Research paper Synthesis and anti-leishmanial evaluation of 1-phenyl-2,3,4,9- tetrahydro-1H-b-carboline derivatives against Leishmania infantum Penta Ashok a , Subhash Chander a , Ana Tejería b , Laura García-Calvo b , Rafael Bala ~ na-Fouce b , Sankaranarayanan Murugesan a, * a Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, India b Departmento de Ciencias Biomedicas, Facultad de Veterinaria, Universidad de Leon, Leon 24071, Spain article info Article history: Received 14 April 2016 Received in revised form 8 August 2016 Accepted 9 August 2016 Available online 10 August 2016 Keywords: Leishmaniasis Neglected disease Tetrahydro-b-carboline Promastigote Amastigote abstract In the present study, antileishmanial activity of sixteen novel series of tetrahydro-b-carboline derivatives against transgenic infrared fluorescent Leishmania infantum strain has been reported. Among these re- ported analogues, most of the compounds exhibited potent inhibition against both promastigote (IC 50 from 1.99 ± 1.40 to 20.69 ± 0.95 mM) and amastigote (IC 50 from 0.67 ± 0.05 to 4.16 ± 0.008 mM) forms of L. infantum. Moreover, compound 7l, displayed most potent and selective inhibition of parasite amasti- gote form with IC 50 0.67 ± 0.05 mM, selectivity index >298.5 and was comparable with standard drug amphotericin B. From this study, a new class of tetrahydro-b-carboline derivatives with potent anti- leishmanial activity was identified and it needs further extensive study to optimize the lead molecules to win the battle against severe and neglected disease leishmaniasis. © 2016 Elsevier Masson SAS. All rights reserved. 1. Introduction Leishmaniasis is one of the major neglected diseases and is prevalent in 98 countries throughout the world. According to WHO reports, 310 millions are living at risk places, 1.3 million new in- fections and 30,000 deaths take place annually [1]. Leishmaniasis has been classified as three different clinical forms (i. e) Cutaneous Leishmaniasis (CL), Mucocutaneous Leishmaniasis (MCL) and Visceral Leishmaniasis (VL) depending on parasite species [2]. Visceral Leishmaniasis (also known as kala azar) is the most severe form of leishmaniasis, caused by L. donovani in Bangladesh, Ethiopia, India, Nepal, South Sudan and Sudan. L. infantum is the etiological agent of VL in countries at both shores of the Mediter- ranean Basin, whereas L. chagasi is the predominant species in South America [3]. VL often affects internal organs such as liver, spleen, bone marrow and is usually fatal if left untreated [4]. Even though, leishmaniasis control mainly depends on chemotherapy, the first-line therapy for leishmaniasis is limited with decade old drugs. Pentavalent antimonials (sodium stibogluconate and meglumine antimoniate) have been used as first line drugs for the last five decades; unfortunately, 60% of VL cases in India (Bihar) become un-responsive to antimonials due to developed resistance. In spite of its adverse effects and cost, polyene antifungal drug amphotericin B is the drug of choice where resistance to antimo- nials is developed [5]. Usefulness of second line drugs such as pentamidine and paromomycin has been restricted [6,7]. Miltefo- sine originally developed as anticancer agent, is the only oral drug used for the treatment of VL and usage is limited with toxic effects like nephrotoxicity, hepatotoxicity and teratogenicity. Moreover, recently low sensitivity to miltefosine is observed in countries like India where it has been used extensively [8]. In addition, enhanced prevalence in immuno compromised patient and lack of effective, safe and availability of antileishmanial drugs increases the need to develop novel antileishmanial agents with good selectivity index (SI). Nature remains as potential source to produce antiinfective agents and large number of natural products especially alkaloids displayed potent antileishmanial activity. Among the various group of natural alkaloids, b-carbolines stay as one of the important alkaloidal group as it present in large number of natural products isolated from different sources like territorial plants [9], marine sponge [10], fast food [11] and humans [12]. b-Carboline skeleton has privileged position in medicinal chemistry with various bio- logical activities such as anticancer [13], antithrombotic [14], * Corresponding author. E-mail address: murugesan@pilani.bits-pilani.ac.in (S. Murugesan). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2016.08.014 0223-5234/© 2016 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 123 (2016) 814e821