Structure modifications of 2-phenylquinoline by Aspergillus genera produce novel derivatives with potent leishmanicidal and anti-inflammatory properties

Abstract

Quinolines are heterocyclic molecules with a wide range of pharmacological purposes. The quinolinic system has been used for the synthesis of derivatives, producing molecules with significant improvement of the original activities. In this work, the alkaloid 2-phenylquinoline, the main substance of the Bolivian tree Galipea longiflora, traditionally employed for treating leishmaniasis, served as a substrate for biotransformation to obtain compounds for leishmaniasis applications. Using Aspergillus fumigatus, the novel and for the first-time reported 5,6-dihydro-5,6-dihydroxy-2-phenylquinoline diol was produced. Its biotransformation by A. flavus resulted in 4′‑hydroxy-2-phenylquinoline. When tested against Leishmania amazonensis, L. infantum, and L. braziliensis promastigotes, both showed time-related leishmanicidal effects significantly higher than those observed for the parental molecule. Transmission electron microscopy revealed that the derivatives affected several cellular structures including the nucleus. When assayed for biological properties within an inflammatory context usually present in leishmaniasis, they were neither toxic for macrophages and fibroblasts nor affected the behavior of immune cells or the expression levels of some adhesion integrins, but significantly altered the chemotaxis of neutrophils, suggesting additional properties in enhancing some important steps necessary for the defense and healing processes that develop just after the sand fly-infected saliva injection that triggers the infection. Our results indicate that monitored biotransformation of 2-phenylquinoline by Aspergillus genera can be a viable route to obtain highly active leishmanicidal substances with additional anti-inflammatory properties not reported before, as particularly observed for the new diol, which may be efficient in controlling leishmaniasis and its parasite burden.