a-Aminophosphonates as novel anti-leishmanial chemotypes: synthesis, biological evaluation, and CoMFA studies† Srikant Bhagat, a Parth Shah, a Sanjeev K. Garg, a Shweta Mishra, a Preet Kamal Kaur, b Sushma Singh b and Asit K. Chakraborti * a A series of twenty six structurally diverse a-aminophosphonates have been synthesized and evaluated for in vitro anti-leishmanial activity and cytotoxicity using the MTT assay. Among them, seven compounds (1–7) exhibited anti-leishmanial potency against the L. donovani promastigote with IC 50 values in the low micromolar range. The structure–activity relationships were quantitatively evaluated by a statistically reliable CoMFA model with high predictive abilities (r 2 pred ¼ 0.87, r 2 ncv ¼ 0.985). 1. Introduction Leishmaniasis, a parasitic disease causes a major public health problem, which is prevalent in some tropical and sub-tropical areas of the world. One of its types, visceral leishmaniasis (VL), also known as kala-azar, is highly endemic in the Indian subcontinent and in East Africa. The majority of VL cases occur in Bangladesh, Brazil, Ethiopia, India, Nepal, and Sudan. 1 It is transmitted by the bite of infected female phlebotomine sand- ies belonging to the genus Leishmania. Leishmaniasis affects an estimated 350 million people worldwide with 1.5–2 million new cases and 70 000 deaths each year. 2 The existing chemo- therapies are not effective enough as these have various draw- backs such as signicant toxicity, variable efficacy, lack of oral bioavailability, and high cost involved during the treatment. The development of resistance against the available therapeu- tics is another major bottleneck in treating the disease condition with the compounded problem of leishmaniasis–HIV co-infections. The pentavalent antimonials, that remained the rst line therapeutic options for more than 50 years, 3 have potential side effects causing acute pancreatitis and cardiac arrhythmia leading to death in extreme cases 4 and have exhibited large scale clinical resistance including in India. 5 The second line drugs pentamidine and amphotericin B are not active orally, need long term treatment and may lead to renal, pancreatic, and hepatic toxicity, hypotension, and dysglycemia. 6 Amphotericin B triggers hypokalemia and nephrotoxicity as the most common side effects apart from the life-threatening rst- dose anaphylaxis. Thus, for the global health programs there has been a pressing need for the discovery of new lead compounds for the treatment of leishmaniasis. 7 The phospho- lipids (Fig. 1), originally discovered as anti-cancer drugs, have emerged as a new class of anti-protozoal/parasitic agents 8 and the analogue miltefosine (1a) has been registered as the rst oral drug for the treatment of the disease in India in 1992 (ref. 7g and 9) and in Colombia in 2005. 10 Other phospholipid analogues as promising drug candidates are edelfosine (1b) and elmofosine (1c). 11 However, 1a has a long half-life (6–8 days) in humans and low therapeutic ratio that are conducive to the development of resistance and it is not suitable for pregnant women as it has potential teratogenic effect and shows severe gastrointestinal side effects 12 and unsatisfactory results for treating HIV co-infected patients. 13 These have directed efforts towards the development of anti-leishmanial phospholipids 14 with an aim of deriving more efficacious drug candidates. We were attracted by the remarkable potential of the a-amino- phosphonate structural motif in medicinal chemistry due to diverse biological activities 15 and report herein a-amino- phosphonates as novel anti-leishmanial chemotypes. Fig. 1 Phospholipids as newly emerged anti-leishmanials. a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India. E-mail: akchakraborti@niper.ac.in; akchakraborti@rediffmail.com; Fax: +91-172 2214692; Tel: +91-172 2214683 b Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India † Electronic supplementary information (ESI) available: Procedures for the synthesis, molecular modelling, spectral characterization and biological evaluation are described. See DOI: 10.1039/c3md00388d Cite this: Med. Chem. Commun. , 2014, 5, 665 Received 17th December 2013 Accepted 19th February 2014 DOI: 10.1039/c3md00388d www.rsc.org/medchemcomm This journal is © The Royal Society of Chemistry 2014 Med. Chem. Commun., 2014, 5, 665–670 | 665 MedChemComm CONCISE ARTICLE Published on 20 February 2014. Downloaded by ST JOHNS UNIVERSITY on 07/06/2014 08:28:55. View Article Online View Journal | View Issue