Antimycobacterial activity of pyrazinoate prodrugs in replicating and non-replicating Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile.

Pyrazinoates as antiparasitic agents against Trypanosoma cruzi

“…Moreover, the cytotoxicity assessment allows the inference that the actions of POA and its derivatives are relatively selective to the parasite. In previous work, we reported that these compounds did not show cytotoxic effects to Vero cells in high concentrations, corroborating with the results here presented. In addition, it can be observed in Figure that compounds 1–4 slightly induced the cellular proliferation (especially on J774 cells), which may be the result of an increased production of proinflammatory cytokines by these compounds.…”

“…The coupling constants are expressed in Hz, when necessary. The experimental spectral data were in accordance to the literature . The compounds were submitted to the biological assay when the purity was >95% assessed by gas chromatography.…”

“…The chemicals and starting material for the preparation of the POA derivatives were purchased from Sigma–Aldrich with adequate purity and used without further purification. POA ( 1 ) and BZN were used from the commercial source directly in the assays, while the derivatives 2–4 were prepared as previously reported by our group . NMR spectra were recorded in a Bruker Advance 300 spectrometer, using the solvent described.…”

“…On the other hand, these PZA‐resistant strains are susceptible to other POA prodrugs which can penetrate the mycobacteria, such as POA esters . Several POA esters have shown good antimycobacterial activity in vitro against PZA‐sensitive and resistant strains of M. tuberculosis …”

Microbial esterases and ester prodrugs: An unlikely marriage for combating antibiotic resistance

“…Tested POA esters included ester moieties with variable alkyl chain lengths and heteroatom substitutions, as well as a pair of “duplicated” prodrugs designed to achieve higher molar ratios of POA inside Mtb after hydrolysis (Figure c). These new compounds further demonstrated that more lipophilic esters achieve better MICs but also showed that growth medium composition affected activity (Fernandes, Pavan, Leite, & Felli, ; Segretti et al, ). Albumin‐containing mediums resulted in observed activity up to 10 times lower, which suggested that albumin bound to the POA esters.…”