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

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.