An amidation/cyclization approach to the synthesis of N-hydroxyquinolinones and their biological evaluation as potential anti-plasmodial, anti-bacterial, and iron(II)-chelating agents Yanbo Teng a , Rossarin Suwanarusk b , Mun Hong Ngai a , Rajavel Srinivasan c , Alice Soh Meoy Ong b , Bow Ho d , Laurent Rénia b , Christina L. L. Chai a,c,⇑ a Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore b Singapore Immunology Network (SIgN), Agency for Science Technology and Research, (A / STAR), 8A Biomedical Grove, Immunos Building, Singapore 138648, Singapore c Institute of Chemical and Engineering Sciences (ICES), Agency for Science Technology and Research, (A / STAR), 8 Biomedical Grove, Singapore 138665, Singapore d Department of Microbiology, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore article info Article history: Received 15 August 2014 Revised 22 November 2014 Accepted 5 December 2014 Available online xxxx Keywords: N-Hydroxyquinolinone Anti-plasmodial activity Anti-bacterial activity Iron chelation abstract A 26-member library of novel N-hydroxyquinolinone derivatives was synthesized by a one-pot Buchwald-type palladium catalyzed amidation and condensation sequence. The design of these rare scaffolds was inspired from N-hydroxypyridones and 2-quinolinones classes of compounds which have been shown to have rich biological activities. The synthesized compounds were evaluated for their anti-plasmodial and anti-bacterial properties. In addition, these compounds were screened for their iron(II)-chelation properties. Notably, four of these compounds exhibited anti-plasmodial activities comparable to that of the natural product cordypyridone B. Ó 2014 Elsevier Ltd. All rights reserved. Molecular hybridization, a strategy of combining pharmaco- phoric elements of two or more biologically active small molecules, results in hybrid compounds that may retain the biological characteristics of the parent compounds or lead to new or enhanced biological activities. 1 These hybridized entities are typi- cally synthetically more accessible than the parent compounds as only the key pharmacologically active groups are necessary. To this end, we envisioned N-hydroxyquinolinones, a scarce and a relatively unexplored scaffold in medicinal chemistry as a blend of N-hydroxypyridone and quinolone scaffolds and anticipate these to possess the combined biological properties of the parent compounds. There is a myriad of known N-hydroxypyridone-based natural products possessing anti-plasmodial, anti-bacterial, and anti-can- cer properties. 2 For example, cordypyridone B (Fig. 1) was reported to display potent anti-plasmodial activity against Plasmodium falciparum (K1 strain) with an IC 50 value of 37 ng/mL 3 as well as display anti-bacterial properties against Staphylococcus aureus. 4 Other examples of naturally occurring N-hydroxypyridones include akanthomycin, an antibiotic isolated from the fungus Akanthomycin gracilis. 4 Moreover, compounds with the N-hydroxy- pyridone motif are widely considered as siderophores and their biological activities have been recognized to originate from their ability to sequester metal ions. 5 For example, pyridoxatin–Fe complex (named terricolin) has been isolated and the absolute structure was elucidated by X-ray crystallographic methods. 6 On the other hand, the 4-quinolone class of compounds has long been used as broad-spectrum antibiotics since its discovery about 40 years ago. 7 4-quinolone drugs (such as sitafloxacin) act as anti-bacterials by inhibiting the topoisomerase ligase domain of the bacteria leading to DNA fragmentation and ultimately cell death. 8 Recently, a 4-quinolone compound, ELQ-300 with an IC 50 value of 14.9 nM against the drug resistant Plasmodium falciparum was identified as a lead candidate for the treatment of malaria (Fig. 1). 9 Despite these developments, there is a continual urgent need to develop new and effective anti-malarial and anti-bacterial therapies as the current suite of marketed drugs are becoming ineffective at an alarming rate due to resistance. To date, it is known that the malaria parasite has developed resistance towards the last-line drug artemisinin and threatens malaria control. 10 Similarly, the emergence of bacterial resistance to all the four generations of quinolone antibiotics necessitates the development of new therapies. 8 http://dx.doi.org/10.1016/j.bmcl.2014.12.014 0960-894X/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Please cite this article in press as: Teng, Y.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.12.014