Benzoic Acid Derivatives as Prodrugs for the Treatment of Tuberculosis

Abstract

One interesting approach to fight tuberculosis is the use of prodrugs that often have shown improved biological activities over drugs with poor absorption or difficulty to cross membranes. Previous studies demonstrate that weak acids such as benzoic acid, present antimycobacterial activity. Moreover, esters of those acids revealed to be a viable alternative since they may diffuse more easily through the cell membranes. Previously we showed that mycobacteria can easily activate benzoic acid esters by conversion to the corresponding acid. Since Zhang postulated that the activity of the acids can be dependent on their pKa, we set up to synthesize a library of benzoates with different electron withdrawing groups (4-chloro, 2,6-dichloro, 3,5-dichloro, 4-nitro, and 3,5 dinitro), to modulate pKa of the liberated acid and different alkoxy substituents (propyl, hexyl, and phenyl) to modulate their lipophilicity, and tested the activity of the esters and the corresponding free acids against mycobacteria. We also studied the activation of the esters by mycobacterial enzymes and the stability of the compounds in buffer and plasma. We concluded that all the benzoates in our study can be activated by mycobacterial enzymes and that the phenyl and hexyl esters presented higher activity than the corresponding free acids, with the nitrobenzoates, and especially the dinitrobenzoates, showing very interesting antitubercular activity that deserve further exploration. Our results did not show a correlation between the activity and the pKa of the acids.

Nitrobenzoates and Nitrothiobenzoates with Activity against M. tuberculosis

“…When testing a series of acids and esters with different pKa, we could not find a relationship between pKa and activity; however, we did find that esters of benzoic acid containing 4-nitro or 3,5-dinitro groups in the aromatic ring demonstrate greater activity than esters of derivatives containing other substituents and similar pKa [15].…”

“…However, the most active compounds are not hydrolysed in mycobacterial homogenate and are stable in phosphate-buffered saline solution (PBS), indicating that in the assay conditions they are acting as drugs and not as prodrugs, as previously hypothesized. Moreover, in the past we compared the activity of the free acids and esters of 4-nitrobenzoates and 3,5-dinitrobenzoates, and we found that the activity of the esters was greater than the corresponding free acids [15], which supports the intrinsic activity of the esters.…”

Virtual and In Vitro Screening of Natural Products Identifies Indole and Benzene Derivatives as Inhibitors of SARS-CoV-2 Main Protease (Mpro)

“…Benzoic acid ester derivatives were demonstrated as potent PDE4 inhibitors for the treatment of respiratory diseases [ 67 ]. Benzoic acid esters have also been shown to have anti-microbial activity against several microbes, including mycobacteria, and represent a valuable potential for the treatment of tuberculosis [ 68 ]. Through computational analysis of the bioactive compounds of the herbal infusion “horchata” from Ecuador, Benzoic acid, 2-(ethylthio)-, ethyl ester was shown to have the lowest predicted free energy of binding to the SARS-CoV-2 M pro [ 69 ].…”

Development of New Drugs to Treat Tuberculosis Based on the Dinitrobenzamide Scaffold

“…Previous work in our lab uncovered that 3,5-dinitrobenzoic acid esters, and especially its amide isosteres, exhibited promising activities against M. tuberculosis [16,17]. A closer look at the literature showed that the compounds were structurally related to the nitrobenzamide family.…”