In VitroandIn VivoEfficacy of Novel Flavonoid Dimers against Cutaneous Leishmaniasis

Abstract

ABSTRACTTreatment of leishmaniasis by chemotherapy remains a challenge because of limited efficacy, toxic side effects, and drug resistance. We previously reported that synthetic flavonoid dimers have potent antipromastigote and antiamastigote activity againstLeishmania donovani, the causative agent of visceral leishmaniasis. Here, we further investigate their leishmanicidal activities against cutaneousLeishmaniaspecies. One of the flavonoid dimers (compound 39) has marked antipromastigote (50% inhibitory concentrations [IC50s], 0.19 to 0.69 μM) and antiamastigote (IC50s, 0.17 to 2.2 μM) activities toward different species ofLeishmaniathat cause cutaneous leishmaniasis, includingLeishmania amazonensis,Leishmania braziliensis,Leishmania tropica, andLeishmania major. Compound 39 is not toxic to peritoneal elicited macrophages, with IC50values higher than 88 μM. In the mouse model of cutaneous leishmaniasis induced by subcutaneous inoculation ofL. amazonensisin mouse footpads, intralesional administration of 2.5 mg/kg of body weight of compound 39.HCl can reduce footpad thickness by 36%, compared with that of controls values. The amastigote load in the lesions was reduced 20-fold. The present study suggests that flavonoid dimer 39 represents a new class of safe and effective leishmanicidal agent against visceral and cutaneous leishmaniasis.