Synthesis, characterization, synergistic antimicrobial properties and molecular docking of sugar modified uridine derivatives

Abstract Nucleosides and their analogues are an important, well-established class of clinically useful medicinal agents that exhibit antiviral and anticancer activity. Thus, our research group has focused on the synthesis of new nucleoside derivatives that could be tested for their broad-spectrum biological activity. In this study, two new series of nucleoside derivatives were synthesized from uridine (1) through facile two-step reactions using the direct acylation method, affording 5’-O-acyl uridine derivatives in good yields. The isolated uridine analogs were further transformed into two series of 2’,3’-di-O-acyl derivatives bearing a wide variety of functionalities in a single molecular framework to evaluate their antimicrobial activity. The new synthesized compounds were characterized through physicochemical, elemental and spectroscopic analysis, and all were screened for their in vitro antimicrobial activity against selected human and plant pathogenic strains. The test compounds revealed moderate to good antibacterial and antifungal activities and were more effective against fungal phytopathogens than against bacterial strains, while many of them exhibited better antimicrobial activity than standard antibiotics. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests against all microorganisms were also conducted for five compounds based on their activity (6, 11, 13, 16, and 17). In addition, all the derivatives were optimized using density functional theory (DFT) B3LYP/6-31g+(d,p) calculations to elucidate their thermal and molecular orbital properties. A molecular docking study was performed using the human protein 5WS1 to predict their binding affinity and modes, and ADMET and SwissADME calculations confirmed the improved pharmacokinetic properties of the compounds. Besides, structure–activity relationship (SAR), thermogravimetric analysis (TGA), and X-ray diffraction (XRD) studies were also performed. Thus, the improvement of the bioactivity of these compounds is expected to significantly contribute to the design of more antimicrobial agents for therapeutic use in the future.

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Rational Synthesis of Some New para-Aminobenzoic Acid Hybrids with Thiazolidin-2,4-diones with Antimicrobial Properties. ADMET and molecular docking evaluation

Revista de Chimie ◽

10.37358/rc.19.3.7004 ◽

2019 ◽

Vol 70 (3) ◽

pp. 769-775 ◽

Cited By ~ 1

Author(s):

Gabriel Marc ◽

Smaranda Oniga ◽

Adrian Pirnau ◽

Mihaela Duma ◽

Laurian Vlase ◽

...

Keyword(s):

Antimicrobial Activity ◽

Molecular Docking ◽

Physicochemical Characterization ◽

Antimicrobial Properties ◽

Docking Study ◽

Aminobenzoic Acid ◽

Molecular Docking Study ◽

E Coli ◽

Activity Screening

The present paper presents the synthesis, physicochemical characterization, in vitro antimicrobial activity and the molecular docking study of a series of ten new thiazolidine-2,4-dione derivatives conjugated to para-aminobenzoic acid (PABA). The lipophilicity of the new molecules was evaluated in silico. Quantitative elemental C, H, N, S analysis and spectral data (mass spectrometry, infrared and nuclear magnetic resonance) were consistent with the expected data. The results of the antimicrobial activity screening revealed that some of the synthesized compounds had moderate to good activity against E. coli ATCC 25922, S. aureus, ATCC 6538P and C. albicans ATCC 10231.

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Antibacterial Activities and Molecular Docking of Novel Sulfone Biscompound Containing Bioactive 1,2,3-Triazole Moiety

Molecules ◽

10.3390/molecules26164817 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4817

Author(s):

Huda R. M. Rashdan ◽

Ihsan A. Shehadi ◽

Mohamad T. Abdelrahman ◽

Bahaa A. Hemdan

Keyword(s):

Molecular Docking ◽

Pathogenic Bacteria ◽

Analytical Data ◽

Docking Study ◽

Antibacterial Activities ◽

Bactericidal Effect ◽

Bacterial Strains ◽

Molecular Docking Study ◽

Synthetic Compound

In this study, a new synthetic 1,2,3-triazole-containing disulfone compound was derived from dapsone. Its chemical structure was confirmed using microchemical and analytical data, and it was tested for its in vitro antibacterial potential. Six different pathogenic bacteria were selected. MICs values and ATP levels were determined. Further, toxicity performance was measured using MicroTox Analyzer. In addition, a molecular docking study was performed against two vital enzymes: DNA gyrase and Dihydropteroate synthase. The results of antibacterial abilities showed that the studied synthetic compound had a strong bactericidal effect against all tested bacterial strains, as Gram-negative species were more susceptible to the compound than Gram-positive species. Toxicity results showed that the compound is biocompatible and safe without toxic impact. The molecular docking of the compound showed interactions within the pocket of two enzymes, which are able to stabilize the compound and reveal its antimicrobial activity. Hence, from these results, this study recommends that the established compound could be an outstanding candidate for fighting a broad spectrum of pathogenic bacterial strains, and it might therefore be used for biomedical and pharmaceutical applications.

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Synthesis, Biological Evaluation and Molecular Docking Study of Pyrazole, Pyrazoline Clubbed Pyridine as Potential Antimicrobial Agents

Anti-Infective Agents ◽

10.2174/2211352517666190627144315 ◽

2020 ◽

Vol 18 (3) ◽

pp. 306-314 ◽

Cited By ~ 2

Author(s):

Nisheeth C. Desai ◽

Darshita V. Vaja ◽

Krunalsinh A. Jadeja ◽

Surbhi B. Joshi ◽

Vijay M. Khedkar

Keyword(s):

Antimicrobial Activity ◽

Molecular Docking ◽

Antimicrobial Agents ◽

Docking Study ◽

Biological Evaluation ◽

Mass Spectral Data ◽

Molecular Docking Study ◽

Mass Spectral ◽

Chemical Structures ◽

Subunit B

Introduction: In continuation of our efforts to find new antimicrobials, herein we report the synthesis of various pyrazole, pyrazoline, and pyridine based novel bioactive heterocycles (3a-t). Methods: Newly synthesized compounds were analysed for their antimicrobial activity. Compounds 3c, 3h, 3i, 3k, 3n, and 3q showed significant antimicrobial activity. Results: Molecular docking study for the most active analogues against DNA gyrase subunit b (PDB ID: 1KZN) corroborated well with the observed antimicrobial potency exhibiting significant binding affinity. Conclusion: Interpretation of the chemical structures reported in this paper was based on IR, 1H NMR, 13C NMR, and mass spectral data.

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Synthesis, Antimicrobial Evaluation and Molecular Docking of Some Potential 2,6-disubstituted 1H-Benzimidazoles; Non-Classical Antifolates

Medicinal Chemistry ◽

10.2174/1573406415666190206231555 ◽

2019 ◽

Vol 15 (7) ◽

pp. 813-832 ◽

Cited By ~ 1

Author(s):

Sunil Harer ◽

Manish Bhatia ◽

Vikram Kawade

Keyword(s):

Antimicrobial Activity ◽

Molecular Docking ◽

Antimicrobial Agents ◽

Cross Reactivity ◽

Diffusion Method ◽

Molecular Docking Study ◽

One Pot ◽

Disk Diffusion Method ◽

Antimicrobial Evaluation

Background: Dihydrofolate reductase is one of the important enzymes for thymidylate and purine synthesis in micro-organisms. A large number of drugs have been designed to inhibit microbial DHFR but over the period of time, some drugs have developed resistance and cross reactivity towards the enzyme. Over the past few decades, benzimidazoles, triazoles and their derivatives have been grabbing the attention of the synthetic chemists for their wide gamut of antibacterial and antifungal activities targeting microbial protein DHFR. Objective: Our goal behind present investigation is to explore benzimidazoles class of drugs as microbial DHFR inhibitors by studying ligand-receptor binding interactions, in vitro enzyme inhibition assay and confirmation of anti-microbial activity against selected pathogenic microorganisms. Methods: A library containing thirty novel 2,6-disubstituted 1H-benzimidazoles was synthesized by one pot condensation of o-nitro aniline or 2,4-dinitro aniline with series of aldehydes or acetophenones using Na2S2O4 or SnCl2 respectively and reflux for 5-6hr. Structures of compounds have been confirmed by spectroscopic methods as 1H and 13C NMR, FT-IR and MS. In vitro DHFR inhibition study was performed by using Epoch microplate reader and IC50 of the test compounds was compared with Trimethoprim. In vitro antimicrobial activity was performed against selected clinical pathogens by agar disk diffusion method and MIC (µg/mL) was reported. Results: Moderate to good level of DHFR inhibition was observed with IC50 values in the range of 7-23 µM. Compounds B1, B19, B22, B24 and B30 expressed 1.1 to 1.4 folds more prominent DHFR inhibitory activity as compared to standard Trimethoprim. Remarkable antimicrobial activity was exhibited by B1, B19, B22, B24 and B30. Molecular docking study revealed perfect binding of test ligands with key amino acids of DHFR as Phe31, Ile94, Ile5, Asp27, Gln32 and Phe36. Conclusion: Nature of 1H-benzimidazole substituents at position 2 and 6 had influence over magnitude and type of molecular binding and variation in the biological activity. The present series of 1H-benzimidazoles could be considered promising broad-spectrum antimicrobial candidates that deserve in future for preclinical antimicrobial evaluation and development of newer antimicrobial agents targeting microbial DHFR.

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SYNTHESIS, ANTIMICROBIAL ACTIVITY AND MOLECULAR DOCKING STUDY OF SOME NEW N-BENZYL AND N-BENZOYL-3-INDOLYL HETEROCYCLES

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2016v8i9.13184 ◽

2016 ◽

Vol 8 (9) ◽

pp. 224

Author(s):

Heba M. Abo-salem ◽

Anhar Abdel-aziem ◽

Inas E. Islam ◽

Mariam M. Yossef ◽

Eslam R. El-sawy

Keyword(s):

Antimicrobial Activity ◽

Molecular Docking ◽

Dihydrofolate Reductase ◽

Docking Study ◽

Phenacyl Bromide ◽

Antimicrobial Compounds ◽

Molecular Docking Study ◽

Enoyl Reductase ◽

Wide Range

Objective: Chalcones are one of the major classes of the natural products, which display a wide range of pharmacological properties. Also, chalcones are well-known intermediates for synthesizing various heterocyclic compounds like pyrazoline and pyrimidine derivatives. The present work is designed to synthesize new 3-indolylheterocycles starting from N-benzyl and N-benzoyl-1H-indole-3-carboxaldehyds and evaluating theirs in vitro antimicrobial activity. In addition, the probability of the most promising antimicrobial compounds to inhibit ATPase, enoyl reductase and dihydrofolate reductase were studied theoretically via molecular docking.Methods: A new series of 3-indolylchalcones 2a,b were prepared and allowed to react with hydrazine hydrate, phenyl hydrazine, hydroxylamine, urea, thiourea and guanidine to afford the corresponding pyrazoles 3a,b-6a,b and pyrimidines derivatives 7a,b-9a,b. On the other hand, the reaction of 2a, b with malononitrile afforded 10a, b, which upon cyclo-condensation with formic acid, formamide, urea or thiourea yielded the fused pyrido [2,3-d]pyrimidine 11a,b-14a,b. Moreover, cyclo-condensation of 2a, b with thiosemicarbazide gave pyrazolin-1-carbothioamides 15a, b, which under cyclization with phenacyl bromide afforded thiazole derivatives 16a and 16b. While the reaction of 2a, b with cyano thioacetamide afforded 2-mercaptonicotinonitriles 17a, b. The reaction of 17a, b with some halo-compounds gave S-alkyl derivatives 18a-d and 19a-d, respectively,which under heating in the presence of piperidine gave the fused thienopyridines 20a-d and 21a-d, respectively. All the newly prepared compounds were evaluated for their in vitro antimicrobial activity. In addition, molecular docking study of the most promising antimicrobial compounds against ATPase, enoyl reductase and dihydrofolate reductase theoretically is discussed.Results: Compounds 17a and 17b were found to be the most potent compounds with MIC of 0.98, 0.49 and 0.98µg/ml against S. pneumoniae (RCMB 010010), E. coli (RCMB 010052) and A. fumigatus (RCMB 02568), respectively compare to the reference drugs. Also, compounds 17a and 17b exhibited good docking scores and could act as inhibitors of enzymes understudied.Conclusion: Further work is recommended to confirm the ability of compounds 17a and 17b to inhibit ATPase, enoyl reductase and dihydrofolate reductase in a specific bioassay.

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Molecular docking study on biomolecules isolated from endophytic fungi

Journal of the Serbian Chemical Society ◽

10.2298/jsc200815002i ◽

2021 ◽

pp. 2-2

Author(s):

Janko Ignjatovic ◽

Nevena Djajic ◽

Jovana Krmar ◽

Ana Protic ◽

Borut Strukelj ◽

...

Keyword(s):

Antimicrobial Activity ◽

Molecular Docking ◽

Endophytic Fungi ◽

Docking Study ◽

Multidrug Resistant ◽

Molecular Docking Study ◽

Different Types ◽

Antibiotic Response ◽

Novel Drug

Recently, growing interest is devoted to investigation of compounds with antimicrobial activity due to rising cases of resistance of microbes to known therapy. Reliable and versatile source of novel drug discovery was recently found among endophytic fungi. Up to now, the research usually enclosed with in vitro evaluation of antimicrobial activity and chemical structure elucidation of biomolecules extracted from fungal material. Therefore, this research was designed as an extension to previous investigations of endophytic fungi growing on conifer needles by means of conducting a molecular docking study. The in silico methods were used with the main goal to make a contribution to the understanding of the mechanisms underlying the interaction of biomolecules isolated from fungus Phomopsis species and eight different types of receptors that belong to usually multidrug resistant bacterial pathogens. The results revealed valuable interactions with receptors 3G7B (Staphylococcus aureus?s gyrase B), 1F0K (1.9 ? structure of Escherichia Coli?s transferase) and 1SHV (Klebsiella pneumoniae?s SHV-1 ? -lactamase) thus pointing out to the receptors which trigger antibiotic response upon activation by the most potent compounds 325-3, 325-5, phomoenamide and phomol. These findings also recommended further discovery of novel potent and broad-spectrum antibiotics based on the structure of selected molecules.

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Preparation, Antimicrobial Activity and Docking Study of Vanadium Mixed Ligand Complexes Containing 4-Amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol and Aminophenol Derivatives

Processes ◽

10.3390/pr9061008 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1008

Author(s):

Doaa Domyati ◽

Sami A. Zabin ◽

Ahmed A. Elhenawy ◽

Mohamed Abdelbaset

Keyword(s):

Molecular Docking ◽

Density Functional ◽

Docking Study ◽

Quantitative Structure Activity Relationship ◽

Mixed Ligand ◽

Mixed Ligand Complexes ◽

Moderate Activity ◽

Bacterial Strains ◽

Functional Theory

The synthesis of mixed-ligand complexes is considered an important strategy for developing new metal complexes of enhanced biological activity. This paper presents the synthesis, characterization, in vitro antimicrobial assessment, and theoretical molecular docking evaluation for synthesized oxidovanadium (V) complexes. The proposed structures of the synthesized compounds were proved using elemental and different spectroscopic analysis. The antimicrobial tests showed moderate activity of the compounds against the Gram-positive bacterial strains and the fungal yeast, whereas no activity was observed against the Gram-negative bacterial strains. The performance of density functional theory (DFT) was conducted to study the interaction mode of the targeted compounds with the biological system. Calculating the quantitative structure-activity relationship (QSPR) was performed depending on optimization geometries, frontier molecular orbitals (FMOs), and chemical reactivities for synthesized compounds. The molecular electrostatic potentials (MEPs) that were plotted link the interaction manner of synthesized compounds with the receptor. The molecular docking evaluation revealed that the examined compounds may possess potential antibacterial activity.

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Biological Evaluation and Molecular Docking with In Silico Physicochemical, Pharmacokinetic and Toxicity Prediction of Pyrazolo[1,5-a]pyrimidines

Molecules ◽

10.3390/molecules25061431 ◽

2020 ◽

Vol 25 (6) ◽

pp. 1431 ◽

Cited By ~ 2

Author(s):

Ahmed M. Naglah ◽

Ahmed A. Askar ◽

Ashraf S. Hassan ◽

Tamer K. Khatab ◽

Mohamed A. Al-Omar ◽

...

Keyword(s):

Molecular Docking ◽

In Silico ◽

Biological Activities ◽

Antimicrobial Properties ◽

Docking Study ◽

Biological Evaluation ◽

Immunomodulatory Activity ◽

Molecular Docking Study ◽

Lipinski’S Rule

Pyrazolo[1,5-a]pyrimidines 5a–c, 9a–c and 13a–i were synthesized for evaluation of their in vitro antimicrobial properties against some microorganisms and their immunomodulatory activity. The biological activities of pyrazolo[1,5-a]pyrimidines showed that the pyrazolo[1,5-a]pyrimidines (5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h) displayed promising antimicrobial and immunomodulatory activities. Studying the in silico predicted physicochemical, pharmacokinetic, ADMET and drug-likeness properties for the pyrazolo[1,5-a]pyrimidines 5a–c, 9a–c and 13a–i confirmed that most of the compounds (i) were within the range set by Lipinski’s rule of five, (ii) show higher gastrointestinal absorption and inhibition of some CYP isoforms, and (iii) have a carcinogenicity test that was predicted as negative and hERG test that presented medium risk. Moreover, the molecular docking study demonstrated that the compounds 5c, 9a, 9c, 13a, 13c, 13d, 13e and 13h are potent inhibitors of 14-alpha demethylase, transpeptidase and alkaline phosphatase enzymes. This study could be valuable in the discovery of a new series of drugs.

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Design, Synthesis, Antimicrobial and Anti-biofilm Evaluation, and Molecular Docking of Newly Substituted Fluoroquinazolinones

Medicinal Chemistry ◽

10.2174/1573406414666181109092944 ◽

2019 ◽

Vol 15 (6) ◽

pp. 659-675

Author(s):

Mohamed F. Zayed ◽

Sabrin R.M. Ibrahim ◽

EL-Sayed E. Habib ◽

Memy H. Hassan ◽

Sahar Ahmed ◽

...

Keyword(s):

Molecular Docking ◽

Antimicrobial Agents ◽

Receptor Site ◽

Docking Study ◽

Diffusion Method ◽

Molecular Docking Study ◽

Active Compounds ◽

Highly Active ◽

Strong Binding ◽

Agar Disc

Background: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. Objective: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. Methods: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. Results: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compounds. Compounds 10b, 10c, and 10d had a good MIC and MBC against Gram-positive bacteria, whereas 10b and 10d showed significant MIC and MBC against Gram-negative bacteria. However, compounds E and F exhibited good MIC and MBC against fungi. Compound 10c and 8 exhibited significant anti-biofilm activity towards S. aureus and M. luteus. Molecular docking study revealed a strong binding of these derivatives with their receptor-site and detected their predicted mode of binding. Conclusion: The synthesized derivatives showed promising antibacterial, antifungal, and antibiofilm activities. Modeling study explained their binding mode and showed strong binding affinity with their receptor-site. The highly active compounds 5 and 10c could be subjected to future optimization and investigation to be effective antimicrobial agents.

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Structure-Based Design, Synthesis, Biological Evaluation and Molecular Docking Study of 4-Hydroxy-N'-methylenebenzohydrazide Derivatives Acting as Tyrosinase Inhibitors with Potentiate Anti-Melanogenesis Activities

Medicinal Chemistry ◽

10.2174/1573406415666190724142951 ◽

2020 ◽

Vol 16 (7) ◽

pp. 892-902 ◽

Cited By ~ 3

Author(s):

Aida Iraji ◽

Mahsima Khoshneviszadeh ◽

Pegah Bakhshizadeh ◽

Najmeh Edraki ◽

Mehdi Khoshneviszadeh

Keyword(s):

Molecular Docking ◽

Active Site ◽

Competitive Inhibition ◽

Docking Study ◽

Biological Evaluation ◽

Primary Response ◽

Ratio Method ◽

Molecular Docking Study ◽

Metal Chelating

Background: Melanogenesis is a process of melanin synthesis, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a ratelimiting 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. Objective: A number of 4-hydroxy-N'-methylenebenzohydrazide analogues with related structure to chalcone and tyrosine were constructed with various substituents at the benzyl ring of the molecule and evaluate as a tyrosinase inhibitor. In addition, computational analysis and metal chelating potential have been evaluated. Methods: Design and synthesized compounds were evaluated for activity against mushroom tyrosinase. The metal chelating capacity of the potent compound was examined using the mole ratio method. Molecular docking of the synthesized compounds was carried out into the tyrosine active site. Results: Novel 4-hydroxy-N'-methylenebenzohydrazide derivatives were synthesized. The two compounds 4c and 4g showed an IC50 near the positive control, led to a drastic inhibition of tyrosinase. Confirming in vitro results were performed via the molecular docking analysis demonstrating hydrogen bound interactions of potent compounds with histatidine-Cu+2 residues with in the active site. Kinetic study of compound 4g showed competitive inhibition towards tyrosinase. Metal chelating assay indicates the mole fraction of 1:2 stoichiometry of the 4g-Cu2+ complex. Conclusion: The findings in the present study demonstrate that 4-Hydroxy-N'- methylenebenzohydrazide scaffold could be regarded as a bioactive core inhibitor of tyrosinase and can be used as an inspiration for further studies in this area.

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