In Vitro and In Vivo Efficacy of Novel Flavonoid Dimers against Cutaneous Leishmaniasis

Iris L K Wong,Zhao-Rong Lun,Tak Hang Chan,Kin-Fai Chan,Larry M C Chow,Yun-Fu Chen

doi:10.1128/aac.02425-13

Abstract

Treatment 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 against Leishmania donovani, the causative agent of visceral leishmaniasis. Here, we further investigate their leishmanicidal activities against cutaneous Leishmania species. 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 of Leishmania that cause cutaneous leishmaniasis, including Leishmania amazonensis, Leishmania braziliensis, Leishmania tropica, and Leishmania major. Compound 39 is not toxic to peritoneal elicited macrophages, with IC50 values higher than 88 μM. In the mouse model of cutaneous leishmaniasis induced by subcutaneous inoculation of L. amazonensis in 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.

Highlights

The present study suggests that flavonoid dimer 39 represents a new class of safe and effective leishmanicidal agent against visceral and cutaneous leishmaniasis
The flavonoid dimers 1 to 3 and 5 to and the aminoethylene glycol-linked flavonoid dimers to 50, 53, 56 to 61, and 68 to 73 were prepared according to the reported procedures, and their chemical structures are shown in Fig. 1 [13,14,15, 19]
We reported the activities of flavonoid dimers toward different species of L. donovani promastigotes and amastigotes, including wild-type LdAG83, sodium stibogluconate (SSG)-resistant Ld39, and pentamidine-resistant LdAG83PentR50 [18]

Summary

Introduction

We previously reported that synthetic flavonoid dimers have potent antipromastigote and antiamastigote activity against Leishmania donovani, the causative agent of visceral leishmaniasis. One of the flavonoid dimers (compound 39) has marked antipromastigote (50% inhibitory concentrations [IC50s], 0.19 to 0.69 ␮M) and antiamastigote (IC50s, 0.17 to 2.2 ␮M) activities toward different species of Leishmania that cause cutaneous leishmaniasis, including Leishmania amazonensis, Leishmania braziliensis, Leishmania tropica, and Leishmania major. Plant-derived natural products such as flavonoids have been reported to have a wide range of biological activities, such as antioxidative and anticancer effects [8, 9] They have been a good source for discovering new antileishmanial agents [10,11,12].

Methods

Results

Conclusion