Received: 28 June 2018 | Revised: 22 October 2018 | Accepted: 4 November 2018 DOI: 10.1002/ardp.201800192 FULL PAPER Anti-proliferative and anti-malarial activities of spiroisoxazoline analogues of artemisinin Surya Pratap 1 | Fatima Naaz 2 | Srinivas Reddy 3,4 | Kunal K. Jha 5 | Kalicharan Sharma 2 | Dinakar Sahal 6 | Mymoona Akhter 2 | Devanna Nayakanti 1 | Halmuthur M. S. Kumar 3 | Vandana Kumari 7 | Kailash Pandey 7,8 | Syed Shafi 9 1 Research Scholar, Department of Biosciences, Jawaharlal Nehru Technological University, Anantapur, India 2 Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India 3 Vaccine Immunology Laboratory, Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India 4 CNRS, Immunopathology and Therapeutic Chemistry/Laboratory of Excellence Medalis, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France 5 Chemical and Biological Crystallography Laboratory, Department of Chemistry, School of Natural Science, Shiv Nadar University, Tehsil Dadri, India 6 Malaria Research Laboratory, ICGEB, New Delhi, India 7 National Institute of Malaria Research, New Delhi, India 8 National Institute for Research in Environmental Health, Bhopal, India 9 Department of Chemistry, School of Chemical and Life Science, Jamia Hamdard, New Delhi, India Correspondence Dr. Syed Shafi, Department of Chemistry, School of Chemical and Life Science, Jamia Hamdard, Hamdard Nagar, New Delhi- 110062, India. Email: syedshafi@jamiahamdard.ac.in Abstract A series of spiroisoxazoline analogues of artemisinin was synthesized by employing 1,3-dipolar cycloaddition between various in situ generated nitrile oxides and artemisitene. All the synthesized compounds were tested for their anti-proliferative and anti-malarial activities. Among the compounds tested, compound 11a was found to be potent against the HCT-15 cancer cell line with IC 50 = 4.04 μM when compared to 5-fluorouracil (IC 50 = 35.53 μM). DNA cell cycle analysis shows that 11a was inhibiting cell proliferation at the G2/M phase. Compound 11b was found to be most active against Plasmodium falciparum with IC 50 = 0.1 μM and also blocked host hemoglobin hydrolysis by the falcipain-3 receptor. It was demonstrated to have better dynamics of parasite killing efficiency than artemisinin. Molecular docking studies revealed that these compounds interacted with falcipain-3 receptor sites. KEYWORDS 1,3-dipolar cycloaddition, anti-malarial activity, anti-proliferative, artemisitene, spiroisoxazoline 1 | INTRODUCTION Artemisinin 1 and its derivatives (dihydroartemisinin, artemether, and artesunate) are currently recommended as front-line anti-malarial drugs for multi-drug resistance malaria Plasmodium falciparum. [1–3] Although the exact mechanism of artemisinin and its analogues is still unclear, it is believed to act by the generation of toxic carbon-centered free radicals after activation by intra-parasitic heme-iron (which Arch Pharm Chem Life Sci. 2018;1–11. wileyonlinelibrary.com/journal/ardp © 2018 Deutsche Pharmazeutische Gesellschaft | 1