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Title: Tricyclic endoperoxide dimers as promising leads for development of new drugs for drug-resistant Leishmaniasis*  

Abstract: Visceral leishmaniasis (VL) caused by protozoan parasite Leishmania donovani, is a major global health challenge. This neglected disease is fatal if left untreated. Current choices of therapies available for VL are limited to few toxic drugs. Most of the available drugs are getting ineffective due to low efficacy and emerging drug-resistance. A set of novel tricyclic endoperoxide (artemisinin) dimers were identified with outstanding antileishmanial activities against both promastigote and intracellular amastigotes of L. donovani. The parent drug artemisinin showed only moderate activity against leishmania cells.   The antileishmanial potencies of some of these dimers are several  folds higher as compared to clinically used antileishmanial drugs. These dimers did not show  any noticeable cytotoxicity against differentiated THP1 cells (a human acute monocytic leukemia cell line) and  Vero cells. The dimer analogs were also active against amphotericin-B resistant L. donovani as well as L. major and L. tropica. Based on their selectivity index (SI), calculated by the ratio of toxicity versus antileishmanial activity, the two most active artemisinin dimers namely, dimer-morpholine (IC50 7 nM, SI >2052), and dimer- GABA (IC50 13 nM, SI >1086) were selected as promising leads for extended evaluation. Further, the mode of their leishmanicidal action was evaluated by flow cytometric annexin V binding-propodium iodide staining assay.  Treatment with dimer-morpholine and dimer-GABA resulted into a time-dependent induction of apoptosis in L. donovani promastigotes. While, the parent drug artemisinin, showed only moderate antileishmanial activity and did not produce any apoptotic effect on L. donovani cells up to 50 µM concentration. The antileishmanial activity of the selected set of dimers was reconfirmed against intracellular L. donovani amastigotes with SYBR green fluorescent-image analysis assay and also against transgenic luciferase expressing L. donovani cells. In vivo pharmacokinetic studies in mice with a dimer oxime analog showed significant oral bioavailability (~20%) and metabolic stability. These dimer analogs represent a novel class of antileishmanial drug leads for further preclinical development. *(Supported by National Institute of Allergy and Infectious Diseases, National Institute of Health USA-1R21AI146729-01A1).

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