New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against <i>Mycobacterium tuberculosis</i>, mono-resistant MTB strains, and nontuberculous strains <i>Mycobacterium abscessus</i> and Myc...

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Autores principales: Oxana Kazakova, Roxana Racoviceanu, Anastasiya Petrova, Marius Mioc, Adrian Militaru, Lucreția Udrescu, Mihai Udrescu, Adrian Voicu, Jason Cummings, Gregory Robertson, Diane J. Ordway, Richard A. Slayden, Codruța Șoica
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Publicado: MDPI AG 2021
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Acceso en línea:https://doaj.org/article/3e7403c52ff547d18f5dcf6d20eacf42
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spelling oai:doaj.org-article:3e7403c52ff547d18f5dcf6d20eacf422021-11-25T17:57:38ZNew Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design10.3390/ijms2222125421422-00671661-6596https://doaj.org/article/3e7403c52ff547d18f5dcf6d20eacf422021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12542https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against <i>Mycobacterium tuberculosis</i>, mono-resistant MTB strains, and nontuberculous strains <i>Mycobacterium abscessus</i> and Mycobacterium <i>avium</i> were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound <b>7</b>), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound <b>7</b> scoring the highest as a potential <i>M. tuberculosis</i> RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound <b>7</b> when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against <i>M. avium</i> with compound <b>14</b> recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.Oxana KazakovaRoxana RacoviceanuAnastasiya PetrovaMarius MiocAdrian MilitaruLucreția UdrescuMihai UdrescuAdrian VoicuJason CummingsGregory RobertsonDiane J. OrdwayRichard A. SlaydenCodruța ȘoicaMDPI AGarticletriterpenoidslupanebetulinazepane<i>M. tuberculosis</i>resistant MTB strainsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12542, p 12542 (2021)
institution DOAJ
collection DOAJ
language EN
topic triterpenoids
lupane
betulin
azepane
<i>M. tuberculosis</i>
resistant MTB strains
Biology (General)
QH301-705.5
Chemistry
QD1-999
spellingShingle triterpenoids
lupane
betulin
azepane
<i>M. tuberculosis</i>
resistant MTB strains
Biology (General)
QH301-705.5
Chemistry
QD1-999
Oxana Kazakova
Roxana Racoviceanu
Anastasiya Petrova
Marius Mioc
Adrian Militaru
Lucreția Udrescu
Mihai Udrescu
Adrian Voicu
Jason Cummings
Gregory Robertson
Diane J. Ordway
Richard A. Slayden
Codruța Șoica
New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design
description Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against <i>Mycobacterium tuberculosis</i>, mono-resistant MTB strains, and nontuberculous strains <i>Mycobacterium abscessus</i> and Mycobacterium <i>avium</i> were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound <b>7</b>), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound <b>7</b> scoring the highest as a potential <i>M. tuberculosis</i> RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound <b>7</b> when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against <i>M. avium</i> with compound <b>14</b> recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.
format article
author Oxana Kazakova
Roxana Racoviceanu
Anastasiya Petrova
Marius Mioc
Adrian Militaru
Lucreția Udrescu
Mihai Udrescu
Adrian Voicu
Jason Cummings
Gregory Robertson
Diane J. Ordway
Richard A. Slayden
Codruța Șoica
author_facet Oxana Kazakova
Roxana Racoviceanu
Anastasiya Petrova
Marius Mioc
Adrian Militaru
Lucreția Udrescu
Mihai Udrescu
Adrian Voicu
Jason Cummings
Gregory Robertson
Diane J. Ordway
Richard A. Slayden
Codruța Șoica
author_sort Oxana Kazakova
title New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design
title_short New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design
title_full New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design
title_fullStr New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design
title_full_unstemmed New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design
title_sort new investigations with lupane type a-ring azepane triterpenoids for antimycobacterial drug candidate design
publisher MDPI AG
publishDate 2021
url https://doaj.org/article/3e7403c52ff547d18f5dcf6d20eacf42
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