The emergence of resistance against to the first line anti-TB drugs, such as pyrazinamide, has led to the need for new approaches. One interesting approach is the use of prodrugs that often have showed improved biological activities over drugs with poor absorption or difficulty to cross membranes.

Previous studies demonstrate that weak acids like benzoic acid, present antimycobacterial activity, which increases at acidic pH. 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 esters of benzoic acid by conversion to the corresponding acid.

Since Zhang postulated that the activity of the acids could be dependent on their pKa, we set up to synthesize a library of benzoates with different electron withdrawing groups (4-chloro, 2,6-dichloro, 4-nitro, 3,5 dinitro), to modulate pka and different alkoxy substituents (propyl, hexyl and phenyl) to modulate their lipophilicity. We tested the activity of the esters and the free acids against mycobacteria and the activation of the esters by mycobacterial enzymes. Since the benzoates must survive the transport phase, we also studied the stability of the compounds in buffer and in plasma.

We concluded that all the benzoates could be activated by mycobacterial enzymes and the esters presented higher activity than the corresponding free acids, with the nitrobenzoates, and specially the dinitrobenzoates, showing very interesting antitubercular activity that deserve further exploration. These results do not show a correlation between the activity and the pKa of the acids.