Conocarpan and Eupomatenoid-6 as Natural Prototypes for Antituberculosis Compounds.

BACKGROUND AND AIM: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and is the leading cause of death from a single bacterium. In addition, the increasing incidence of multidrug-resistant tuberculosis (MDR-TB) has led to the research of new compounds that are effective against Mtb. Therefore, in this study we evaluated the in vitro cytotoxicity and activity of two neolignans-conocarpan (1) and eupomatenoid-6 (2)-isolated from Piper solmsianum, against drug-susceptible and multidrug-resistant (MDR-TB) Mtb isolates, as well as other bacteria.

EXPERIMENTAL PROCEDURE: Compounds were obtained through high-performance liquid chromatography. The in vitro activities were determined by the resazurin microtiter assay, and their combinatory effect with anti-TB and antiretroviral were determined by the resazurin drug combination microtiter assay against Mtb H37Rv and 14 clinical isolates (including 10 MDR-TB). The cytotoxicity was evaluated in J774.A1, HeLa, VERO, and MRC-5 cells by MTT assay. The analysis of the absorption, distribution, metabolism, and excretion of neolignans was performed on Swiss ADME.

KEY

RESULTS

Compounds (1) and (2) showed activity against Mtb H37Rv, 14 Mtb clinical isolates, Mycobacterium abscessus, and Staphylococcus aureus, with the minimum inhibitory concentrations ranging from 3.90 to 125 μg/mL. Only (1) exhibited synergism with rifampicin, and none of them presented an antagonistic effect. Both substances were more selective against bacteria, and (2) was the least cytotoxic. The (1) and (2) have high gastrointestinal permeability and do not violate the Lipinski rules.

CONCLUSIONS AND IMPLICATIONS: The synergistic interaction between conocarpan and rifampicin, coupled with the lack of antagonism with antiretroviral drugs, suggests that these neolignans are promising candidates for further development in the treatment of drug-resistant TB and TB/HIV coinfection.