Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine

Abstract Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). The present work reports the design and synthesis of a hybrid of the precursors of rifampicin and clofazimine, which led to the discovery of a novel Rifaphenazine (RPZ) molecule with potent a...

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Autores principales:	Pasupathy Saravanan, V. N. Azger Dusthackeer, R. S. Rajmani, B. Mahizhaveni, Christy R. Nirmal, Sam Ebenezer Rajadas, Neerupma Bhardwaj, C. Ponnuraja, Adhin Bhaskar, A. K. Hemanthkumar, Geetha Ramachandran, Srikanth P. Tripathy
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/56b9adfff36d4fa4b354549045157315
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spelling	oai:doaj.org-article:56b9adfff36d4fa4b3545490451573152021-12-02T14:01:38ZDiscovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine10.1038/s41598-020-80439-22045-2322https://doaj.org/article/56b9adfff36d4fa4b3545490451573152021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80439-2https://doaj.org/toc/2045-2322Abstract Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). The present work reports the design and synthesis of a hybrid of the precursors of rifampicin and clofazimine, which led to the discovery of a novel Rifaphenazine (RPZ) molecule with potent anti-TB activity. In addition, the efficacy of RPZ was evaluated in-vitro using the reference strain Mtb H37Rv. Herein, 2,3 diamino phenazine, a precursor of an anti-TB drug clofazimine, was tethered to the rifampicin core. This 2,3 diamino phenazine did not have an inherent anti-TB activity even at a concentration of up to 2 µg/mL, while rifampicin did not exhibit any activity against Mtb at a concentration of 0.1 µg/mL. However, the synthesized novel Rifaphenzine (RPZ) inhibited 78% of the Mtb colonies at a drug concentration of 0.1 µg/mL, while 93% of the bacterial colonies were killed at 0.5 µg/mL of the drug. Furthermore, the Minimum Inhibitory Concentration (MIC) value for RPZ was 1 µg/mL. Time-kill studies revealed that all bacterial colonies were killed within a period of 24 h. The synthesized novel molecule was characterized using high-resolution mass spectroscopy and NMR spectroscopy. Cytotoxicity studies (IC50) were performed on human monocytic cell line THP-1, and the determined IC50 value was 96 µg/mL, which is non-cytotoxic.Pasupathy SaravananV. N. Azger DusthackeerR. S. RajmaniB. MahizhaveniChristy R. NirmalSam Ebenezer RajadasNeerupma BhardwajC. PonnurajaAdhin BhaskarA. K. HemanthkumarGeetha RamachandranSrikanth P. TripathyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pasupathy Saravanan V. N. Azger Dusthackeer R. S. Rajmani B. Mahizhaveni Christy R. Nirmal Sam Ebenezer Rajadas Neerupma Bhardwaj C. Ponnuraja Adhin Bhaskar A. K. Hemanthkumar Geetha Ramachandran Srikanth P. Tripathy Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
description	Abstract Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). The present work reports the design and synthesis of a hybrid of the precursors of rifampicin and clofazimine, which led to the discovery of a novel Rifaphenazine (RPZ) molecule with potent anti-TB activity. In addition, the efficacy of RPZ was evaluated in-vitro using the reference strain Mtb H37Rv. Herein, 2,3 diamino phenazine, a precursor of an anti-TB drug clofazimine, was tethered to the rifampicin core. This 2,3 diamino phenazine did not have an inherent anti-TB activity even at a concentration of up to 2 µg/mL, while rifampicin did not exhibit any activity against Mtb at a concentration of 0.1 µg/mL. However, the synthesized novel Rifaphenzine (RPZ) inhibited 78% of the Mtb colonies at a drug concentration of 0.1 µg/mL, while 93% of the bacterial colonies were killed at 0.5 µg/mL of the drug. Furthermore, the Minimum Inhibitory Concentration (MIC) value for RPZ was 1 µg/mL. Time-kill studies revealed that all bacterial colonies were killed within a period of 24 h. The synthesized novel molecule was characterized using high-resolution mass spectroscopy and NMR spectroscopy. Cytotoxicity studies (IC50) were performed on human monocytic cell line THP-1, and the determined IC50 value was 96 µg/mL, which is non-cytotoxic.
format	article
author	Pasupathy Saravanan V. N. Azger Dusthackeer R. S. Rajmani B. Mahizhaveni Christy R. Nirmal Sam Ebenezer Rajadas Neerupma Bhardwaj C. Ponnuraja Adhin Bhaskar A. K. Hemanthkumar Geetha Ramachandran Srikanth P. Tripathy
author_facet	Pasupathy Saravanan V. N. Azger Dusthackeer R. S. Rajmani B. Mahizhaveni Christy R. Nirmal Sam Ebenezer Rajadas Neerupma Bhardwaj C. Ponnuraja Adhin Bhaskar A. K. Hemanthkumar Geetha Ramachandran Srikanth P. Tripathy
author_sort	Pasupathy Saravanan
title	Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
title_short	Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
title_full	Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
title_fullStr	Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
title_full_unstemmed	Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
title_sort	discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/56b9adfff36d4fa4b354549045157315
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Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine

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