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Synthesis, antimycobacterial evaluation, and QSAR analysis of meso-dihydroguaiaretic acid derivatives

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Abstract

The increasing incidence of new tuberculosis cases and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis have drawn the attention of researchers to the chemical derivatization of promising antimycobacterial natural products. Meso-dihydroguaiaretic acid (meso-DGA) has reported to possess modest activity against sensitive (H37Rv) and resistant M. tuberculosis strains. To improve the antimycobacterial properties of meso-DGA, a series of 19 meso-DGA derivatives bearing carbamates and ethers were synthesized and tested against H37Rv and two MDR strains. Among the carbamates, 2, 3, 5, and 6 exhibited the lowest minimal inhibitory concentration (MIC) values against one MDR strain (MICs of 25 and 12.5 µg/mL), with 6 being the most lipophilic and potent. On the other hand, ethers 10, 12, 14, and 18 showed MIC values in the range of 6.25–50 µg/mL against the three strains, with 14 being the most potent. The larger the chain length in the mono-alkenylated ethers (10, 12, and 14), the lower the MIC value; moreover, a correlation between the chain length of these ethers and the lipophilic character and antimycobacterial activity was observed. The safety profile of the most bioactive derivatives 6 and 14 indicated that 6 (SI > 10) was more toxic to sensitive and MDR strains than to Vero cells, whereas 14 (SI < 3) was more toxic to mammalian cells than to M. tuberculosis strains. Nevertheless, the safety profile of 6 and the potent antimycobacterial activity of 14 make them potential candidates for further studies.

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Acknowledgements

Financial support is gratefully acknowledged to CONACYT-México through project number 237248. We also give thanks to Foundation IMSS for the grant received by Rosa Esther Moo-Puc.

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Authors and Affiliations

  1. Universidad Autónoma de Nuevo León, Facultad de Ciencias Químicas, Av. Universidad s/n, Ciudad Universitaria, 66455, San Nicolás de los Garza, Nuevo León, Mexico

    Karen G. Chávez-Villarreal, Abraham García & María del Rayo Camacho-Corona

  2. Universidad Autónoma de Querétaro, Facultad de Química, Centro Universitario, 76010, Querétaro, Querétaro, Mexico

    Antonio Romo-Mancillas

  3. Universidad Autónoma de Nuevo León, Servicio de Gastroenterología y Departamento de Patología Clínica, Hospital Universitario Dr. José Eleuterio González, Madero y Aguirre Pequeño, Mitras Centro, 64460, Monterrey, Nuevo León, Mexico

    Elvira Garza-González

  4. Universidad Autónoma de Nuevo León, Facultad de Medicina, Madero y Aguirre Pequeño, Mitras Centro, 64460, Monterrey, Nuevo León, Mexico

    Noemí Waksman de Torres

  5. Universidad Nacional Autónoma de México, Instituto de Química, Circuito Exterior s/n, Ciudad universitaria, Coyoacán, 04510, Ciudad de México, Mexico

    Luis D. Miranda

  6. Unidad de Investigación Médica Yucatán, Unidad Médica de Alta Especialidad, Centro Médico Ignacio García Téllez, Instituto Mexicano del Seguro Social (IMSS), Calle 41 No. 439, Col. Industrial, 97150, Mérida, Yucatán, Mexico

    Rosa Esther Moo-Puc

  7. Laboratorio de Vigilancia e Investigación Epidemiológica, Unidad Médica de Alta Especialidad, Centro Médico Ignacio García Téllez, IMSS, 97150, Mérida, Yucatán, Mexico

    Juan Chale-Dzul

Authors
  1. Karen G. Chávez-Villarreal
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  2. Abraham García
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  3. Antonio Romo-Mancillas
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  4. Elvira Garza-González
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  5. Noemí Waksman de Torres
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  6. Luis D. Miranda
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  7. Rosa Esther Moo-Puc
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  8. Juan Chale-Dzul
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  9. María del Rayo Camacho-Corona
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Corresponding authors

Correspondence to Abraham García or María del Rayo Camacho-Corona.

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Chávez-Villarreal, K.G., García, A., Romo-Mancillas, A. et al. Synthesis, antimycobacterial evaluation, and QSAR analysis of meso-dihydroguaiaretic acid derivatives. Med Chem Res 27, 1026–1042 (2018). https://doi.org/10.1007/s00044-017-2125-1

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