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.

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.

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.

scholarly journals Anti-HIV, Antitubercular and Antibacterial Activities of Novel 3-(Substituted Quinazolinylamino)-2-phenyl quinazolin-4(3H)ones

2019 ◽  
Vol 32 (2) ◽  
pp. 281-286
Author(s):  
M.T. Sulthana ◽  
K. Chitra ◽  
V. Alagarsamy
Keyword(s):  
Antibacterial Activity ◽  
Antitubercular Activity ◽  
Antibacterial Activities ◽  
Primary Amines ◽  
Dilution Method ◽  
Agar Dilution Method ◽  
E Coli ◽  
Agar Dilution ◽  
Anti Hiv Agents ◽  
Anti Hiv

In the present study, we have synthesized a series of novel 2-phenyl-3-(substituted quinazolinylamino)quinazolin-4(3H)-ones by the reaction of 3-(substituted)-2-hydrazinoquinazoline-4(3H)-ones with 2-phenyl-3,1-benzoxazin-4-one. The starting material 3-(substituted)-2-hydrazinoquinazolin-4(3H)-ones were synthesized from various primary amines. All the synthesized compounds were screened for their antitubercular, anti-HIV and antibacterial activity against different Grampositive and Gram-negative strains by agar dilution method. Among the test compounds, 3-(4-nitrophenyl)-2-(4-oxo-2-phenylquinazolin-3(4H)-ylamino)quinazolin-4(3H)-one (BQZ6) and 3-(4-chlorophenyl)-2-(4-oxo-2-phenylquinazolin-3(4H)-ylamino)quinazolin-4(3H)-one (BQZ7) shown most potent antibacterial activity against E. coli, P. aeruginosa and S. aureus with the MIC of 3 μg/mL. The compound BQZ7 exhibited the antitubercular activity with the MIC of 25 μg/mL and anti-HIV activity with the MIC of 35.4 μg/mL against HIV1 and HIV2 and offers potential lead for further optimization and development to new antitubercular and anti-HIV agents. The results from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities and are new scaffolds for antimicrobial activity

Design, Synthesis and Evaluation of Thiourea Derivatives as Antimicrobial and Antiviral Agents

2019 ◽  
Vol 16 (6) ◽  
pp. 618-624 ◽  
Author(s):  
Veerasamy Ravichandran ◽  
Sivadasan Shalini ◽  
Krishnan Suresh Kumar ◽  
Harish Rajak ◽  
Ram Kishore Agrawal
Keyword(s):  
Spectral Analysis ◽  
Antimicrobial Agents ◽  
Antiviral Agents ◽  
Drug Resistant ◽  
Design Synthesis ◽  
Thiourea Derivatives ◽  
Structure Activity ◽  
Antiviral Activities ◽  
Anti Hiv

Background: The development of drug-resistant by bacteria appears rapidly and thus making the effectiveness of antibiotics severely limited. Methods: A series of thiourea derivatives was synthesized, characterized and evaluated for their in vitro antibacterial, antifungal and antiviral activities. Results: Structures of the newly synthesized compounds were confirmed by elemental and spectral analysis. The biological results showed that some of the target compounds displayed comparable antimicrobial and antiviral activities with reference drugs. Structure-activity relationship studies revealed that the ortho- chloro or fluoro substituted phenyl at Ar1 and substituted pyridinyl at Ar2 positions of the thiourea nucleus are essential for their in vitro antimicrobial and anti-HIV activity. In particular, compounds 8 and 10 showed better activity against the tested bacteria, fungi and viral strains than other synthesized PET derivatives reported in the present study. Conclusion: These results provide an encouraging lead that could be used for the development of new potent antiviral and antimicrobial agents

scholarly journals Potent Synergistic Anti-Human Immunodeficiency Virus (HIV) Effects Using Combinations of the CCR5 Inhibitor Aplaviroc with Other Anti-HIV Drugs

2008 ◽  
Vol 52 (6) ◽  
pp. 2111-2119 ◽  
Author(s):  
Hirotomo Nakata ◽  
Seth M. Steinberg ◽  
Yasuhiro Koh ◽  
Kenji Maeda ◽  
Yoshikazu Takaoka ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Synergistic Effects ◽  
Immunodeficiency Virus ◽  
Approved Drugs ◽  
Hiv Drugs ◽  
Nonparametric Statistical ◽  
Anti Hiv ◽  
Ccr5 Inhibitor ◽  
Hiv 1

ABSTRACT Aplaviroc (AVC), an experimental CCR5 inhibitor, potently blocks in vitro the infection of R5-tropic human immunodeficiency virus type 1 (R5-HIV-1) at subnanomolar 50% inhibitory concentrations. Although maraviroc is presently clinically available, further studies are required to determine the role of CCR5 inhibitors in combinations with other drugs. Here we determined anti-HIV-1 activity using combinations of AVC with various anti-HIV-1 agents, including four U.S. Food and Drug Administration-approved drugs, two CCR5 inhibitors (TAK779 and SCH-C) and two CXCR4 inhibitors (AMD3100 and TE14011). Combination effects were defined as synergistic or antagonistic when the activity of drug A combined with B was statistically greater or less, respectively, than the additive effects of drugs A and A combined and drugs B and B combined by using the Combo method, described in this paper, which provides (i) a flexible choice of interaction models and (ii) the use of nonparametric statistical methods. Synergistic effects against R5-HIV-1Ba-L and a 50:50 mixture of R5-HIV-1Ba-L and X4-HIV-1ERS104pre (HIV-1Ba-L/104pre) were seen when AVC was combined with zidovudine, nevirapine, indinavir, or enfuvirtide. Mild synergism and additivity were observed when AVC was combined with TAK779 and SCH-C, respectively. We also observed more potent synergism against HIV-1Ba-L/104pre when AVC was combined with AMD3100 or TE14011. The data demonstrate a tendency toward greater synergism with AVC plus either of the two CXCR4 inhibitors compared to the synergism obtained with combinations of AVC and other drugs, suggesting that the development of effective CXCR4 inhibitors may be important for increasing the efficacies of CCR5 inhibitors.

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 Mechanism of Action and In Vitro Activity of 1′,3′-Dioxolanylpurine Nucleoside Analogues against Sensitive and Drug-Resistant Human Immunodeficiency Virus Type 1 Variants

1999 ◽  
Vol 43 (10) ◽  
pp. 2376-2382 ◽  
Author(s):  
Zhengxian Gu ◽  
Mark A. Wainberg ◽  
Nghe Nguyen-Ba ◽  
Lucille L’Heureux ◽  
Jean-Marc de Muys ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Nucleoside Analogues ◽  
Drug Resistant ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT (−)-β-d-1′,3′-Dioxolane guanosine (DXG) and 2,6-diaminopurine (DAPD) dioxolanyl nucleoside analogues have been reported to be potent inhibitors of human immunodeficiency virus type 1 (HIV-1). We have recently conducted experiments to more fully characterize their in vitro anti-HIV-1 profiles. Antiviral assays performed in cell culture systems determined that DXG had 50% effective concentrations of 0.046 and 0.085 μM when evaluated against HIV-1IIIB in cord blood mononuclear cells and MT-2 cells, respectively. These values indicate that DXG is approximately equipotent to 2′,3′-dideoxy-3′-thiacytidine (3TC) but 5- to 10-fold less potent than 3′-azido-2′,3′-dideoxythymidine (AZT) in the two cell systems tested. At the same time, DAPD was approximately 5- to 20-fold less active than DXG in the anti-HIV-1 assays. When recombinant or clinical variants of HIV-1 were used to assess the efficacy of the purine nucleoside analogues against drug-resistant HIV-1, it was observed that AZT-resistant virus remained sensitive to DXG and DAPD. Virus harboring a mutation(s) which conferred decreased sensitivity to 3TC, 2′,3′-dideoxyinosine, and 2′,3′-dideoxycytidine, such as a 65R, 74V, or 184V mutation in the viral reverse transcriptase (RT), exhibited a two- to fivefold-decreased susceptibility to DXG or DAPD. When nonnucleoside RT inhibitor-resistant and protease inhibitor-resistant viruses were tested, no change in virus sensitivity to DXG or DAPD was observed. In vitro drug combination assays indicated that DXG had synergistic antiviral effects when used in combination with AZT, 3TC, or nevirapine. In cellular toxicity analyses, DXG and DAPD had 50% cytotoxic concentrations of greater than 500 μM when tested in peripheral blood mononuclear cells and a variety of human tumor and normal cell lines. The triphosphate form of DXG competed with the natural nucleotide substrates and acted as a chain terminator of the nascent DNA. These data suggest that DXG triphosphate may be the active intracellular metabolite, consistent with the mechanism by which other nucleoside analogues inhibit HIV-1 replication. Our results suggest that the use of DXG and DAPD as therapeutic agents for HIV-1 infection should be explored.

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.

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