Targeting the human parasite Leishmania donovani: Discovery of a new promising anti-infectious pharmacophore in 3-nitroimidazo[1,2-a]pyridine series Caroline Castera-Ducros a , Lucie Paloque b , Pierre Verhaeghe a , Magali Casanova b , Christophe Cantelli a , Sébastien Hutter b , Floriane Tanguy a , Michèle Laget b , Vincent Remusat a , Anita Cohen b , Maxime D. Crozet a , Pascal Rathelot a , Nadine Azas b,⇑ , Patrice Vanelle a,⇑ a Equipe Pharmacochimie Radicalaire, Faculté de Pharmacie, Aix-Marseille Université – UMR CNRS 7273, Institut de Chimie Radicalaire, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille Cedex 05, France b Infections Parasitaires, Transmission, Physiopathologie et Thérapeutique, UMR MD3, Faculté de Pharmacie, Aix-Marseille Université, 27 Boulevard Jean Moulin-CS30064, 13385 Marseille Cedex 05, France article info Article history: Received 13 April 2013 Revised 29 August 2013 Accepted 1 September 2013 Available online 11 September 2013 Keywords: Leishmania donovani Imidazo[1,2-a]pyridine Structure–activity relationships HepG2 in vitro cytotoxicity abstract We report herein the discovery of antileishmanial molecules based on the imidazo[1,2-a]pyridine ring. In vitro screenings of imidazopyridines belonging to our chemical library, toward the promastigotes stage of Leishmania donovani, J774A.1 murine and HepG2 human cells, permitted to identify three selective hit- compounds (12, 20 and 28). New derivatives were then synthesized to allow structure–activity and –tox- icity relationships analyses, enabling to characterize a lead-compound (44) displaying both a high potency (IC 50 = 1.8 lM) and a good selectivity index, in comparison with three antileishmanial reference drug-compounds (amphotericin B, miltefosine and pentamidine). Moreover, lead-compound 44 also exhibits good in vitro activity against the intracellular amastigote stage of L. donovani. Thus, the 6-halo-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridine scaffold appears as a new promising selective antileishmanial pharmacophore, especially when substituted at position 8 by a bromine atom. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Leishmaniasis is a parasitic infection second to malaria in terms of parasite-related mortality. Leishmaniasis pathologies include cutaneous leishmaniasis (CL), muco-cutaneous leishmaniasis (MCL) and visceral leishmaniasis (VL), depending on Leishmania species. Visceral leishmaniasis is the most severe clinical form of the disease, lethal in untreated patients. There are an estimated 14 million people infected by leishmaniasis in 98 countries world- wide, mainly in tropical and sub-tropical regions, but also in south- ern Europe, especially around the Mediterranean area. The annual incidence of leishmaniasis is two million with about 50,000 estimated deaths due to its visceral form. The number of cases is certainly under-evaluated as leishmaniasis are reportable diseases in only 40 countries. 1 These parasitic infections are caused by a protozoan of the Leishmania genus transmitted to its mammal hosts (humans, dogs, monkeys, rodents...) by the bite of an infected sandfly (Phlebotominae). Leishmania parasites exist in two major morphological stages: extracellular flagellated prom- astigotes in the digestive tract of their sandfly vector and nonmo- tile intracellular amastigotes in cells of their host mononuclear phagocytic system. 2,3 There are very few drugs available for treating leishmaniasis: pentavalent antimonials (sodium stibogluconate and meglumine antimoniate), liposomal amphotericin B, pentamidine, paromomy- cin and miltefosine. 4,5 Some other drugs are in clinical trials: sitamaquine, imiquimod and antifungal azoles. 6,7 Currently, the drugs used in the treatment of leishmaniasis present major limita- tions such as nonoral routes of administration (apart for miltefo- sine), high toxicity of antimonials and pentamidine, and teratogenicity for miltefosine. 8 Moreover, the expensive cost of liposomal amphotericin B, and the socio-economic problems encountered in endemic areas, lead to patients withdrawing from treatment and global emergence of resistant strains. 9 During the last decade, antimonial resistance reached epidemic dimension in Bihar, India, where about 60% of newly diagnosed visceral leish- maniasis do not respond to these molecules. 10 Evaluation of the in vitro susceptibility of Indian Leishmania donovani patient isolates to antimonials, amphotericin B and miltefosine indicates that cross-resistance may be emerging among these three drugs. Despite the absence of reported cases of clinical resistance to 0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2013.09.002 ⇑ Corresponding authors. Tel.: +33 491 835 564 (N.A.); tel.: +33 491 835 580; fax: +33 491 794 677 (P.V.). E-mail addresses: nadine.azas@univ-amu.fr (N. Azas), patrice.vanelle@ univ-amu.fr (P. Vanelle). Bioorganic & Medicinal Chemistry 21 (2013) 7155–7164 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc