Synthesis and evaluation of a pyrazinoic acid prodrug in Mycobacterium tuberculosis.

Tuberculosis (TB) is a disease caused mainly by infection of Mycobacterium tuberculosis affecting more than ten million people around the world. Despite TB can be treated, the rise of MDR-TB and XDR-TB cases put the disease in a worrying status. As pyrazinamide-resistant strains exhibit low or none pyrazinamidase activity, it is proposed that the active form of pyrazinamide (PZA) is pyrazinoic acid (POA), although this acid has poor penetration in mycobacteria. In this work, we present a convenient one-pot synthesis of 2-chloroethyl pyrazinoate, and its activity in M. tuberculosis H37Rv (ATCC27294) in MIC assay using the MABA technique. The obtained MIC of the compound was 3.96 g/mL, and discussion about the activity profile of some previously evaluated pyrazinoates is also performed.

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

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.

Planejamento e síntese de aminoacilderivados de sulfonamidas e trimetoprima potencialmente antimaláricos / Design and synthesis of aminoacylderivatives potentially antimalarial of sulfonamides and trimethoprim

Ligaram-se aminoácidos à trimetoprima, ao sulfametoxazol e ao sulfatiazol, esperando-se com isso que maior quantidade do fármaco atinja seu local de ação, o interior do eritrócito, e exerça a ação antimalárica desejada. Os derivados foram preparados de duas maneiras: a primeira mediante reação da trimetoprima e sulfonamidas com os aminoácidos na forma de ésteres e a segunda com os aminoácidos protegidos em seu grupamento amínico. A análise espectrométrica, análise cromatográfica e ponto de fusão dos produtos permitiram concluir que os produtos desejados foram obtidos