Design, Synthesis, Toxicity Estimation and Molecular Docking Studies of N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimine as Antitubercular Agents

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Abstract

A series of novel N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimines (Fa-e) were synthesized and evaluated for antitubercular activity against Mycobacterium tuberculosis (H ₃₇Rv) strain by using alamar blue assay. The synthesized compounds were characterized based on IR, ¹HMR and mass spectral analysis. The toxicity profile was predicted by organic chemistry portal, a web based application for predicting in silico absorption, distribution, metabolism, excretion and toxicity, and the novel derivatives under study did not show any toxicity issues. The mechanism of action of the titled derivatives was predicted by docking on the Mycobacterium tuberculosis Enoyl-ACP reductase enzyme. The docking study concluded that Fb and Fa possessed good binding energy indicating more prominent interaction towards the active sites NAD and TYR 158. The antitubercular studies showed that the both Fa and Fb possessed significant activity with the MIC as low as 3.125 μg/ml.

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Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites.

Alasdair Laurie, Richard Jackson (2005)

Identifying the location of ligand binding sites on a protein is of fundamental importance for a range of applications including molecular docking, de novo drug design and structural identification and comparison of functional sites. Here, we describe a new method of ligand binding site prediction called Q-SiteFinder. It uses the interaction energy between the protein and a simple van der Waals probe to locate energetically favourable binding sites. Energetically favourable probe sites are clustered according to their spatial proximity and clusters are then ranked according to the sum of interaction energies for sites within each cluster. There is at least one successful prediction in the top three predicted sites in 90% of proteins tested when using Q-SiteFinder. This success rate is higher than that of a commonly used pocket detection algorithm (Pocket-Finder) which uses geometric criteria. Additionally, Q-SiteFinder is twice as effective as Pocket-Finder in generating predicted sites that map accurately onto ligand coordinates. It also generates predicted sites with the lowest average volumes of the methods examined in this study. Unlike pocket detection, the volumes of the predicted sites appear to show relatively low dependence on protein volume and are similar in volume to the ligands they contain. Restricting the size of the pocket is important for reducing the search space required for docking and de novo drug design or site comparison. The method can be applied in structural genomics studies where protein binding sites remain uncharacterized since the 86% success rate for unbound proteins appears to be only slightly lower than that of ligand-bound proteins. Both Q-SiteFinder and Pocket-Finder have been made available online at http://www.bioinformatics.leeds.ac.uk/qsitefinder and http://www.bioinformatics.leeds.ac.uk/pocketfinder

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Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium.

L. Collins, S Franzblau (1997)

In response to the need for rapid, inexpensive, high-throughput assays for antimycobacterial drug screening, a microplate-based assay which uses Alamar blue reagent for determination of growth was evaluated. MICs of 30 antimicrobial agents against Mycobacterium tuberculosis H37Rv, M. tuberculosis H37Ra, and Mycobacterium avium were determined in the microplate Alamar blue assay (MABA) with both visual and fluorometric readings and compared to MICs determined in the BACTEC 460 system. For all three mycobacterial strains, there was < or = 1 dilution difference between MABA and BACTEC median MICs in four replicate experiments for 25 to 27 of the 30 antimicrobics. Significant differences between MABA and BACTEC MICs were observed with 0, 2, and 5 of 30 antimicrobial agents against H37Rv, H37Ra, and M. avium, respectively. Overall, MICs determined either visually or fluorometrically in MABA were highly correlated with those determined in the BACTEC 460 system, and visual MABA and fluorometric MABA MICs were highly correlated. MICs of rifampin, rifabutin, minocycline, and clarithromycin were consistently lower for H37Ra compared to H37Rv in all assays but were similar for most other drugs. M. tuberculosis H37Ra may be a suitable surrogate for the more virulent H37Rv strain in primary screening of compounds for antituberculosis activity. MABA is sensitive, rapid, inexpensive, and nonradiometric and offers the potential for screening, with or without analytical instrumentation, large numbers of antimicrobial compounds against slow-growing mycobacteria.

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Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis.

Kuni Takayama, Cindy Wang, Gurdyal S Besra (2005)

Mycobacterium tuberculosis is known to synthesize alpha-, methoxy-, and keto-mycolic acids. We propose a detailed pathway to the biosynthesis of all mycolic acids in M. tuberculosis. Fatty acid synthetase I provides C(20)-S-coenzyme A to the fatty acid synthetase II system (FAS-IIA). Modules of FAS-IIA and FAS-IIB introduce cis unsaturation at two locations on a growing meroacid chain to yield three different forms of cis,cis-diunsaturated fatty acids (intermediates to alpha-, methoxy-, and keto-meroacids). These are methylated, and the mature meroacids and carboxylated C(26)-S-acyl carrier protein enter into the final Claisen-type condensation with polyketide synthase-13 (Pks13) to yield mycolyl-S-Pks13. We list candidate genes in the genome encoding the proposed dehydrase and isomerase in the FAS-IIA and FAS-IIB modules. We propose that the processing of mycolic acids begins by transfer of mycolic acids from mycolyl-S-Pks13 to d-mannopyranosyl-1-phosphoheptaprenol to yield 6-O-mycolyl-beta-d-mannopyranosyl-1-phosphoheptaprenol and then to trehalose 6-phosphate to yield phosphorylated trehalose monomycolate (TMM-P). Phosphatase releases the phosphate group to yield TMM, which is immediately transported outside the cell by the ABC transporter. Antigen 85 then catalyzes the transfer of a mycolyl group from TMM to the cell wall arabinogalactan and to other TMMs to produce arabinogalactan-mycolate and trehalose dimycolate, respectively. We list candidate genes in the genome that encode the proposed mycolyltransferases I and II, phosphatase, and ABC transporter. The enzymes within this total pathway are targets for new drug discovery.

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Journal

Journal ID (nlm-ta): Indian J Pharm Sci

Journal ID (iso-abbrev): Indian J Pharm Sci

Journal ID (publisher-id): IJPhS

Title: Indian Journal of Pharmaceutical Sciences

Publisher: Medknow Publications & Media Pvt Ltd (India )

ISSN (Print): 0250-474X

ISSN (Electronic): 1998-3743

Publication date (Print): Sep-Oct 2014

Volume: 76

Issue: 5

Pages: 401-406

Affiliations

[1]Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad-678 004, India

[1 ]Department of Pharmaceutical Chemistry, College of Pharmacy, Madras Medical College Chennai-600 003, India

[2 ]Department of Pharmaceutical Chemistry, College of Pharmacy, SRIPS, Coimbatore-641 044, India

[3 ]Department of Pharmaceutical Chemistry, College of Pharmaceutical Science, Govt. Medical College, Trivandrum-695 011, India

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[* ] Address for correspondence E-mail: bijovilaventgu@ 123456gmail.com

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Publisher ID: IJPhS-76-401

PMC ID: 4243256

SO-VID: f5e9f76d-8f3e-4777-befa-5b9dc3bb0c2d

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This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Design, Synthesis, Toxicity Estimation and Molecular Docking Studies of N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimine as Antitubercular Agents

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Most cited references 30

Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites.

Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium.

Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis.

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