Antitubercular Drugs: Synthesis, Mechanism and Application

A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Applied Biosciences and Bioengineering".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 7414

Special Issue Editors


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Guest Editor
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA
Interests: tuberculosis drug discovery; antitubercular drug modes of action; biosynthesis of mycobacterial cell walls; structure, localization, and biological activities of actinobacterial glycolipids and glycans

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Guest Editor
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA
Interests: biogenesis of mycobacterial cell envelope; functional characterization of mycobacterial genes; biochemical validation of drug targets; enzymatic assay development; screening of inhibitors; rational drug design

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Guest Editor
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, USA
Interests: medicinal chemistry; immunochemistry; glycochemistry; glycobiology; small molecules design; synthesis

Special Issue Information

Dear Colleagues,

Tuberculosis, caused by Mycobacterium tuberculosis, remains a major public health problem worldwide and is responsible for nearly 1.5 million deaths annually. The increase of tuberculosis cases in recent years is related to an emergence of multidrug-resistant and extensive drug-resistant strains of M. tuberculosis and the AIDS pandemic. Although tuberculosis is a curable disease, its treatment requires multidrug and lengthy therapy associated with severe adverse effects, often leading to poor patient adherence. In the last two decades, great progress in tuberculosis drug discovery has been made while searching for the most suitable approach to lead generation. Although there are currently several drug candidates in the late stages of development and new drugs have been recently introduced into the antitubercular drug regimen, more compounds presenting a better efficacy, less-toxicity, and targeting different subpopulations of M. tuberculosis, which, simultaneously, are not affected by the existing resistance mechanisms, are certainly urgently needed. This is approached by both the discovery of new molecular scaffolds and reposing the old antitubercular drugs. 

In this Special Issue, we invite submissions exploring tuberculosis drug discovery including, but not limited to, the synthesis, mode of action, and determining the efficacy of compounds. Reviews and original research papers are welcome.

Dr. Anna Grzegorzewicz
Dr. Zuzana Palčeková
Dr. Prithwiraj De
Guest Editors

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Keywords

  • tuberculosis
  • tuberculosis drug discovery
  • drug synthesis
  • hit and lead generation
  • compounds screening
  • minimal inhibitory concentration
  • pharmacokinetic properties
  • drug target
  • mode of action
  • intrinsic and acquired resistance
  • persisters
  • antitubercular drug regimen
  • drug development pipeline

Published Papers (3 papers)

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Research

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20 pages, 1931 KiB  
Article
Synthesis and Critical View on the Structure-Activity Relationships of N-(Substituted phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as Antimycobacterial Agents
by Jana Čurillová, Mária Pecháčová, Tereza Padrtová, Daniel Pecher, Šárka Mascaretti, Josef Jampílek, Ľudmila Pašková, František Bilka, Gustáv Kováč and Ivan Malík
Appl. Sci. 2022, 12(1), 300; https://doi.org/10.3390/app12010300 - 29 Dec 2021
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Abstract
This research focused on a three-step synthesis, analytical, physicochemical, and biological evaluation of hybrid molecules 6ag, containing a lipophilic 3-trifluoromethylphenyl moiety, polar carbamoyloxy bridge, 2-hydroxypropan-1,3-diyl chain and 4-(substituted phenyl)-/4-diphenylmethylpiperazin-1-ium-1-yl fragment. The estimation of analytical and physicochemical descriptors (m/ [...] Read more.
This research focused on a three-step synthesis, analytical, physicochemical, and biological evaluation of hybrid molecules 6ag, containing a lipophilic 3-trifluoromethylphenyl moiety, polar carbamoyloxy bridge, 2-hydroxypropan-1,3-diyl chain and 4-(substituted phenyl)-/4-diphenylmethylpiperazin-1-ium-1-yl fragment. The estimation of analytical and physicochemical descriptors (m/zmeasured via HPLC-UV/HR-MS, log ε2 (Ch–T) from UV/Vis spectrophotometry and log kw via RP-HPLC) as well as in vitro antimycobacterial and cytotoxic screening of given compounds were carried out (i.e., determination of MIC and IC50 values). These highly lipophilic molecules (log kw = 4.1170–5.2184) were tested against Mycobacterium tuberculosis H37Ra ATCC 25177 (Mtb H37Ra), M. kansasii DSM 44162 (MK), M. smegmatis ATCC 700084 (MS), and M. marinum CAMP 5644 (MM). The impact of the 6ag set on the viability of human liver hepatocellular carcinoma (HepG2) cells was also investigated. 1-[2-Hydroxypropyl-{(3-trifluoromethyl)- phenyl}carbamoyloxy]-4-(3,4-dichlorophenyl)piperazin-1-ium chloride (6e) and 1-[2-hydroxy- propyl-{(3-trifluoromethyl)phenyl}carbamoyloxy]-4-(4-diphenylmethyl)piperazin-1-ium chloride (6g) most effectively inhibited the growth of Mtb H37Ra (MIC < 3.80 μM). The substance 6g also showed interesting activity against MM (MIC = 8.09 μM). All obtained data served as input values for structure-activity relationship evaluations using statistical principal component analysis. In fact, the toxicity of both 6e (IC50 = 29.39 μM) and 6g (IC50 = 22.18 μM) in HepG2 cells as well as selectivity index (SI) values (SI < 10.00) prevented to consider these promising antimycobacterials safe. Full article
(This article belongs to the Special Issue Antitubercular Drugs: Synthesis, Mechanism and Application)
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14 pages, 853 KiB  
Article
Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis
by Sarah M. Hopfner, Bei Shi Lee, Nitin P. Kalia, Marvin J. Miller, Kevin Pethe and Garrett C. Moraski
Appl. Sci. 2021, 11(19), 9092; https://doi.org/10.3390/app11199092 - 29 Sep 2021
Cited by 3 | Viewed by 2274
Abstract
The development of cytochrome bd oxidase (cyt-bd) inhibitors are needed for comprehensive termination of energy production in Mycobacterium tuberculosis (Mtb) to treat tuberculosis infections. Herein, we report on the structure-activity-relationships (SAR) of 22 new N-phenethyl-quinazolin-4-yl-amines that target cyt-bd. [...] Read more.
The development of cytochrome bd oxidase (cyt-bd) inhibitors are needed for comprehensive termination of energy production in Mycobacterium tuberculosis (Mtb) to treat tuberculosis infections. Herein, we report on the structure-activity-relationships (SAR) of 22 new N-phenethyl-quinazolin-4-yl-amines that target cyt-bd. Our focused set of compounds was synthesized and screened against three mycobacterial strains: Mycobacterium bovis BCG, Mycobacterium tuberculosis H37Rv and the clinical isolate Mycobacterium tuberculosis N0145 with and without the cytochrome bcc:aa3 inhibitor Q203 in an ATP depletion assay. Two compounds, 12a and 19a, were more active against all three strains than the naturally derived cyt-bd inhibitor aurachin D. Full article
(This article belongs to the Special Issue Antitubercular Drugs: Synthesis, Mechanism and Application)
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Review

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17 pages, 7713 KiB  
Review
Tuberculosis Vaccines: An Update of Recent and Ongoing Clinical Trials
by Sean Saramago, Joana Magalhães and Marina Pinheiro
Appl. Sci. 2021, 11(19), 9250; https://doi.org/10.3390/app11199250 - 05 Oct 2021
Cited by 14 | Viewed by 2700
Abstract
TB remains a global health challenge and, until now, only one licensed vaccine (the BCG vaccine) is available. The main goal of this work is to assess the progress in the development of new TB vaccines and highlight the research in nanovaccines. A [...] Read more.
TB remains a global health challenge and, until now, only one licensed vaccine (the BCG vaccine) is available. The main goal of this work is to assess the progress in the development of new TB vaccines and highlight the research in nanovaccines. A review was conducted using a methodology with the appropriate keywords and inclusion and exclusion criteria. The search revealed 37 clinical trials that were further reviewed. The results available have reported good immunogenicity and safety profiles for the vaccines under investigation. Over the last five years, the vaccines, VPM1002 and Vaccae, have moved ahead to phase III clinical trials, with the remaining candidate vaccines progressing in phase I and II clinical trials. RUTI and ID93+GLA-SE involve the use of nanoparticles. This strategy seems promising to improve the delivery, efficacy, cost, and storage conditions of the existing TB vaccines. In conclusion, the use of nanovaccines may be an option for both prevention and treatment. However, further studies are necessary for the development of novel TB vaccines. Full article
(This article belongs to the Special Issue Antitubercular Drugs: Synthesis, Mechanism and Application)
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