Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents q S. N. Suryawanshi a,⇑ , Santosh Kumar a , Avinash Tiwari a , Rahul Shivahare b , Yashpal Singh Chhonker c , Susmita Pandey a , Nishi Shakya b , Rabi Sankar Bhatta c , Suman Gupta b a Division of Medicinal Chemistry, CSIR-Central Drug Research Institute, Chattar Manzil Palace, P.O. Box 173, Mahatma Gandhi Road, Lucknow 226001, India b Division of Parasitology, CSIR-Central Drug Research Institute, Chattar Manzil Palace, P.O. Box 173, Mahatma Gandhi Road, Lucknow 226001, India c Division of Pharmacokinetics and Metabolism, CSIR-Central Drug Research Institute, Chattar Manzil Palace, P.O. Box 173, Mahatma Gandhi Road, Lucknow 226001, India article info Article history: Received 28 September 2012 Revised 5 April 2013 Accepted 9 April 2013 Available online 26 April 2013 Keywords: Aryl S,N-ketene acetal Leishmania donovani Antileishmanial activity Hamster Pharmacokinetic studies abstract A series of aryl S,N-ketene acetals 7(a–f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC 50 values ranging from 1.2 to 3.5 lM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromo- mycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Cl int ) of compound 7b in hamster liver microsomes. Ó 2013 Elsevier Ltd. All rights reserved. Leishmaniasis is a group of parasitic diseases that affect about twelve million people in tropical and subtropical areas provoking three clinical expressions: visceral leishmaniasis (VL) that is fatal in the absence of treatment, 1 muco-cutaneous leishmaniasis and cutaneous leishmaniasis, the last one often self-curing. 2 Pentava- lent antimonials remain the first-line treatment in most parts of the world, but in India, its use is restricted due to the high level of drug resistance. There has been a significant improvement in the number of treatments available for VL during the past decade, with both new drugs and new formulations of old drugs either re- cently approved or in clinical trial. These new treatments include: AmBisome™, a liposomal amphotericin-B formulation, registered for VL in the USA and Europe in the 1990s with remarkable activity, even at a single dose in India; oral miltefosine, registered in India in 2002 (later in Bangladesh); and a low cost intramuscular formu- lation of paromomycin (aminosidine), registered in India in 2006 and in phase III trial in East Africa by DNDi. Unfortunately, all of these drugs have significant drawbacks that limit their utilization in disease endemic areas. These include route of administration, length of treatment (21–28 days), toxicity and cost. 3 Thus, the development of new, efficient, and safe drugs for the treatment of this disease is imperative. In this endeavour, diarylheptanoids, 4 oxygenated abietanes, 5 diterpenequinones 6,7 and chalcones 8 showed promising results as antileishmanial agents. Curcumin 1 isolated from Curcuma longa Linn., well known as an anticancer agent, 4a also showed antileishmanial activity in in vitro studies. 4b,9 Exhaustive analoging of curcumin has generated some interesting results. 10 Licochalcone 2 isolated from Glycerrhiza sp., first reported for its antibacterial activity 11 has also showed promising antileish- manial activity. 12 Chemical library generated on the basis of licoch- alcone as a lead molecule was found active in in vitro studies. 8a Phenolic diketone 3 isolated from Zingiber offıcinale, 13 a structural mimic of 1 and 2 shows radical scavenging activities, quite compa- rable to curcumin 1. In continuation of our efforts to generate nat- ural product based novel antileishmanial agents 14 coupled with encouraging results of 1–3 (Fig. 1), we have synthesized some no- vel aryl S,N-ketene acetals for their in vitro and in vivo antileish- manial activity profile and preliminary in vitro metabolic studies. The findings are reported in this communication . a-Oxoketene dithioacetals of aromatic substrates are very use- ful synthons in the synthesis of variety of heterocyclic and carbo- cyclic compounds. 15 Various aryl S,N-ketene acetals have been synthesized from a-oxoketene dithioacetals. 16a–c However; they have not been fully exploited for their biological activity profile. 3,4,5-trimethoxy aryl S,N-ketene acetals 7(a–f) were prepared as shown in Scheme 1. The reaction of 3,4,5-trimethoxybenzaldehyde (tri-o-methylgallaldehyde) 4 with acetone based ketene dithioace- tal 5 furnished 6 which on further reaction with primary amines 0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.04.025 q CDRI Communication No. 272/2011/SNS. ⇑ Corresponding author. Tel.: +91 522 221 2411 18; fax: +91 522 222 3405. E-mail address: shivajins1952@gmail.com (S.N. Suryawanshi). Bioorganic & Medicinal Chemistry Letters 23 (2013) 3979–3982 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl