Synthesis and in-vitro anti-leishmanial activity of (4-arylpiperazin-1-yl) (1-(thiophen-2-yl)-9H-pyrido[3,4-b]indol-3-yl)methanone derivatives Penta Ashok a , Subhash Chander a , Larry M.C. Chow b , Iris L.K. Wong b , Rajnish Prakash Singh c , Prabhat Nath Jha c , Murugesan Sankaranarayanan a,⇑ a Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science, Pilani 333031, India b Department of Applied Biology and Chemical Technology and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hong Kong c Department of Biological Sciences, Birla Institute of Technology & Science, Pilani 333031, Rajasthan, India article info Article history: Received 19 June 2016 Revised 8 October 2016 Accepted 27 November 2016 Available online xxxx Keywords: Leishmaniasis Promastigote Amastigote b-carboline abstract In the present study, we have reported synthesis and biological evaluation of a series of fifteen 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole derivatives against both promastigotes and amastigotes of Leishmania parasites responsible for visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis. Among these reported analogues, compounds 7b, 7c, 7f, 7g, 7i, 7j, 7m, 7o displayed potent activity (15.55, 7.70, 7.00, 3.80, 14.10, 9.25, 3.10, 4.85 lM, respectively) against L. donovani promastigotes than standard drugs miltefosine (15.70 lM) and pentamidine (32.70 lM) with good selectivity index. In further, in-vitro evaluation against amastigote forms, two compounds 7g (8.80 lM) and 7i (7.50 lM) showed significant inhibition of L. donovani amastigotes. Standard drug amphotericin B is also used as control to compare inhibition potency of compounds against both promastigote (0.24 lM) and amastigote (0.05 lM) forms. Ó 2016 Elsevier Inc. All rights reserved. 1. Introduction Leishmaniasis is a group of diseases caused by protozoan para- sites of the genus Leishmania. It is considered as one of the most neglected diseases and is endemic in 90 countries. It is estimated that, currently 350 millions are living at risk places and 12 millions are affected with annual mortality of 50,000 [1]. Traditionally, leishmaniasis has been classified into three different clinical forms (i.e.) Cutaneous Leishmaniasis (CL), Mucocutaneous Leishmaniasis (MCL) and Visceral Leishmaniasis (VL) [2]. CL is the most common form of the infection, 90% of cases occurs in countries like Afghani- stan, Algeria, Brazil, Pakistan, Peru, Saudi Arabia and Syria. Nearly about 20 species of Leishmania are responsible for CL which includes Leishmania amazensis, Leishmania major, Leishmania braziliensis, Leishmania mexicana and Leishmania panamensi. Although, CL is often self-healing, it can create serious permanent disfiguring scars on exposed parts of the body, such as the face, arms and legs [3,4]. Mucocutaneous Leishmaniasis (also called Espundia in South America) produces lesion on mucous mem- branes of the nose, mouth, throat cavities and surrounding tissues. These lesions can lead to partial or total destruction of the affected organs [5]. Pathogenesis of MCL is still un-clear, genetic factor of infected people plays an important role in progression of the dis- ease. Visceral Leishmaniasis (also known as kala azar) is the most severe form of Leishmaniasis, caused by Leishmania donovani and Leishmania infantum. More than 90% of cases occurs in five coun- tries: India, Bangladesh, Nepal, Sudan and Brazil [6]. Symptoms of VL are irregular fever, weight loss, mucosal ulcers, swelling of liver, spleen and anaemia. Unlike the cutaneous forms, VL affects internal organs such as liver, spleen, bone marrow and is usually fatal if left untreated [7]. Leishmaniasis control is mainly depends on decade old drugs, due to lack of availability of effective vaccine. Pentavalent antimo- nials (sodium stibogluconate and meglumine antimoniate) are being used in the treatment of leishmaniasis more than five dec- ades and still they are the first line drugs of choice where resis- tance is not reported. In spite of its adverse effects, polyene antifungal drug, amphotericin B is the drug of choice where resis- tance to antimonials has been developed. Usefulness of second line drugs like diamidine, pentamidine and aminoglycoside antibiotic paromomycin has been limited [8,9]. Miltefosine is the only oral drug used for the treatment of leishmaniasis, originally developed as anticancer agent. Risk to develop parasite resistance against mil- tefosine is high, because of its long half-life (150 h) and its use dur- ing pregnancy is restricted. Low efficacy of miltefosine is observed in countries like India where leishmaniasis is more prevalent [10]. http://dx.doi.org/10.1016/j.bioorg.2016.11.013 0045-2068/Ó 2016 Elsevier Inc. All rights reserved. ⇑ Corresponding author. E-mail addresses: penta.ashok@gmail.com (P. Ashok), larry.chow@polyu.edu.hk (L.M.C. Chow), murugesan@pilani.bits-pilani.ac.in (M. Sankaranarayanan). Bioorganic Chemistry xxx (2016) xxx–xxx Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg Please cite this article in press as: P. Ashok et al., Bioorg. Chem. (2016), http://dx.doi.org/10.1016/j.bioorg.2016.11.013