Synthesis and preclinical pharmacokinetic study of DHA-10, a novel potential antifungal pogostone analogue

Objectives: The emergence of fungal disease calls for the urgency of development of novel drug. In this study, we developed a novel pogostone analogue, DHA-10 and investigated its preclinical pharmacokinetics, tissue distribution, excretion and protein binding rate in rats. Methods: DHA-10 was synthesized with dehydroacetic acid (DHA) as the starting material and the structure confirmed by NMR and HRMS. The LC-MS/MS was applied to quantitative analysis of DHA-10 concentrations in the biological samples. Key finding: DHA-10 was eliminated rapidly in rat plasma with half-lives of 3.39 ± 0.5, 3.24 ± 0.32 and 3.80 ± 0.40 h after single oral doses of 70, 140 and 280 mg/kg, respectively, and showed linear pharmacokinetic within the examined dosage range. The oral bioavailability of DHA-10 was 69.09 ± 3.9%. DHA-10 distributed widely in tissues with highest tissue concentration was found in small intestine at 2.5 h postdose, followed by the stomach, liver and uterus. Approximately, 1.50 ± 0.26% and 9.12 ± 2.53% of parent drug was excreted via the urine and faeces within 48 h, respectively; 1.45 ± 0.12% was excreted into the bile up to 36 h after a single oral administration of 140 mg/kg. Binding rate of DHA-10 with plasma protein was about 78.80 ± 1.75% in a concentration-independent manner. Conclusions: DHA-10 was successfully synthesized and characterized. The preclinical pharmacokinetics study in rats supported the further development of this new antifungal candidate compound.