screening of six databases. CONCLUSION: The compound with the best score from ChEMBL was 2016904, previously reported as a VEGFR-2 inhibitor. The 11 compounds selected presented the best Gold scores with drug-like properties and can be used for drug development.

Identification of Essential 2D and 3D Chemical Features for Discovery of the Novel Tubulin Polymerization Inhibitors.

BACKGROUND: Tubulin polymerization inhibitors interfere with microtubule assembly and their functions lead to mitotic arrest, therefore they are attractive target for design and development of novel anticancer compounds. OBJECTIVE: The proposed novel and effective structures following the use of three-dimensionalquantitative structure activity relationship (3D-QSAR) pharmacophore based virtual screening clearly demonstrate the high efficiency of this method in modern drug discovery. METHODS: Combined computational approach was applied to extract the essential 2D and 3D features requirements for higher activity as well as identify new anti-tubulin agents. RESULTS: The best quantitative pharmacophore model, Hypo1, exhibited good correlation of 0.943 (RMSD=1.019) and excellent predictive power in the training set compounds. Generated model AHHHR, was well mapped to colchicine site and three-dimensional spatial arrangement of their features were in good agreement with the vital interactions in the active site. Total prediction accuracy (0.92 for training set and 0.86 for test set), enrichment factor (4.2 for training set and 4.5 for test set) and the area under the ROC curve (0.86 for training set and 0.94 for the test set), the developed model using Extended Class FingerPrints of maximum diameter 4 (ECFP_4) was chosen as the best model. CONCLUSION: Developed computational platform provided a better understanding of requirement features for colchicine site inhibitors and we believe the results of this study might be useful for the rational design and optimization of new inhibitors.

Gp41 inhibitory activity prediction of theaflavin derivatives using ligand/structure-based virtual screening approaches.

Gp41 and its conserved hydrophobic groove on the NHR region is one of the attractive targets in the design of HIV-1 entry inhibitory agents. This hydrophobic pocket is very critical for the progression of HIV and host cell fusion. In this study different ligand-based (structure similarity search) and structure-based (molecular docking and molecular dynamic simulation) methods were performed in a virtual screening procedure to select the best compounds with the most probable HIV-1 gp41 inhibitory activities. In silico pharmacokinetics and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties filtration also was considered to choose the compounds with best drug-like properties. The results of molecular docking and molecular dynamic simulations of the final selected compounds showed suitable stabilities of their complexes with gp41. The final selected hits could have better pharmacokinetics properties than the template compound, theaflavin digallate (TF3), a naturally-originated potent gp41 inhibitor.

Synthesis and In vitro Leishmanicidal Activities of Six Quercetin Derivatives.

BACKGROUND: Today, leishmaniasis is a widespread, infectious parasitic disease caused by Leishmania spp. Natural-derived compounds are likely to provide a valuable source of new pharmaceuticals, and among them, quercetin derivatives may have antileishmanial effects. The antileishmanial activity of 3,5,7,3',4'-pentahydroxyflavonol (quercetin) derivatives is partly attributed to the position and pKa of phenolic or catechol hydroxyl groups. Therefore, to optimize their leishmanicidal effect, the structural features of quercetin and its derivatives were improved by acylation or alkylation of hydroxyl groups and changing their pKa and consequently their activities. MATERIALS AND METHODS: In this study, during a regioselective method, quercetin derivatives were synthesized. The structures of synthesized compounds were confirmed by mass, IR, 1H-, and 13C-NMR spectral data. The antileishmanial activities of compounds 1-6 were compared with glucantime as the standard drug against promastigotes of Leishmania major using standard cell-based leishmanicidal assay. RESULTS: In this study, during a regioselective method, two 7-O-quercetin derivatives (5 and 6), and three quercetin acetate derivatives (2, 3, and 4) were synthesized. In detail, the IC50 values found against L. major were (1) 2.5 ± 0.92; (2) 2.85 ± 0.99; (3) 15.5 ± 1.95; (4) 13.5 ± 3.5; (5) 2.6 ± 0.57; and (6) 1.3 ± 0.35 µM while IC50 value of glucantime as the standard drug was 88.5 ± 9.47 µM. CONCLUSIONS: The present study showed an effective antileishmanial activity of quercetin semisynthetic compounds (1-6) against in vitro promastigotes of L. major. Among them, quercetin analogs with more lipophilic and iron-chelating activity showed more antiparasite activity.

Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands.

A novel series of antimony (V) complexes with the hydroxypyranone and hydroxypyridinone ligands were synthesized and characterized by 1HNMR, FT-IR and electron spin ionization mass spectroscopic (ESI-MS) techniques. The synthesis process involved protection of hydroxyl group followed by the reaction of the intermediate with primary amines and finally deprotection. All compounds were evaluated for in vitro activities against the amastigote and promastigote forms of Leishmania major. Most of the synthesized compounds exhibited good antileishmanial activity against both forms of L. major. IC50 values of the most active compounds; 9d, 9d and 9e, after 24, 48 and 72 h against amastigote model were 15, 12.5 and 5.5 µg/mL, respectively. 9e, 11 and 9e inhibited the promastigote form of parasite after 24, 48 and 72 h with IC50 values of 10, 2 and 1 µg/mL, respectively.

Quantum mechanical/molecular mechanical and docking study of the novel analogues based on hybridization of common pharmacophores as potential anti-breast cancer agents.

In an attempt to identify some new potential leads as anti-breast cancer agents, novel hybrid compounds were designed by molecular hybridization approach. These derivatives were structurally derived from hybrid benzofuran-imidazole and quinazolinone derivatives, which had shown good cytotoxicity against the breast cancer cell line (MCF-7). Since aromatase enzyme (CYP19) is highly expressed in the MCF-7 cell line, the binding of these novel hybrid compounds to aromatase was investigated using the docking method. In this study, due to the positive charge on the imidazole ring of the designed ligands and also, the presence of heme iron in the active site of the enzyme, it was decided to optimize the ligand inside the protein to obtain more realistic atomic charges for it. Quantum mechanical/molecular mechanical (QM/MM) method was used to obtain more accurate atomic charges of ligand for docking calculations by considering the polarization effects of CYP19 on ligands. It was observed that the refitted charge improved the binding energy of the docked compounds. Also, the results showed that these novel hybrid compounds were adopted properly within the aromatase binding site, thereby suggesting that they could be potential inhibitors of aromatase. The main binding modes in these complexes were through hydrophobic and H bond interactions showing agreement with the basic physicochemical features of known anti aromatase compounds. Finally, the complex structures obtained from the docking study were used for single point QM/MM calculations to obtain more accurate electronic interaction energy, considering the electronic polarization of the ligand by its protein environment.

A study on the anti-inflammatory effects of new derivatives of 3-hydroxy pyridine-4-one.

BACKGROUND: Derivatives of pyridine-4-one act as iron chelators and possess various pharmacological effects such as antifungal, antimalarial, antiviral, anti-inflammatory, and analgesic effects. The aim of our study was to evaluate the anti-inflammatory effects of the three new derivatives of pyridine-4-one. MATERIALS AND METHODS: Carrageenan-induced paw edema in rats and croton oil-induced ear edema in mice were used to evaluate the anti-inflammatry effects of three 3-hydroxy-pyridine-4-one derivatives (compounds A, B, and C). Compound A (10, 20 mg/kg), compound B (200, 400 mg/kg), and compound C (100, 200 mg/kg), vehicle (1 mL/kg), and indomethacin as standard drug (10 mg/kg) were injected intraperitoneally 30 min prior to carrageenan injection and 4 h later, the paw volume was measured using a mercury plethysmograph. The maximum dose of each test compound was used in the croton oil-induced ear edema test. RESULTS: All compounds showed significant anti-inflammatory activity in both tests. On a molar basis, compound A had the greatest potency, which may be due to the presence of a benzyl group substitution on the pyridine ring. CONCLUSIONS: Because cyclooxygenase and lipoxygenase as key enzymes of the inflammation pathway are heme-dependent, it seems that the anti-inflammatory effect of derivatives of pyridine-4-one may be related to their iron chelating properties. However, more investigations are needed to find out their exact mechanism of actions.

Computer-aided design of novel antibacterial 3-hydroxypyridine-4-ones: application of QSAR methods based on the MOLMAP approach.

3-Hydroxypyridine-4-one derivatives have shown good inhibitory activity against bacterial strains. In this work we report the application of MOLMAP descriptors based on empirical physicochemical properties with genetic algorithm partial least squares (GA-PLS) and counter propagation artificial neural networks (CP-ANN) methods to propose some novel 3-hydroxypyridine-4-one derivatives with improved antibacterial activity against Staphylococcus aureus. A large collection of 302 novel derivatives of this chemical scaffold was selected for this purpose. The activity classes of these compounds were determined using the two quantitative structure activity relationships models. To evaluate the predictability and accuracy of the obtained models, nineteen compounds belonging to all three activity classes were prepared and the activity of them was determined against S. aureus. Comparing the experimental results and the predicted activity classes revealed the accuracy of the obtained models. Seventeen of the nineteen synthesized molecules were correctly predicted by GA-PLS model according to the antimicrobial evaluation method. Molecules 5f and 5h proved to be moderately active and active experimentally, but were predicted as inactive and moderately active compounds, respectively by this model. The CP-ANN based prediction was correct for sixteen out of the nineteen synthesized molecules. 5a, 5h and 5q were moderately active and active based on the antimicrobial assays, but they were introduced as members of inactive, moderately active and inactive classes of compounds, respectively according to CP-ANN model.