Synthesis, spectral, crystal structure, drug‐likeness, in silico and in vitro biological screening of halogen [Cl, Br] substituted N ‐Phenylbenzo [ g ]indazole derivatives as antimicrobial agents

2020 ◽  
Author(s):  
S. Murugavel ◽  
J. Mohan Raj ◽  
C. Ravikumar ◽  
R. Ranganathan ◽  
G. Jaabil ◽  
...  
Keyword(s):  
Crystal Structure ◽  
In Silico ◽  
Antimicrobial Agents ◽  
Biological Screening

Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

2020 ◽  
Vol 20 (3) ◽  
pp. 192-208 ◽  
Author(s):  
Talita Odriane Custodio Leite ◽  
Juliana Silva Novais ◽  
Beatriz Lima Cosenza de Carvalho ◽  
Vitor Francisco Ferreira ◽  
Leonardo Alves Miceli ◽  
...  
Keyword(s):  
In Silico ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Mass Spectrometry Analysis ◽  
World Health ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Dione Derivative ◽  
In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

Novel Spiro/non-Spiro Pyranopyrazoles: Eco-Friendly Synthesis, In-vitro Anticancer Activity, DNA Binding, and In-silico Docking Studies

2019 ◽  
Vol 15 (2) ◽  
pp. 257-267 ◽  
Author(s):  
Paritosh Shukla ◽  
Ashok Sharma ◽  
Leena Fageria ◽  
Rajdeep Chowdhury
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
In Silico ◽  
Antimicrobial Agents ◽  
Docking Studies ◽  
Bioactive Molecules ◽  
Microwave Assisted Synthesis ◽  
Binding Affinities ◽  
In Silico Docking

Background: Cancer being a deadly disease, many reports of new chemical entities are available. Pyranopyrazole (PPZ) compounds have also been disclosed as bioactive molecules but mainly as antimicrobial agents. Based on one previous report and our interest in anticancer drug design, we decided to explore PPZs as anticancer agents. To the best of our knowledge, we found that a comprehensive study, involving synthesis, in-vitro biological activity determination, exploration of the mechanism of inhibition and finally in-silico docking studies, was missing in earlier reports. This is what the present study intends to accomplish. Methods: Ten spiro and eleven non-spiro PPZ molecules were synthesized by environment-friendly multicomponent reaction (MCR) strategy. After subjecting each of the newly synthesized molecules to Hep3b hepatocellular carcinoma cell lines assay, we selectively measured the Optical Density (OD) of the most active ones. Then, the compound exhibiting the best activity was docked against human CHK- 1 protein to get an insight into the binding affinities and a quick structure activity relationship (SAR) of the PPZs. Results: The two series of spiro and non-spiro PPZs were easily synthesized in high yields using microwave assisted synthesis and other methods. Among the synthesized compounds, most compounds showed moderate to good anticancer activity against the MTT assay. After performing the absorbance studies we found that the non-spiro molecules showed better apoptosis results and appeared to bind to DNA causing disruption in their structures. Finally, the docking results of compound 5h (having N,Ndimethylamino substituted moiety) clearly showed good binding affinities as predicted by our experimental findings. Conclusion: The paper describes a comprehensive synthesis, in-vitro and docking studies done on new PPZs. The newly synthesized series of spiro and non-spiro PPZs were found to possess antineoplasmic activity as evinced by the studies on hep3b cells. Also, the UV visible absorbance study gave clues to the possible binding of these molecules to the DNA. Docking studies corroborated well with the experimental results. Thus, these new molecules appear to be potential anticancer agents, but further studies are required to substantiate and elaborate on these findings.

Synthesis and structural elucidation for new pyrano thiazole complexes: Biological screening and effects on DNA through in-vitro and in-silico approaches

2021 ◽  
Vol 332 ◽  
pp. 115844
Author(s):  
Seraj Omar Alzahrani ◽  
Ahmed M. Abu-Dief ◽  
Kholood Alkhamis ◽  
Fatmah Alkhatib ◽  
Tarek El-Dabea ◽  
...  
Keyword(s):  
In Silico ◽  
Structural Elucidation ◽  
Biological Screening

scholarly journals Bacterial Cellulose Containing Combinations of Antimicrobial Peptides with Various QQ Enzymes as a Prototype of an “Enhanced Antibacterial” Dressing: In Silico and In Vitro Data

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1155
Author(s):  
Aysel Aslanli ◽  
Ilya Lyagin ◽  
Nikolay Stepanov ◽  
Denis Presnov ◽  
Elena Efremenko
Keyword(s):  
Antimicrobial Peptides ◽  
Bacterial Cellulose ◽  
In Silico ◽  
Antimicrobial Agents ◽  
Penicillin Acylase ◽  
Signal Molecules ◽  
Bacterial Cells ◽  
Gram Positive ◽  
Gram Negative

To improve the action of already in use antibiotics or new antimicrobial agents against different bacteria, the development of effective combinations of antimicrobial peptides (AMPs) with enzymes that can quench the quorum (QQ) sensing of bacterial cells was undertaken. Enzymes hydrolyzing N-acyl homoserine lactones (AHLs) and peptides that are signal molecules of Gram-negative and Gram-positive bacterial cells, respectively, were estimated as “partners” for antibiotics and antimicrobial peptides in newly designed antimicrobial–enzymatic combinations. The molecular docking of six antimicrobial agents to the surface of 10 different QQ enzyme molecules was simulated in silico. This made it possible to choose the best variants among the target combinations. Further, bacterial cellulose (BC) was applied as a carrier for uploading such combinations to generally compose prototypes of effective dressing materials with morphology, providing good absorbance. The in vitro analysis of antibacterial activity of prepared BC samples confirmed the significantly enhanced efficiency of the action of AMPs (including polymyxin B and colistin, which are antibiotics of last resort) in combination with AHL-hydrolyzing enzymes (penicillin acylase and His6-tagged organophosphorus hydrolase) against both Gram-negative and Gram-positive cells.

scholarly journals Antimicrobial activity of Tachyplesin 1 againstBurkholderia pseudomallei: an in vitro and in silico approach

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2468 ◽  
Author(s):  
Lyn-Fay Lee ◽  
Vanitha Mariappan ◽  
Kumutha Malar Vellasamy ◽  
Vannajan Sanghiran Lee ◽  
Jamuna Vadivelu
Keyword(s):  
In Silico ◽  
Antimicrobial Agents ◽  
Protein A ◽  
Surface Protein ◽  
In Vitro Study ◽  
Planktonic Cell ◽  
Mammalian Cell Lines ◽  
Electrostatic Contribution ◽  
Conventional Antibiotics

Burkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to many conventional antibiotics. Therefore, alternative antimicrobial agents such as antimicrobial peptides (AMPs) are extensively studied to combat this issue. Our study aims to identify and understand the mode of action of the potential AMP(s) that are effective againstB. pseudomalleiin both planktonic and biofilm state as well as to predict the possible binding targets on using in vitro and in silico approaches. In the in vitro study, 11 AMPs were tested against 100B. pseudomalleiisolates for planktonic cell susceptibility, where LL-37, and PG1, demonstrated 100.0% susceptibility and TP1 demonstrated 83% susceptibility. Since theB. pseudomalleiactivity was reported on LL-37 and PG1, TP1 was selected for further investigation. TP1 inhibitedB. pseudomalleicells at 61.69 μM, and membrane blebbing was observed using scanning electron microscopy. Moreover, TP1 inhibitedB. pseudomalleicell growth, reaching bactericidal endpoint within 2 h post exposure as compared to ceftazidime (CAZ) (8 h). Furthermore, TP1 was shown to suppress the growth ofB. pseudomalleicells in biofilm state at concentrations above 221 μM. However, TP1 was cytotoxic to the mammalian cell lines tested. In the in silico study, molecular docking revealed that TP1 demonstrated a strong interaction to the common peptide or inhibitor binding targets for lipopolysaccharide ofEscherichia coli, as well as autolysin, pneumolysin, and pneumococcal surface protein A (PspA) ofStreptococcus pneumoniae. Homology modelledB. pseudomalleiPspA protein (YDP) also showed a favourable binding with a strong electrostatic contribution and nine hydrogen bonds. In conclusion, TP1 demonstrated a good potential as an anti-B. pseudomalleiagent.

scholarly journals In silico drug discovery strategies identified ADMET properties of decoquinate RMB041 and its potential drug targets against Mycobacterium Tuberculosis

2021 ◽  
Author(s):  
Kirsten Elke Knoll ◽  
Mietha M. van der Walt ◽  
Du toit Loots
Keyword(s):  
Mycobacterium Tuberculosis ◽  
In Silico ◽  
Drug Targets ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Antimicrobial Agents ◽  
Screening Methods ◽  
Discovery Studio ◽  
Optimal Drug

The highly adaptive cellular response of Mycobacterium tuberculosis to various antibiotics and the high costs for clinical trials, hampers the development of novel antimicrobial agents with improved efficacy and safety. Subsequently, in silico drug screening methods are more commonly being used for the discovery and development of drugs, and have been proven useful for predicting the pharmacokinetics, toxicities, and targets, of prospective new antimicrobial agents. In this investigation, we used a reversed target fishing approach to determine potential hit targets and their possible interactions between M. tuberculosis and decoquinate RMB041, a propitious new antituberculosis compound. Two of the thirteen identified targets, Cyp130 and BlaI, were strongly proposed as optimal drug-targets for dormant M. tuberculosis, of which the first showed the highest comparative binding affinity to decoquinate RMB041. The metabolic pathways associated to the selected target proteins were compared to previously published molecular mechanisms of decoquinate RMB041 against M. tuberculosis, whereby we confirmed disrupted metabolism of proteins, cell wall components, and DNA. We also described the steps within these pathways that are inhibited and elaborated on decoquinate RMB041's activity against dormant M. tuberculosis. This compound has previously showed promising in vitro safety and good oral bioavailability, which were both supported by this in silico study. The pharmacokinetic properties and toxicity of this compound were predicted and investigated using the online tools pkCSM and SwissADME, and Discovery Studio software, which furthermore supports previous safety and bioavailability characteristics of decoquinate RMB041 for use as an antimycobacterial medication.

scholarly journals In Silico and In Vitro Experimental Studies of New Dibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)-oximes Designed as Potential Antimicrobial Agents

Molecules ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 321 ◽  
Author(s):  
Ilinca Margareta Vlad ◽  
Diana Camelia Nuta ◽  
Cornel Chirita ◽  
Miron Teodor Caproiu ◽  
Constantin Draghici ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
In Silico ◽  
Antimicrobial Agents ◽  
Experimental Studies ◽  
In Silico Analysis ◽  
Maximum Tolerated Dose ◽  
In Vitro Cytotoxicity ◽  
Cell Membrane Permeability ◽  
Biofilm Growth

In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a–j) were confirmed by 1H-NMR, 13C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a–j, characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus, B. subtilis, Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues.

In Silico and In Vitro Investigation of the Antifungal Activity of Isoeugenol against Penicillium citrinum

2019 ◽  
Vol 18 (25) ◽  
pp. 2186-2196 ◽  
Author(s):  
Sávio Benvindo Ferreira ◽  
Tassiana Barbosa Dantas ◽  
Daniele de Figuerêdo Silva ◽  
Paula Benvindo Ferreira ◽  
Thamara Rodrigues de Melo ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
In Silico ◽  
Antimicrobial Agents ◽  
In Silico Analysis ◽  
Penicillium Citrinum ◽  
Toxicity Tests ◽  
In Vitro Investigation ◽  
Pass Online

Introduction: This increase in the prevalence of drug-resistant pathogens occurs at a time when the discovery and development of new antimicrobial agents occur slowly. In this context, the objective of this study was to investigate the antifungal activity of isoeugenol, a phenylpropanoid, by in vitro and in silico assays against Penicillium citrinum strains. Material and Method: For in silico analysis, the software PASS online, Molinspiration and Osíris were used. For the determination of Minimum Inhibitory Concentration (MIC) and Minimal Fungicide Concentration (MFC) of isoeugenol and voriconazole were carried out using the broth microdilution technique. PASS online has shown that isoeugenol has the opportunity to present antiseptic, antifungal, antibacterial, antimycobacterial activities. Molinspiration showed that the phytoconstituent has good potential for oral bioavailability. Conclusion: In the analysis with the Osiris program, it was demonstrated that isoeugenol has low irritant and tumorigenic risk. The MIC of isoeugenol varied between 256 and 32 µg/mL, MIC50 of 64 µg/mL and MIC90 was 128 µg/mL. The MFC50, MFC90 and MFC of the isoeugenol for P. citrinum species were 64, 256 and 518 μg/mL, respectively. After analysis, it was verified that the isoeugenol have bactericidal effect against the strains of P. citrinum. After these results, it is important to discover the mechanism of action involved in the antifungal action of the compound, as well as in vitro and in vivo toxicity tests.

Synthesis, Antimicrobial Evaluation and In silico Studies of Novel 2,4- disubstituted-1,3-thiazole Derivatives

2018 ◽  
Vol 16 (2) ◽  
pp. 160-173 ◽  
Author(s):  
Mir Mohammad Masood ◽  
Mohammad Irfan ◽  
Shadab Alam ◽  
Phool Hasan ◽  
Aarfa Queen ◽  
...  
Keyword(s):  
In Silico ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Docking Studies ◽  
Bacterial Strains ◽  
Thiazole Derivatives ◽  
Standard Drug ◽  
Hek 293 ◽  
In Silico Studies

Background: 2,4-disubstituted-1,3-thiazole derivatives (2a–j), (3a–f) and (4a–f) were synthesized, characterized and screened for their potential as antimicrobial agents. In the preliminary screening against a panel of bacterial strains, nine compounds showed moderate to potent antibacterial activity (IC50 = 13.7-90.8 μg/ml). </P><P> Methods: In the antifungal screening, compound (4c) displayed potent antifungal activity (IC50 = 26.5 &#181;g/ml) against Candida tropicalis comparable to the standard drug, fluconazole (IC50 = 10.5 &#181;g/ml). Based on in vitro antimicrobial results, compounds 2f, 4c and 4e were selected for further pharmacological investigations. Hemolytic activity using human red blood cells (hRBCs) and cytotoxicity by MTT assay on human embryonic kidney (HEK-293) cells revealed non-toxic nature of the selected compounds (2f, 4c and 4e). To ascertain their possible mode of action, docking studies with the lead inhibitors (2f, 4c and 4e) were performed using crystal structure coordinates of bacterial methionine aminopeptidases (MetAPs), an enzyme involved in bacterial protein synthesis and maturation. Results: The results of in vitro and in silico studies provide a rationale for selected compounds (2f, 4c and 4e) to be carried forward for further structural modifications and structure-activity relationship (SAR) studies against these bacterial infections. Conclusion: The study suggested binding with one or more key amino acid residues in the active site of Streptococcus pneumoniae MetAP (SpMetAP) and Escherichia coli MetAP (EcMetAP). In silico physicochemical properties using QikProp confirmed their drug likeliness.

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