Synthesis, biological evaluation, molecular docking, MD simulation and DFT analysis of new 3-hydroxypyridine-4-one derivatives as anti-tyrosinase and antioxidant agents.

In the present study, ten new substituted 3-hydroxypyridine-4-one derivatives were synthesized in a four-step method, and their chemical structures were confirmed using various spectroscopic techniques. Subsequently, the inhibitory activities of these derivatives against tyrosinase enzyme and their antioxidant activities were evaluated. Amongest the synthesized compounds, 6b bearing a 4-OH-3-OCH3 substitution was found to be a promising tyrosinase inhibitor with an IC50 value of 25.82 µM, which is comparable to the activity of kojic acid as control drug. Kinetic study indicated that compound 6b is a competitive inhibitor of tyrosinase enzyme, which was confirmed by molecular docking results. The molecular docking study and MD simulation showed that compound 6b was properly placed within the tyrosinase binding pocket and interacted with key residues, which is consistent with its biological activity. The DFT analysis demonstrated that compound 6b is kinetically more stable than the other compounds. In addition, compounds 6a and 6b exhibited the best antioxidant activities. The findings indicate that compound 6b could be a promising lead for further studies.

New 3-Hydroxypyridine-4-one Analogues: Their Synthesis, Antimicrobial Evaluation, Molecular Docking, and In Silico ADME Prediction.

INTRODUCTION: Drug resistance to existing antimicrobial drugs has become a serious threat to human health, which highlights the need to develop new antimicrobial agents. METHOD: In this study, a new set of 3-hydroxypyridine-4-one derivatives (6a-j) was synthesized, and the antimicrobial effects of these derivatives were evaluated against a variety of microorganisms using the microdilution method. The antimicrobial evaluation indicated that compound 6c, with an electron-donating group -OCH3 at the meta position of the phenyl ring, was the most active compound against S. aureus and E. coli species with an MIC value of 32 µg/mL. Compound 6c was more potent than ampicillin as a reference drug. RESULT: The in vitro antifungal results showed that the studied derivatives had moderate effects (MIC = 128-512 µg/mL) against C. albicans and A. niger species. The molecular modeling studies revealed the possible mechanism and suitable interactions of these derivatives with the target protein. CONCLUSION: The obtained biological results offer valuable insights into the design of more effective antimicrobial agents.

Synthesis, design, biological evaluation, and computational analysis of some novel uracil-azole derivatives as cytotoxic agents.

The design and synthesis of novel cytotoxic agents is still an interesting topic for medicinal chemistry researchers due to the unwanted side effects of anticancer drugs. In this study, a novel series of uracil-azole hybrids were designed and synthesized. The cytotoxic activity, along with computational studies: molecular docking, molecular dynamic simulation, density functional theory, and ADME properties were also, evaluated. The compounds were synthesized by using 3-methyl-6-chlorouracil as the starting material. Cytotoxicity was determined using MTT assay in the breast carcinoma cell line (MCF-7) and Hepatocellular carcinoma cell line (HEPG-2). These derivatives demonstrated powerful inhibitory activity against breast and hepatocellular carcinoma cell lines in comparison to Cisplatin as positive control. Among these compounds, 4j displayed the best selectivity profile and good activity with IC50 values of 16.18 ± 1.02 and 7.56 ± 5.28 µM against MCF-7 and HEPG-2 cell lines respectively. Structure-activity relationships revealed that the variation in the cytotoxic potency of the synthesized compounds was affected by various substitutions of benzyl moiety. The docking output showed that 4j bind well in the active site of EGFR and formed a stable complex with the EGFR protein. DFT was used to investigate the reactivity descriptors of 4a and 4j. The outputs demonstrated that these uracil-azole hybrids can be considered as potential cytotoxic agents.

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

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

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

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

Comparison of Protective Effects of Phenolic Acids on Protein Glycation of BSA Supported by In Vitro and Docking Studies.

Several diabetic complications are associated with forming advanced glycation end products (AGEs). Different chemical and natural compounds are able to prevent the development of these products. In this study, glycosylation was induced as a model by incubating bovine serum albumin (BSA) with glucose. Consequently, BSA was treated with glucose and different concentrations (1.25, 2.5, and 5 µM) of syringic acid, gallic acid, ellagic acid, ferulic acid, paracoumaric acid, and caffeic acid for 4 and 6 weeks. Biochemical experiments comprise measurements of fluorescent AGEs, protein carbonyl contents, total thiol, hemolysis tests, and also malondialdehyde (MDA) levels in RBC. These demonstrated the antiglycating mechanism of these phenolic acids. Most of the phenolic acids used in this study reduced MDA levels and protected thiol residues in protein structures. They also inhibited the formation of fluorescent AGEs and RBC lysis, except gallic acid. Moreover, ferulic acid, paracoumaric acid, and caffeic acid proteins significantly prevent carbonylation. Molecular docking and simulation studies showed that ellagic, caffeic, gallic, and syringic acids could interact with lysine and arginine residues in the active site of BSA and stabilize its structure to inhibit the formation of AGEs. Our results suggest that phenolic acid could be used as a potential phytochemical against protein glycation and related diabetic complications.

Quinazoline analogues as cytotoxic agents; QSAR, docking, and in silico studies.

BACKGROUND AND PURPOSE: Synthesis and investigation of pharmacological activity of novel compounds are time and money-consuming. However, computational techniques, docking, and in silico studies have facilitated drug discovery research to design pharmacologically effective compounds. EXPERIMENTAL APPROACH: In this study, a series of quinazoline derivatives were applied to quantitative structure-activity relationship (QSAR) analysis. A collection of chemometric methods were conducted to provide relations between structural features and cytotoxic activity of a variety of quinazoline derivatives against breast cancer cell line. An in silico-screening was accomplished and new impressive lead compounds were designed to target the epidermal growth factor receptor (EGFR)-active site based on a new structural pattern. Molecular docking was performed to delve into the interactions, free binding energy, and molecular binding mode of the compounds against the EGFR target. FINDINGS/RESULTS: A comparison between different methods significantly indicated that genetic algorithm-partial least-squares were selected as the best model for quinazoline derivatives. In the current study, constitutional, functional, chemical, resource description framework, 2D autocorrelation, and charge descriptors were considered as significant parameters for the prediction of anticancer activity of quinazoline derivatives. In silico screening was employed to discover new compounds with good potential as anticancer agents and suggested to be synthesized. Also, the binding energy of docking simulation showed desired correlation with QSAR and experimental data. CONCLUSION AND IMPLICATIONS: The results showed good accordance between binding energy and QSAR results. Compounds Q1-Q30 are desired to be synthesized and applied to in vitro evaluation.

Synthesis of some novel dibromo-2-arylquinazolinone derivatives as cytotoxic agents.

Recently the quinazoline derivatives have attracted much attention for their anticancer properties. In this study a series of new brominated quinazoline derivatives (1a-1g) were synthesized in two steps. In the first step we used N-bromosuccinimide to brominate the anthranilamid. Then in the second step we closed the quinazoline ring by different aromatic aldehydes. Our aldehydes contain different electron donating or electron withdrawing groups at different positions of the aromatic ring. The chemical structures of products were confirmed by spectroscopic methods such as IR, 1HNMR, 13CNMR, and mass spectroscopy. The cytotoxic activities of the compounds were assessed on three cancerous cell lines including MCF-7, A549, and SKOV3 using colorimetric MTT cytotoxic assay in comparison with cisplatin as a standard drug. Our results collectively indicated that 1f and 1g, exhibited the best anti-proliferative activities on three investigated cancerous cell lines.

Novel Catechol Derivatives of Arylimidamides as Antileishmanial Agents.

Two novel bis-arylimidamide derivatives with terminal catechol moieties (9a and 10a) and two parent compounds with terminal phenyl groups (DB613 and DB884) were synthesized as dihydrobromide salts (9b and 10b). The designed compounds were hybrid molecules consisting of a catechol functionality embedded in an arylimidamide moiety. All compounds were examined for in vitro antiparasitic activity upon promastigotes of Leishmania major and L. infantum as well as axenic amastigotes of L. major. It was shown that conversion of terminal phenyl groups into catechol moieties resulted in more than 10-fold improvement in potency, coupled with lower cytotoxicity against fibroblast cells, compared to the corresponding parent compounds. The furan-containing analog 9a exhibited the highest activity with submicromolar IC50 values, ranging from 0.29 to 0.36 µm, which is comparable in efficacy to the reference drug amphotericin B (IC50 0.28 - 0.33 µm). The results justify further study of this class of compounds. It seems that the combination of catechol chelating groups with potent antiparasitic agents could improve the efficacy by presenting novel hybrid compounds.

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.

QSAR study of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2 using LS-SVM and GRNN based on principal components.

Quantitative relationships between molecular structure and methionine aminopeptidase-2 inhibitory activity of a series of cytotoxic anthranilic acid sulfonamide derivatives were discovered. We have demonstrated the detailed application of two efficient nonlinear methods for evaluation of quantitative structure-activity relationships of the studied compounds. Components produced by principal component analysis as input of developed nonlinear models were used. The performance of the developed models namely PC-GRNN and PC-LS-SVM were tested by several validation methods. The resulted PC-LS-SVM model had a high statistical quality (R(2)=0.91 and R(CV)(2)=0.81) for predicting the cytotoxic activity of the compounds. Comparison between predictability of PC-GRNN and PC-LS-SVM indicates that later method has higher ability to predict the activity of the studied molecules.

QSAR study of isatin analogues as in vitro anti-cancer agents.

Quantitative structure activity relationships (QSAR) of anti-cancer isatin derivatives were discovered by multiple linear regressions (MLR) and genetic algorithm partial least squares (GA-PLS) methods. Topological, chemical, geometrical and functional groups descriptors were found to be effective parameters on the cytotoxic activity. The positive effects of the number of halogen atoms and the number of total secondary carbons, and the negative effects of the number of secondary amides, and the number of ketones on the anti-cancer activity were in agreement with previous SAR studies. Hansch analysis showed the importance of lipophilic R(3) and R(5) substituents. Between MLR and GA-PLS, MLR represented superior results with a high statistical quality (R(2)=0.92 and Q(2)=0.90) for predicting the activity of the compounds.

Quantitative structure-activity relationship studies on 2-amino-6-arylsulfonylbenzonitriles as human immunodeficiency viruses type 1 reverse transcriptase inhibitors using descriptors obtained from substituents and whole molecular structures.

The human immunodeficiency viruses type 1 reverse transcriptase is a major target for drug development. Inhibition of this enzyme has been one of the primary therapeutic strategies in suppressing the replication of human immunodeficiency viruses type 1. A series of 2-amino-6-arylsulfonylbenzonitrile derivatives was subjected to quantitative structure-activity relationship analysis. The newly proposed substituent electronic descriptors were investigated for quantitative structure-activity relationship modeling of the compounds and a comparison was made with the conventional molecular descriptors. Two chemometrics methods including multiple linear regressions and partial least squares combined with genetic algorithm for variable selection were employed to make connections between structural parameters and enzyme inhibition. The results revealed the significant roles of topological, geometrical and substituent electronic descriptor parameters on the human immunodeficiency viruses type 1 reverse transcriptase inhibitory activity of the studied molecules. The selected substituent electronic descriptor parameters revealed that more electronegative and less polar substituents as meta position and more electrophile substituents as para positions are favorable for higher activity. It was found that electronic descriptors calculated for substituents (substituent electronic descriptor parameters) could explain 80% of variances in the biological activity data. The most significant quantitative structure-activity relationship model, obtained by partial least squares combined with genetic algorithm, could explain and predict 90% and 85% of variances in the pIC(50) data, respectively.

QSAR study of PETT derivatives as potent HIV-1 reverse transcriptase inhibitors.

A series of phenylethylthiazolylthiourea (PETT) derivatives was subjected to quantitative structure-activity relationship (QSAR) analysis to find the structural requirements for ligand binding. The structural invariants used in this study were those obtained from whole molecular structures: chemical, quantum, topological, geometrical, constitutional and functional groups. Four chemometrics methods including multiple linear regressions (MLRs), factor analysis-MLR (FA-MLR), principal component regression analysis (PCRA) and partial least squares combined with genetic algorithm for variable selection (GA-PLS) were employed to make connections between structural parameters and enzyme inhibition. Using the pool of all types of calculated descriptors a QSAR model was derived for selected calibration set compounds indicating the importance of geometrical and chemical parameters on the Human Immunodeficiency Virus Type-1 (HIV-1) reverse transcriptase inhibitory activity. The results of FA-MLR analysis revealed the effects of geometrical and chemical indices on the inhibitory activity too. GA-PLS analysis showed the constitutional and geometrical indices to be the most significant parameters on inhibitory activity. A comparison between the different statistical methods employed indicated that PCRA represented superior results and it could explain and predict 74% and 79% of variances in the pIC(50) data, respectively.

Synthesis and antitubercular activity of novel 4-substituted imidazolyl-2,6-dimethyl-N3,N5-bisaryl-1,4-dihydropyridine-3,5-dicarboxamides.

A series of 4-substituted imidazolyl-2,6-dimethyl-N(3),N(5)-bisaryl-1,4-dihydropyridine-3,5-dicarboxamides were prepared. They were screened as antitubercular agents against Mycobacterium tuberculosis H(37)Rv. Minimum inhibitory concentrations (MICs) were determined using agar proportion method. Compound 3i with 1-benzyl-2-methylthio-1H-imidazole-5-yl substituent at C-4 position and 4'-chloromophenyl group at C-3 and C-5 positions of the 1,4-dihydropyridine ring was the most potent one among the tested compounds. It was as potent as rifampicin against M. tuberculosis H(37)RV. Compound 3l also was an active antitubercular agent with the same substituent as compound 3i at the C-4 position and 3'-pyridyl group at C-3 and C-5 positions of the 1,4-dihydropyridine ring.

Synthesis, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives.

A series of Mannich bases of 2-alkyl-3-hydroxy-pyridine-4-ones, namely 2-alkyl-3-hydroxy-5-N-piperidylmethyl or N,N-dialkylaminomethyl pyridine-4-ones 9, 10 and 15-18, two derivatives of N-aryl-2-methyl-3-hydroxy-pyridine-4-ones 19, 20 and two N-alkyl derivatives of maltol, 21 and 22 were prepared. They were screened for their antibacterial and antifungal activities against a variety of microorganisms using micro plate Alamar Blue((R)) assay (MABA) method. Multiple linear regressions (MLR) analysis was performed for the synthesized compounds as well as a series of pyridinone and pyranone derivatives 23-43 which have been synthesized and evaluated for antimicrobial activity by other researchers previously. Studied compounds showed a better quantitative structure-activity relationship (QSAR) model for the antimicrobial activity against Candida albicans and Staphylococcus aureus in comparison with other tested microorganisms.

QSAR study of p56(lck) protein tyrosine kinase inhibitory activity of flavonoid derivatives using MLR and GA-PLS.

Quantitative relationships between molecular structure and p56(lck) protein tyrosine kinase inhibitory activity of 50 flavonoid derivatives are discovered by MLR and GA-PLS methods. Different QSAR models revealed that substituent electronic descriptors (SED) parameters have significant impact on protein tyrosine kinase inhibitory activity of the compounds. Between the two statistical methods employed, GA-PLS gave superior results. The resultant GA-PLS model had a high statistical quality (R(2) = 0.74 and Q(2) = 0.61) for predicting the activity of the inhibitors. The models proposed in the present work are more useful in describing QSAR of flavonoid derivatives as p56(lck) protein tyrosine kinase inhibitors than those provided previously.

QSAR study of antimicrobial 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives using different chemometric tools.

A series of 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives were subjected to quantitative structure-antimicrobial activity relationships (QSAR) analysis. A collection of chemometrics methods, including factor analysis-based multiple linear regression (FA-MLR), principal component regression (PCR) and partial least squares combined with genetic algorithm for variable selection (GA-PLS) were employed to make connections between structural parameters and antimicrobial activity. The results revealed the significant role of topological parameters in the antimicrobial activity of the studied compounds against S. aureus and C. albicans. The most significant QSAR model, obtained by GA-PLS, could explain and predict 96% and 91% of variances in the pIC(50) data (compounds tested against S. aureus) and predict 91% and 87% of variances in the pIC(50) data (compounds tested against C. albicans), respectively.