A natural product inspired hybrid approach towards the synthesis of novel pentamidine based scaffolds as potential anti-parasitic agents Vikas Tyagi a , Shahnawaz Khan a , Rahul Shivahare b , Khushboo Srivastava b , Suman Gupta b , Saqib Kidwai b , Kumkum Srivastava b , S. K. Puri b , Prem M. S. Chauhan a,⇑ a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226001, India b Parasitology Division, CSIR-Central Drug Research Institute, Lucknow 226001, India article info Article history: Received 16 August 2012 Revised 26 September 2012 Accepted 23 October 2012 Available online 1 November 2012 Keywords: Pyrimidine Chalcone Pentamidine Anti-leishmanial activity Anti-malarial activity abstract A natural product inspired molecular hybridization approach led us to a series of novel pentamidine based pyrimidine and chalcone scaffolds. All the hybrids were evaluated for their anti-leishmanial poten- tial. Most of the screened compounds have showed significant in vitro anti-leishmanial activity with less cytotoxicity in comparison to the standard drugs (pentamidine, sodium stibogluconate, and miltefosine). Additionally, anti-malarial screening of these compounds was also done and four compounds have shown superior activity against chloroquine resistance strain (K1) of Plasmodium falciparum. Ó 2012 Elsevier Ltd. All rights reserved. Nowadays, neglected tropical disease (NTDs) affect more than one billion people worldwide, causes over 550,000 deaths annu- ally. 1 Research projects aiming to discover new drugs for NTDs have discouraged drug companies from investing due to the low returns of investment. 2 Owing to this, drug discovery pipeline is still almost dry for NTDs. Among NTDs, Chagas disease, sleeping sickness, malaria, and leishmaniasis are the major NTDs with the highest rates of death. 3 In particular, leishmania is responsible for cutaneous and visceral infections, endemic in 88 countries in the Horn of Africa, South Asia, and Latin America. 4 Leishmaniasis is a vector born disease caused by different species belonging to the genus Leishmania, a protozoa transmitted by the bite of a tiny long (2–3 mm) insect vector, the phlebotomine sandfly. 5 Leishmania is manifested in four major clinical forms i.e. cutaneous leishmania- sis, mucocutaneous leishmaniasis, visceral leishmaniasis, and post kala-azar dermal leishmaniasis or PKDL. Among all the four forms, visceral leishmaniasis (VL), caused by the parasite Leishmania donovani, is nearly always fatal if not treated. 6 The first line drugs for the treatment of leishmania are pentava- lent antimonial compounds, which were discovered almost 70 years ago, and generally require high dose of parental adminis- tration. Moreover, this class of drugs need long-term treatment associated with severe side effects including cardiac arrhythmia and pancreatitis. 7 Pentamidine, miltefosine, and amphotericin-B, are the second line drugs for the treatment of VL, which also suffer from moderate to severe side effects. 8 Pentamidine, an aromatic diamidine, is orally inactive and may demonstrate renal, hepatic and pancreatic toxicity beside with hypotension and dysglycemia. 9 Amphotericin-B and its lipid complex is a most useful alternative, however, major draw backs associated with amphotericin-B, such as its high cost leave out of the reach of poor people. 10 Furthermore, recently introduced first orally active drug Mil- tefosine, a phosphocholine analogue, has a long half-life (100– 200 h) in humans and a low therapeutic ratio, presenting severe gastrointestinal problems and also shows teratogenic effects and cannot be used in the pregnant women. 11 Since the chemotherapy against leishmaniasis is still inefficient, as a result the finding of more effective and safer drug for treating leishmaniasis remains desirable. The natural product inspired molecular hybridization approach has been emerged as a powerful tool for tackling the problems associated with the standard drugs. 12 Recently, some hybrid mole- cules of pentamidine with other heterocycles have been synthe- sized, which showed potent anti-leishmanial activity with low cytotoxicity. 13 Furthermore, following the same approach some pyrimidines and chalcone based hybrids were synthesized and evaluated for their anti-parasitic potential. 14 Annomontin, a pyrimidine-b-carboline alkaloid, has showed antileishmanial activity 34.8 ± 1.5 against the Leishmania brazilien- sis. On the other hand, licochalcone A, is a well known anti-parasitic 0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2012.10.101 ⇑ Corresponding author. Tel.: +91 522 2262411x4470; fax: +91 522 2623405. E-mail addresses: premsc58@hotmail.com, prem_chauhan_2000@yahoo.com (P.M.S. Chauhan). Bioorganic & Medicinal Chemistry Letters 23 (2013) 291–296 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl