To make advances in the treatment of cryptococcal meningitis, it is crucial to know a given drug's free fraction that reaches the biophase. In the present study, we applied microdialysis (D) as a tool to determine the free levels reached by voriconazole (VRC) in the brains of healthy and Cryptococcus neoformans-infected rats. The infection was induced by the intravenous (i.v.) administration of 1 ϫ 10 5 CFU of yeast. The dose administered was 5 mg/kg (of body weight) of VRC, given i.v. Plasma and microdialysate samples were analyzed by liquid chromatographytandem mass spectrometry (LC-MS/MS) and LC-UV methods. The free brain/free plasma ratio (fT) and population pharmacokinetic (popPK) analyses were performed to evaluate the impact of infection on PK parameters of the drug. The brain penetration ratio showed an increase on brain exposure in infected animals (fT healthy ϭ 0.85 versus fT infected ϭ 1.86). The structural PK model with two compartments and Michaelis-Menten (MM) elimination describes the VRC concentration-time profile in plasma and tissue simultaneously. The covariate infection was included in volume of distribution in the peripheral compartment in healthy animals (V 2 ) and maximum rate of metabolism (V M ). The levels reached in infected tissues were higher than the values described for MIC of VRC for Cryptococccus neoformans (0.03 to 0.5 g ml Ϫ1 ), indicating its great potential to treat meningitis associated with C. neoformans.

Using cycloalkyl and electron-donating groups to decrease the carbonyl electrophilicity, a novel series of 2-(quinoline-4-yloxy)­acetamides was synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Structure–activity relationship studies led to selective and potent antitubercular agents with minimum inhibitory concentrations in the submicromolar range against drug-sensitive and drug-resistant Mtb strains. An evaluation of the activity of the lead compounds against a spontaneous qcrB mutant strain indicated that the structures targeted the cytochrome bc 1 complex. In addition, selected molecules inhibited Mtb growth in a macrophage model of tuberculosis infection. Furthermore, the leading compound was chemically stable depending on the context and showed good kinetic solubility, high permeability, and a low rate of in vitro metabolism. Finally, the pharmacokinetic profile of the compound was assessed after oral administration to mice. To the best of our knowledge, for the first time, a 2-(quinoline-4-yloxy)­acetamide was obtained with a sufficient exposure, which may enable in vivo effectiveness and its further development as an antituberculosis drug candidate.

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FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 μg/mL.