Benzimidazole derivatives endowed with potent antileishmanial activity

Michele Tonelli,Elena Gabriele,Francesca Piazza,Nicoletta Basilico,Silvia Parapini,Bruno Tasso,Roberta Loddo,Fabio Sparatore,Anna Sparatore

doi:10.1080/14756366.2017.1410480

Michele Tonelli, Elena Gabriele + Show 7 more

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https://doi.org/10.1080/14756366.2017.1410480

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Abstract

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC50 values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles.

Highlights

IntroductionLeishmaniasis is the second most prevalent parasite infection worldwide for mortality in humans
After malaria, leishmaniasis is the second most prevalent parasite infection worldwide for mortality in humans1
Compounds were generally characterised by 1H and 13C NMR spectra and elemental analysis or Highresolution mass spectra (HRMS); a few intermediates were characterised by elemental ana- (50 MHz, CDCl3): 154.1, 136.5, 121.1, 113.6, 30.9, 28.6, 28.4, 28.3, lysis and 1H NMR

Summary

Introduction

Leishmaniasis is the second most prevalent parasite infection worldwide for mortality in humans. Leishmaniasis is the second most prevalent parasite infection worldwide for mortality in humans1 It is transmitted by the bite of a sand-fly infected by a flagellate protozoan of the genus Leishmania. Three different forms of the disease are described: visceral, cutaneous and muco-cutaneous leishmaniasis. The disease is endemic in many tropical and subtropical Countries, leading annually to an estimated 700,000–1 million new cases and 20,000–30,000 deaths, mostly due to the visceral form caused by Leishmania donovani. The parasite exists in the ovoid non-flagellate form (amastigote) and in the flagellate promastigote, found in the sand-fly. The therapy of leishmaniasis is still based on pentavalent antimonials (sodium stibogluconate and meglumine antimoniate) as first choice drug2a,2b, whereas amphotericin B, miltefosine, paromomycin and pentamidine are considered second-line drugs3a–c. Some other drugs as edelfosine, sitamaquine, fexinidazole, tamoxifene, imiquimod and pentoxyphylline are reported to give variable cure rates when used either alone or, better, in association with antimonials to overcome resistance (Figure 1)

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