Activity of (-)-Camphene Derivatives Against Mycobacterium tuberculosis in Acidic pH

Author(s): Hayalla Corrêa de Carvalho, Andressa Lorena Ieque, Tamires Leite Valverde, Vanessa Pietrowski Baldin, Jean Eduardo Meneguello, Paula Aline Zanetti Campanerut-Sá, Fábio Vandresen, Luciana Dias Ghiraldi Lopes, Mariana Regina Passos Souza, Nathally Claudiane de Souza Santos, Vera Lucia Dias Siqueira, Katiany Rizzieri Caleffi-Ferracioli, Regiane Bertin Lima Scodro, Rosilene Fressatti Cardoso*

Journal Name: Medicinal Chemistry

Volume 17 , Issue 5 , 2021

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Graphical Abstract:


Background: For more than 60 years, the lack of new anti-tuberculosis drugs and the increase of resistant Mycobacterium tuberculosis lineages exhibit a therapeutic challenge, demanding new options for the treatment of resistant tuberculosis.

Objective: Herein, we determined the (i) activities of (-)-camphene and its derivatives and (ii) combinatory effect with pyrazinamide (PZA) against Mycobacterium tuberculosis in acidic pH and (iii) cytotoxicity on VERO cells.

Methods: The activity of (-)-camphene and its 15 derivatives was determined in M. tuberculosis H37Rv in culture medium at pH 6.0 by Resazurin Microtiter Assay Plate (REMA). The activity and combinatory study of three (-)-camphene derivatives with PZA was carried out on seven multidrugresistant (MDR) clinical isolates by REMA and Checkerboard, respectively. The assay of 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide in VERO cells was used to determine the derivatives’ cytotoxicity.

Results: Four (-)-camphene derivatives, (4), (5a) (5d) and (5h), showed a reduction in the MIC value at pH 6.0 compared to the MIC detected at pH 6.8 in M. tuberculosis H37Rv and multidrug resistant clinical isolates. Three (-)-camphene derivatives, (4), (5d) and (5h), showed synergistic effect (FICI ≤ 0.5) combined with PZA and were more selective for M. tuberculosis than VERO cell (selective index from 7.7 to 84.2).

Conclusion: Three (-)-camphene derivatives have shown to be promising anti-TB molecule scaffolds due to their low MIC values in acidic pH against MDR M. tuberculosis clinical isolates, synergism with PZA and low cytotoxicity.

Keywords: Tuberculosis, (-)-camphene derivative, acidic pH, synergism, REMA, pyrazinamide.

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Article Details

Year: 2021
Published on: 24 May, 2021
Page: [485 - 492]
Pages: 8
DOI: 10.2174/1573406415666191106124016
Price: $65

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