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      Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds †

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          Abstract

          Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.

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          The influence of drug-like concepts on decision-making in medicinal chemistry.

          Paul Leeson, Brian Springthorpe (2007)
          The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.
          Article 0 comments Cited 365 times – based on 0 reviews     Review now
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            Advances in the development of new tuberculosis drugs and treatment regimens.

            Alimuddin Zumla, Payam Nahid, Stewart Cole (2013)
            Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.
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              Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis.

              Sheshagiri Gaonkar, Vadim Makarov, V. Balasubramanian … (2009)
              New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.
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                Author and article information

                Contributors
                Jean Jacques Vanden Eynde: Role: Academic Editor
                Journal
                Journal ID (nlm-ta): Pharmaceuticals (Basel)
                Journal ID (iso-abbrev): Pharmaceuticals (Basel)
                Journal ID (publisher-id): pharmaceuticals
                Title: Pharmaceuticals
                Publisher: MDPI
                ISSN (Electronic): 1424-8247
                Publication date (Electronic): 01 June 2017
                Publication date Collection: June 2017
                Volume: 10
                Issue: 2
                Electronic Location Identifier: 51
                Affiliations
                [1 ]Institute of Chemistry, São Paulo State University (UNESP), Araraquara 14800060, Brazil; guilhermefelipe@ 123456outlook.com
                [2 ]School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara 14800903, Brazil; chungmanchin@ 123456gmail.com
                Author notes
                [* ]Correspondence: santosjl@ 123456fcfar.unesp.br ; Tel.: +55-16-3301-6972
                [†]

                The best presentation at the 2nd International Electronic Conference on Medicinal Chemistry.

                Article
                Publisher ID: pharmaceuticals-10-00051
                DOI: 10.3390/ph10020051
                PMC ID: 5490408
                PubMed ID: 28587160
                SO-VID: 716bbba6-e83f-40f1-aed8-f57beb252e1c
                Copyright © © 2017 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 04 April 2017
                Date accepted : 29 May 2017
                Categories
                Subject: Review

                Keywords: tuberculosis,drug discovery,antitubercular compounds,multidrug-resistant tuberculosis
                Data availability:
                Keywords: tuberculosis, drug discovery, antitubercular compounds, multidrug-resistant tuberculosis

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