Development of fluorinated rhodacyanine analogues for anti-leishmaniasis

Abstract

Recently, fluorinated rhodacyanine has been disclosed as a highly effective agent against Leishmania donovani; it was shown that replacement of hydrogen with a fluorine atom on a benzothiazole unit significantly enhanced the anti-leishmanial activity. However, the role of the fluorine substituent in this analogue has not yet been clarified and mechanism of actions remains unclear. In this research, fifteen novel and three known fluorine-containing rhodacyanine analogues (10c, and 11a-11q) were synthesized and tested the anti-leishmanial activity against promastigote and axenic amastigote stages of L. martiniquensis and L. orientalis, the indigenous Leishmania species of Thailand. The SAR knowledge of this series reveals that the introduction of fluorine atom(s) at different positions on the benzothiazole units, including C-5, 6, 5’, or 6’, led to enhance the activities, which correlates with the less negative reduction potentials of the fluorinated analogues confirmed by the electrochemical study. In contrast, the introduction of -CF3 and -OCF3 led to a dramatic decrease in the bioactivity due to the poor solubility confirmed by the predicted ADMET properties. Although these analogues seem to be rapidly metabolized in human liver microsomes, other predicted properties indicate that this series could be potential for an administrated orally anti-leishmanial drug. Moreover, these analogues may be suitable for treating cerebral leishmaniasis or other nervous system diseases. This information could become valuable for the drug discovery for the development of cyanine-base anti-leishmanial drug in the future.