Phenotype screening of a bisindole chemical library identifies URB1483 as a new Antileishmanial agent with Topoisomerase IB as possible molecular target

Leishmaniasis is one of the most dangerous neglected tropical diseases, second only to malaria in parasitic causes of death. [1] Caused by global warming, the endemic regions of leishmaniasis are continuously spreading to non-tropical areas, including Europe. So far, no vaccine against leishmaniasis is on the market. [2] Approved drugs are currently limited and/or exorbitantly priced (i.e. amphothericin B; paromomycin; miltefosine; pentamidine) with few of them effective on antimonial-resistant Leishmania strains. Moreover, the use of these agents on infected patients is seriously hampered by the insurgence of acute and/or chronic toxicity. Therefore, there is an urgent need for developing safe, effective, and affordable drugs for the treatment of leishmaniasis. To fill this therapeutic gap, several research groups introduced new classes of active compounds against leishmaniasis, including bisindole derivatives. [3] As part of our ongoing investigations on the biological activities and applications of bisindole derivatives [4] and leishmaniasis [3,5], in this contribution, a phenotypic screening of a small library of azole-bisindoles against several human and canine L. infantum strains was performed. Most of the tested compounds showed good activity against the promastigotes (IC50 values < 10 M). Among these, URB1483, a pyrrole-bisindole derivative (figure 1), showed good activity against intracellular amastigotes, comparable to that of the approved drug pentamidine, and it did not display cytotoxic effects on canine and human cell lines, with a selectivity index > 50. Biochemical studies based on DNA-plasmid relaxation assay point at Leishmania topoisomerase IB as molecular-target for URB1483. Docking studies together with metadynamics simulations support the hypothesis that URB1483 might undertake interactions within the topoisomerase IB similar to that of the topoisomerase poison topotecan [3]. Taken together, these data indicate that URB1483 may represent a promising lead compound for the generation of new Leishmania topoisomerase IB poisons with low toxicity on host cells. [1] A. S. Nagle, V. Molteni, et al., Chem. Rev. 2014, 114, 11305; [2] S. Srivastava, P. Shankar, J. Mishra, S. Singh, Parasites & Vectors 2016, 9, 277; [3] A. Roy, A. Desideri, H. K. Majumder, et al., PLoS ONE 2011, 6 (12), e28493; [4] R. Campana, S. Lucarini, et al., Pharmaceuticals 2020, 13 (9), 210; [5] A. Diotallevi, G. Buffi, L. Galluzzi, et al., Acta Tropica 2020, 201, 105178.