Synthesis and evaluation of 7-chloro-4-(piperazin-1-yl)quinoline- sulfonamide as hybrid antiprotozoal agents Attar Salahuddin a , Afreen Inam a , Robyn L. van Zyl b , Donovan C. Heslop b , Chien-Teng Chen b , Fernando Avecilla c , Subhash M. Agarwal d,⇑ , Amir Azam a,⇑ a Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India b Pharmacology Division, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of Witwatersrand, Johannesburg 2193, South Africa c Departamento de Química Fundamental, Universidade da Coruña, Campus da Zapateira s/n, 15071 A Coruña, Spain d Bioinformatics Division, Institute of Cytology and Preventive Oncology (ICMR) I-7, Sector-39, Noida 201301, Uttar Pradesh, India article info Article history: Received 31 January 2013 Revised 16 March 2013 Accepted 19 March 2013 Available online 2 April 2013 Keywords: Antiprotozoal agents Sulfonamides Entamoeba histolytica Plasmodium falciparum Cytotoxicity Homology modeling Docking abstract A new series of 4-aminochloroquinoline based sulfonamides were synthesized and evaluated for anti- amoebic and antimalarial activities. Out of the eleven compounds evaluated (F1–F11), two of them (F3 and F10) showed good activity against Entamoeba histolytica (IC 50 <5 lM). Three of the compounds (F5, F7 and F8) also displayed antimalarial activity against the chloroquine-resistant (FCR-3) strain of Plasmodium falciparum with IC 50 values of 2 lM. Compound F7, whose crystal structure was also deter- mined, inhibited b-haematin formation more potently than quinine. To further understand the action of hybrid molecules F7 and F8, molecular docking was carried out against the homology model of P. falci- parum enzyme dihydropteroate synthase (PfDHPS). The complexes showed that the inhibitors place themselves nicely into the active site of the enzyme and exhibit interaction energy which is in accordance with our activity profile data. Application of Lipinski ‘rule of five’ on all the compounds (F1–F11) sug- gested high drug likeness of F7 and F8, similar to quinine. Ó 2013 Elsevier Ltd. All rights reserved. 1. Introduction Diseases caused by protozoal organisms are responsible for con- siderable mortality and morbidity, affecting more than 500 million people in the world. 1 Two such protozoan diseases are malaria caused by Plasmodium falciparum and amoebiasis caused by Ent- amoeba histolytica. 2,3 Malaria alone affects nearly 40% of the global population, while amoebiasis results in 50 million cases of invasive disease and up to a million fatalities per year. 3 Chemotherapy re- mains the mainstay as the control strategy for both these diseases. 7-Chloroquinolines and nitroimidazoles as core moieties are active against malaria and amoebiasis, respectively. Chloroquines, amodi- aquine and ferroquine are the standard drugs that bear 4-amino- chloroquinoline core in their structures while metronidazole, ornidazole and tinidazole are a class of nitroimidazole ring bearing drugs. The protozoan parasites have now become resistant to some of the more effective antiprotozoal drugs, thereby pressurizing the control measures in place to treat patients infected with malaria and amoebiasis. This scenario has necessitated the search for novel drugs to contribute to the global chemotherapeutic regimens. 4 Presently, the most promising and so far successful strategy in fighting malaria is the artemisinin combination chemotherapy (ACT), in which an artemisinin derivative is used together with conventional antimalarial drug to improve efficacy and to delay the onset of resistance. 5 A recent rational approach of antimalarial drug design characterized as ‘covalent bitherapy’ involves linking two molecules with individual intrinsic activity into a single agent, thus packaging dual activity into a single hybrid molecule. 6,7 Cur- rent research in this field seems to support hybrid molecules as the next-generation antimalarial drugs, for example Trioxaferroqu- ines. 6–8 Many conjugates of the available drugs for malaria have been reported since the establishment of the concept of covalent bitherapy. 9 In many cases the conjugates have displayed more po- tency towards both drug resistant and non-resistant strains. The two enzymes DHPS (dihydropteroate synthetase) and DHFR (dihydrofolate reductase) present within folate biosynthetic path- way are ideal targets for antimicrobial therapy as folate is neces- sary for the cell to synthesize nucleic acids and in its absence cells is unable to divide. Sulfonamides are well known competitive inhibitors of the enzyme DHPS 10 which catalyses the conversion of PABA (para-aminobenzoic acid) to dihydropteroate, a key step in 0968-0896/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2013.03.052 ⇑ Corresponding authors. Tel.: +91 11 26983253; fax: +91 11 26980229. E-mail addresses: smagarwal@yahoo.com (S.M. Agarwal), amir_sumbul@yahoo.- co.in (A. Azam). Bioorganic & Medicinal Chemistry 21 (2013) 3080–3089 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc