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Pharmaceuticals
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Drug Candidates for the Treatment of Tuberculosis 2021
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Drug Candidates for the Treatment of Tuberculosis 2021

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 July 2022) | Viewed by 7820

Special Issue Editor

Dr. Christian Lherbet

E-Mail Website
Guest Editor
LSPCMIB, UMR-CNRS 5068, Université Paul Sabatier-Toulouse III, 118, route de Narbonne, 236 Cours Eugène Cosserat, CEDEX, 31062 Toulouse, France
Interests: bioorganic chemistry, chemical biology; drug design; enzyme inhibitors; antitubercular agents; InhA, tuberculosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) is a scourge and the leading cause from a single infectious agent worldwide. In 2018, 1.5 million TB deaths including about 300,000 deaths among HIVpositive people were estimated. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb) strains has exacerbated the situation.  Effective drug treatments were first developed in the 1940s. Isoniazid, pyrazinamide, ethambutol and rifampicin, considered as first-line drugs, were used for tuberculosis chemotherapy for years. During 50 years, no antituberculosis drug has been found.  However, drugs such as bedaquiline, delamanid and pretomanid appeared recently as new antitubercular agents for the treatment of drug-resistance-TB.  Even if in recent years, considerable efforts have been made in developing a TB drug pipeline, there is an urgent need to discover new drugs to combat existing drug-resistance and accelerate eradication of TB forever.

This special issue “Drug Candidates for the Treatment of Tuberculosis 2021” in Pharmaceuticals aims to provide the opportunity to share new findings and progress of research into new anti-tuberculosis drugs.  Topics will include drug design, protein inhibitors, high throughput screening, hit generation, lead optimization and modification, drug mechanism, drug candidate. Contributions in other topics will be also considered. Both research articles and reviews in this field are welcome. Dr. Christian LherbetGuest editor 

Dr. Christian Lherbet
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug candidates
  • tuberculosis
  • enzyme inhibitors
  • medicinal chemistry

Published Papers (3 papers)

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Research

15 pages, 3143 KiB  
Article
Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity
by Ebru Koçak Aslan, Muhammed İhsan Han, Vagolu Siva Krishna, Rasoul Tamhaev, Cagatay Dengiz, Şengül Dilem Doğan, Christian Lherbet, Lionel Mourey, Tone Tønjum and Miyase Gözde Gündüz
Pharmaceuticals 2022, 15(10), 1301; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101301 - 21 Oct 2022
Cited by 7 | Viewed by 2822
Abstract
Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In [...] Read more.
Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In the present study, we aimed to chemically tailor INH to overcome this resistance. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge (SIH1–SIH13). Following structural characterization by FTIR, 1H NMR, 13C NMR, and HRMS, all compounds were screened for their antitubercular activity against Mtb H37Rv strain and INH-resistant clinical isolates carrying katG and inhA mutations. Additionally, the cytotoxic effects of SIH1–SIH13 were assessed on three different healthy host cell lines; HEK293, IMR-90, and BEAS-2B. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. Moreover, the stability of the hydrazone moiety in the chemical structure of the final compounds was confirmed by using UV/Vis spectroscopy in both aqueous medium and DMSO. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH. Although most of the synthesized compounds are hosted by the InhA binding pocket, SIH1–SIH13 do not primarily show their antitubercular activities by direct InhA inhibition. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1–SIH13 adhered to Lipinski’s rule of five. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Tuberculosis 2021)
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31 pages, 2512 KiB  
Article
Synthesis and Structure–Activity Relationships for the Anti-Mycobacterial Activity of 3-Phenyl-N-(Pyridin-2-ylmethyl)Pyrazolo[1,5-a]Pyrimidin-7-Amines
by Hamish S. Sutherland, Peter J. Choi, Guo-Liang Lu, Anna C. Giddens, Amy S. T. Tong, Scott G. Franzblau, Christopher B. Cooper, Brian D. Palmer and William A. Denny
Pharmaceuticals 2022, 15(9), 1125; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091125 - 08 Sep 2022
Cited by 4 | Viewed by 1551
Abstract
Pyrazolo[1,5-a]pyrimidines have been reported as potent inhibitors of mycobacterial ATP synthase for the treatment of Mycobacterium tuberculosis (M.tb). In this work, we report the design and synthesis of approximately 70 novel 3,5-diphenyl-N-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amines and their comprehensive [...] Read more.
Pyrazolo[1,5-a]pyrimidines have been reported as potent inhibitors of mycobacterial ATP synthase for the treatment of Mycobacterium tuberculosis (M.tb). In this work, we report the design and synthesis of approximately 70 novel 3,5-diphenyl-N-(pyridin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amines and their comprehensive structure–activity relationship studies. The most effective pyrazolo[1,5-a]pyrimidin-7-amine analogues contained a 3-(4-fluoro)phenyl group, together with a variety of 5-alkyl, 5-aryl and 5-heteroaryl substituents. A range of substituted 7-(2-pyridylmethylamine) derivatives were also active. Some of these compounds exhibited potent in vitro M.tb growth inhibition, low hERG liability and good mouse/human liver microsomal stabilities, highlighting their potential as inhibitors of M.tb. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Tuberculosis 2021)
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15 pages, 1719 KiB  
Article
Pyrazole and Triazole Derivatives as Mycobacterium tuberculosis UDP-Galactopyranose Inhibitors
by Dalia M. Ahmed, Jeffrey M. Chen and David A. R. Sanders
Pharmaceuticals 2022, 15(2), 197; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15020197 - 04 Feb 2022
Cited by 4 | Viewed by 2071
Abstract
UDP-galactopyranose mutase (UGM) is an essential enzyme involved in the bacterial cell wall synthesis, and is not present in mammalian cells. Thus, UGM from Mycobacterium tuberculosis (Mtb) represents a novel and attractive drug target for developing antituberculosis agents. A pyrazole-based compound, [...] Read more.
UDP-galactopyranose mutase (UGM) is an essential enzyme involved in the bacterial cell wall synthesis, and is not present in mammalian cells. Thus, UGM from Mycobacterium tuberculosis (Mtb) represents a novel and attractive drug target for developing antituberculosis agents. A pyrazole-based compound, MS208, was previously identified as a mixed inhibitor of MtbUGM which targets an allosteric site. To understand more about the structure activity relationship around the MS208 scaffold as a MtbUGM inhibitor, thirteen pyrazoles and triazole analogues were synthesized and tested against both MtbUGM and Mycobacterium tuberculosis in vitro. While the introduced structural modifications to MS208 did not improve the antituberculosis activity, most of the compounds showed MtbUGM inhibitory activity. Interestingly, the pyrazole derivative DA10 showed a competitive model for MtbUGM inhibition with improved Ki value of 51 ± 4 µM. However, the same compound did not inhibit the growth of Mycobacterium tuberculosis. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Tuberculosis 2021)
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