scholarly journals e-Pharmacophore model-guided design of potential DprE1 inhibitors: synthesis, in vitro antitubercular assay and molecular modelling studies

2021 ◽  
Author(s):  
Avinash Kumar ◽  
Revathi Rajappan ◽  
Suvarna G. Kini ◽  
Ekta Rathi ◽  
Sriram Dharmarajan ◽  
...  
Keyword(s):  
Pharmacophore Model ◽  
Antitubercular Activity ◽  
Stable Complex ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Standard Drug ◽  
Docking Score ◽  
Mycobacterium Tuberculosis H37rv ◽  
Cytotoxicity Studies

AbstractTuberculosis continues to wreak havoc worldwide and caused around 1.4 million deaths in 2019. Hence, in our pursuit of developing novel antitubercular compounds, we are reporting the e-Pharmacophore-based design of DprE1 (decaprenylphosphoryl-ribose 2′-oxidase) inhibitors. In the present work, we have developed a four-feature e-Pharmacophore model based on the receptor–ligand cavity of DprE1 protein (PDB ID 4P8C) and mapped our previous reported library of compounds against it. The compounds were ranked on phase screen score, and the insights obtained from their alignment were used to design some novel compounds. The designed compounds were docked with DprE1 protein in extra-precision mode using Glide module of Maestro, Schrodinger. Some derivatives like B1, B2, B4, B5 and B12 showed comparable docking score (docking score > − 6.0) with respect to the co-crystallized ligand. The designed compounds were synthesized and characterized. In vitro antitubercular activity was carried out on Mycobacterium tuberculosis H37Rv (ATCC27294) strain using the agar dilution method, and minimum inhibitory concentration (MIC) was determined. The compound B12 showed a MIC value of 1.56 μg/ml which was better than the standard drug ethambutol (3.125 μg/ml). Compounds B7 and B11 were found to be equipotent with ethambutol. Cytotoxicity studies against Vero cell lines proved that these compounds were non-cytotoxic. Molecular dynamic simulation study also suggests that compound B12 will form a stable complex with DprE1 protein and will show the crucial H-bond interaction with LYS418 residue. Further in vitro enzyme inhibition studies are required to validate these findings.

An efficient synthesis of some new chalcone, acetyl pyrazoline and amino pyrimidine bearing 1,3,5- triazine nucleus as potential antimicrobial and antitubercular agent

2019 ◽  
Author(s):  
Chem Int
Keyword(s):  
Antimicrobial Activity ◽  
Guanidine Hydrochloride ◽  
Antitubercular Activity ◽  
Dilution Method ◽  
Mycobacterium Tuberculosis H37rv ◽  
New Class ◽  
Chemical Structures ◽  
Lowenstein Jensen ◽  
Amino Pyrimidine

In an attempt to find a new class of antimicrobial and antitubercular agent, a new series of chalcone, acetyl pyrazoline and amino pyrimidine bearing 1,3,5- triazine nucleus were synthesized with appropriate chemical reagent. Chalcones (D1-D5) were synthesized by the classical Claisen-Schmidt condensation of substituted ketone (C) with variously substituted aldehydes via conventional method. Now treatment of chalcones with hydrazine hydrate/glacial acetic acid and guanidine hydrochloride/Alkali afforded the corresponding acetyl pyrazoline (E1-E5) and amino pyrimidine (F1-F5) derivatives respectively. The chemical structures of all newly synthesized compounds were established on the basis of their FTIR, 1H NMR, 13C NMR, LC-MS as well as elemental analysis. All the newly design compounds were assayed for their in vitro antimicrobial activity against selected pathogens by the Broth dilution method and in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv using Lowenstein-Jensen MIC method. Most of the compounds showed appreciable antimicrobial activity against the all tested strains. Among the synthesized compounds D1, D2, D3, E1, E3, E4, F3 and F4 exhibited excellent antimicrobial activity and said to be the most proficient members of the series. Compound D5 and F5 exhibited promising antitubercular activity.

Design, Synthesis, Pharmacological evaluation, in silico modeling, prediction of toxicity and metabolism studies of novel 1-(substituted)-2-methyl-3-(4-oxo-2-phenyl quinazolin-3(4H)-yl)isothioureas

2020 ◽  
Vol 16 ◽  
Author(s):  
M. T. Sulthana ◽  
V. Alagarsamy ◽  
K. Chitra
Keyword(s):  
Antitubercular Activity ◽  
Assay Method ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Drug Resistant ◽  
Alkyl Aryl ◽  
Design Synthesis ◽  
Hiv Drugs ◽  
Anti Hiv

Background: Although exhaustive efforts to prevent and treat tuberculosis (TB) was taken the problem still continues due to multi-drug-resistant (MDR) and extensively drug resistant TB (XDR-TB). It clearly highlights the urgent need to develop novel “druggable” molecules for the co-infection treatment and strains of MDR-TB and XDR-TB. Objective: In this approach a hybrid molecule was created by merging two or more pharmacophores. Active site of targets may be addressed by each of the pharmacophores and proffers the opportunity for selectivity. In addition, it also reduced the undesirable side effects and drug-resistant. Methods: In this study, a novel quinazolinone analog was designed and synthesized by substituting thiourea nucleus and phenyl ring at N-3 and C-2 position of quinazoline ring respectively. All title compounds were tested for antitubercular activity by in-vitro M. tuberculosis and anti-human immunodeficiency virus (HIV) activity by MT-4 cell assay method. The agar dilution method was used to test the antibacterial potency of entire prepared derivatives against various strains of gram positive and gram-negative microorganism. Results: The title compounds, 1-(substituted)-2-methyl-3-(4-oxo-2-phenyl quinazolin-3(4H)-yl) isothioureas (QTS1 – QTS15) are synthesized by reaction between key intermediate 3-amino-2-phenylquinazolin-4(3H)-one with various alkyl/aryl isothiocyanates followed by methylation with dimethyl sulphate. Among the series, compound 1-(3-chlorophenyl)-2-methyl-3-(4-oxo-2-phenyl quinazolin- 3(4H)-yl) isothioureas (QTS14) shown highest potency against B. subtilis, K. pneumonia and S. aureus at 1.6 µg/mL. The compound QTS14 exhibited the most potent antitubercular activity at with the MIC of 0.78 µg/mL and anti-HIV activity at 0.97µg/mL against HIV1 and HIV2. Conclusion: The results obtained from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities. The new scaffolds for proffers plausible lead for further development and optimization to novel antitubercular and anti-HIV drugs.

scholarly journals Synthesis, Spectral Analysis, Molecular Docking and Biological Evaluation of Cyclohepta[b]indole Derivatives

2019 ◽  
Vol 92 (3) ◽  
pp. 347-356 ◽  
Author(s):  
Ayyachamy Pandian Amuthavalli ◽  
Babu Prakash ◽  
David Edison ◽  
Rajendran Velmurugan
Keyword(s):  
Cancer Cell Line ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Cervical Cancer Cell Line ◽  
Indole Derivatives ◽  
Standard Drug ◽  
Cell Line Hela

A new series of specifically substituted cyclohepta[b]indole derivatives from the precursor thiophen-2-ylmethylene has been synthesized. The structures of synthesized derivatives were established by spectral and elemental analyses. The docking studies with protein kinase CK2 was performed, derivative 6c exhibited the most excellent glide and E model score of –7.61 and –58.27, respectively. In-vitro anticancer activity against cervical cancer cell line (HeLa) was studied. The IC50 values were compared with the standard drug Ellipticine. Compounds 5c, 6c and 6d showed better IC50 value when compared to the other molecules. The derivatives were evaluated for their antibacterial activity against the reference drugs Sparfloxacin and Norfloxacin using agar dilution method. The derivatives 4a–d exhibited better MIC values against Gram-positive bacteria and Gram-negative bacteria when compared with remaining derivatives. Structure activity relationship (SAR) analyses established that the derivatives are potential lead compounds for future drug development studies.

scholarly journals Antifungal and Antibacterial Metabolites from a French Poplar Type Propolis

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Séverine Boisard ◽  
Anne-Marie Le Ray ◽  
Anne Landreau ◽  
Marie Kempf ◽  
Viviane Cassisa ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Antifungal Activity ◽  
Antimicrobial Effect ◽  
Antibacterial Activities ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Gram Positive ◽  
Weak Activity ◽  
Agar Dilution

During this study, thein vitroantifungal and antibacterial activities of different extracts (aqueous and organic) obtained from a French propolis batch were evaluated. Antifungal activity was evaluated by broth microdilution on three pathogenic strains:Candida albicans, C. glabrata, andAspergillus fumigatus. Antibacterial activity was assayed using agar dilution method on 36 Gram-negative and Gram-positive strains includingStaphylococcus aureus. Organic extracts showed a significant antifungal activity againstC. albicansandC. glabrata(MIC80between 16 and 31 µg/mL) but only a weak activity towardsA. fumigatus(MIC80= 250 µg/mL). DCM based extracts exhibited a selective Gram-positive antibacterial activity, especially againstS. aureus(SA) and several of its methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) strains (MIC10030–97 µg/mL). A new and active derivative of catechin was also identified whereas a synergistic antimicrobial effect was noticed during this study.

scholarly journals IDENTIFICATION AND DETECTION OF BIOFILM PRODUCING STAPHYLOCOCCUS AUREUS AND ITS ANTIBIOGRAM ACTIVITIES

2021 ◽  
pp. 150-156
Author(s):  
SAPANA SHARMA ◽  
UPASHANA BHANDARI ◽  
YOGESH OLI ◽  
GANESH BHANDARI ◽  
SUNITA BISTA ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Disk Diffusion ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Methicillin Resistant ◽  
Clinical Specimens ◽  
Biofilm Production ◽  
Diffusion Technique ◽  
Almost All

Objectives: The main aim of this work is to determine the antibiogram profile of biofilm-producing Staphylococcus aureus from various clinical specimens of the patients. Methods: Various bacterial cultures of non-repeated clinical specimens from a total of 3388 patients were determined using standard microbiological and biochemical methods. Results: Out of 3388 only 604 (17.02%) displayed growth positive. A total of 65 (51.58%) S. aureus isolates were recovered, 25 (38.46%) were identified as methicillin-resistant S. aureus (MRSA) by Cefoxitin (30 μg) disk diffusion technique, of which majority were from pus/wound swab 22 (37.29%). The antibiogram of the isolates was analyzed by Kirby-Bauer disk diffusion technique analyzing Linezolid to be the most effective drug with susceptibility of 100% to both MRSA and methicillin-sensitive S. aureus, followed by vancomycin, tigecycline, and tetracycline. In vitro biofilm production by tissue culture plate (TCP) and Congo red agar method detected 52 (80%) and 25 (38.46%) as biofilm producers, respectively. TCP identified 2 (3.07%), 7 (10.76%), and 44 (67.69%) as strongly, moderately, and weakly adherent. About 30.7% of MRSA obtained were positive biofilm producers. The minimum inhibitory concentration value of Oxacillin for S. aureus by agar dilution method ranged from 0.025 μg/mL to 128 μg/mL. Conclusion: This study shows that biofilm production was more in methicillin-resistant strains and displayed a high degree of resistance to almost all groups of antibiotics.

Ginseng aqueous extract attenuates the production of virulence factors, stimulates twitching and adhesion, and eradicates biofilms of Pseudomonas aeruginosa

2011 ◽  
Vol 89 (6) ◽  
pp. 419-427 ◽  
Author(s):  
Misagh Alipour ◽  
Abdelwahab Omri ◽  
Zacharias E. Suntres
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Aqueous Extract ◽  
North American ◽  
American Ginseng ◽  
Antimicrobial Activities ◽  
Live Cells ◽  
Dilution Method ◽  
Agar Dilution Method

This study was carried out to examine the antimicrobial activity of the aqueous extract of Panax quinquefolius from North American ginseng (NAGE) root against Pseudomonas aeruginosa . The minimum inhibitory concentrations of reference and clinical isolates of Pseudomonas aeruginosa were measured by a standard agar-dilution method. At subinhibitory NAGE concentrations, the secretion of virulence factors, motility on agar, and adhesion to 96-well microplates were studied on the nonmucoid Pseudomonas aeruginosa O1 strain. At suprainhibitory concentrations, the activity of NAGE against mature biofilm complexes formed in the Calgary Biofilm Device and the Stovall flow cell were assessed. NAGE possessed an antibacterial activity against all the Pseudomonas aeruginosa strains at 1.25%–2.5% w/v. NAGE also significantly attenuated pyocyanin, pyoverdine, and lipase concentrations, stimulated twitching, and attenuated swarming and swimming motility. At 1.25% w/v, NAGE augmented adhesion, and at 5% w/v detached 1-day-old biofilms in microplates. The extract also eradicated 6-day-old mature biofilms (5% w/v), and fluorescence microscopy displayed a reduction of live cells and biofilm complexes compared with nontreated biofilms. These data suggest that the aqueous extract from North American ginseng possesses antimicrobial activities in vitro.

scholarly journals Radiometric studies of mycobacterium tuberculosis

1987 ◽  
Vol 29 (1) ◽  
pp. 18-25
Author(s):  
Edwaldo E. Camargo ◽  
Judith A. Kertcher ◽  
Marianne F. Chen ◽  
Patricia Charache ◽  
Henry N. Wagner Jr
Keyword(s):  
Palmitic Acid ◽  
Lauric Acid ◽  
Bacterial Suspension ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Experimental Conditions ◽  
Vitro Assay ◽  
Minimal Inhibitory Concentrations ◽  
Different Strains

An in vitro assay system that included automated radiometric quantification of 14CO2 released as a result of oxidation of 14C- substrates was applied for studying the metabolic activity of M. tuberculosis under various experimental conditions. These experiments included the study of a) mtabolic pathways, b) detection times for various inoculum sizes, c) effect of filtration on reproducibility of results, d) influence of stress environment e) minimal inhibitory concentrations for isoniazid, streptomycin, ethambutol and rifampin, and f) generation times of M. tuberculosis and M. bovis. These organisms were found to metabolize 14C-for-mate, (U-14C) acetate, (U-14C) glycerol, (1-14C) palmitic acid, 1-14C) lauric acid, (U-14C) L-malic acid, (U-14C) D-glucose, and (U-14C) D-glucose, but not (1-14C) L-glucose, (U-14C) glycine, or (U-14C) pyruvate to 14CO2. By using either 14C-for-mate, (1-14C) palmitic acid, or (1-14C) lauric acid, 10(7) organisms/vial could be detected within 24 48 hours and as few as 10 organisms/vial within 16-20 days. Reproducible results could be obtained without filtering the bacterial suspension, provided that the organisms were grown in liquid 7H9 medium with 0.05% polysorbate 80 and homogenized prior to the study. Drugs that block protein synthesis were found to have lower minimal inhibitory concentrations with the radiometric method when compared to the conventional agar dilution method. The mean generation time obtained for M. bovis and different strains of M. tuberculosis with various substrates was 9 ± 1 hours.

Design and Synthesis of Novel 1-substituted-3-(3-(3-nitrophenyl)-4-oxo-3,4-dihydrobenzopyrimidin-2-yl amino) Isothioureas for their Anti-HIV, Antibacterial Activities, Graph Theoretical Analysis, Insilico Modeling, Prediction of Toxicity and Metabolic Studies

Drug Research ◽  
2020 ◽  
Vol 70 (08) ◽  
pp. 348-355
Author(s):  
Bandi Narendhar ◽  
Veerachamy Alagarsamy ◽  
Chitra Krishnan
Keyword(s):  
Antitubercular Activity ◽  
Antibacterial Activities ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
Gram Positive ◽  
Alkyl Aryl ◽  
Design And Synthesis ◽  
Modeling Prediction ◽  
Anti Hiv Agents ◽  
Anti Hiv

AbstractIn the present study, we have placed the substituted thiosemicarbazide moiety at the C-2 position and 3-nitrophenyl group at N-3 position of benzopyrimidines and studied their antitubercular, anti-HIV and antibacterial activities against selected gram positive and negative bacteria. The target compounds 1-substituted-3-(3-(3-nitrophenyl)-4-oxo-3,4-dihydrobenzopyrimidin-2-ylamino) isothioureas (PTS1 – PTS15 ) were obtained by the reaction of 2-hydrazino-3-(3-nitrophenyl) benzopyrimidin-4(3 H)-one (5) with different alkyl/aryl isothiocyanates followed by methylation with dimethyl sulphate. All synthesized compounds were screened for their antitubercular, anti-HIV and antibacterial activity against selective gram positive and gram negative bacteria by agar dilution method. Among the series, compound 2-methyl-3-(3-(3-nitrophenyl)-4-oxo-3,4-dihydrobenzopyrimidin-2-ylamino)-1-(3-chlorophenyl)isothiourea (PTS14) shown most potent activity against Klebsiella pneumoniae, Proteus vulgaris and Staphylococcus aureus; PTS14 exhibited the antitubercular activity at the minimum microgram of 1.56 µg/mL and anti-HIV activity at 0.96 µg/mL against HIV1 and HIV2 and offers potential for further optimization and development to new antitubercular and anti-HIV agents. The results obtained from this study confirm that the synthesized and biologically evaluated benzopyrimidines showed promising antimicrobial, antitubercular and anti-HIV activities and are new scaffolds for antimicrobial activity.

3,4-Dihydropyrimidin-2(1H)-One Analogues: Microwave irradiated Synthesis with Antimicrobial and Antituberculosis Study

2019 ◽  
Vol 6 (1) ◽  
pp. 61-70
Author(s):  
Navin Patel ◽  
Sabir Pathan ◽  
Hetal I. Soni
Keyword(s):  
Microwave Irradiation ◽  
Biginelli Reaction ◽  
Antitubercular Activity ◽  
Antimicrobial Activities ◽  
Chemical Diversity ◽  
Spectral Studies ◽  
Dilution Method ◽  
Bacterial Strains ◽  
Microwave Irradiation Method

Background: For rapid and sustainable synthesis, microwave irradiation method is serviceable. This present study deals with the preparation of oxadiazole and pyridine bearing 1,2,3,4- tetrahydro pyrimidine derivatives by microwave irradiation. Objective: The present study aims to carry out rapid synthesis of chloro-acetamides of oxadiazoles of Biginelli product and amino cyano derivative of pyridine by microwave-assisted heating. Our efforts are focused on the introduction of chemical diversity in the molecular framework in order to synthesize pharmacologically interesting compounds. Methods:: Microwave irradiation was used for the synthesis of 2-((3-cyano-4-(3,4-dichloro phenyl)- 6-(4-hydroxy-3-methoxyphenyl) pyridin-2-yl) amino)-N-(5-(substituted) -(6-methyl-2-oxo -1,2,3,4- tetrahydro pyrimidin-5-yl)-1,3,4-oxadiazol-2-yl)acetamide by using Biginelli reaction. New structural analogues were confirmed by spectral studies followed by their screening for in vitro antibacterial activity against Staphylococcus aureus, Staphylococcus Pyogenus, Escherichia coli and Pseudomonas aeruginosa bacterial strains and for antifungal activity against Candida albicans, Aspergillus niger and Aspergillus clavatus by micro-broth dilution method. In vitro antimycobacterial activity determined out against (Mycobacterium tuberculosis) H37Rv strain using Lowenstein-Jensen medium. Results: As compared to the conventional method, microwave irradiation method is advantageous for the synthesis of 1,2,3,4-tetrahydropyrimidin derivatives. Potent antimicrobial activities and antitubercular activity were found for some of the compounds. Conclusion: Microwave irradiation method provided an effective way to discover a novel class of antimicrobial and antituberculosis agents. 1,2,3,4-tetrahydropyrimidin derivatives showed improved antimicrobial and good antituberculosis activity.

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