Anti-proliferative and anti-malarial activities of spiroisoxazoline analogues of artemisinin

Surya Pratap; Fatima Naaz; Srinivas Reddy; Kunal K Jha; Kalicharan Sharma; Dinakar Sahal; Mymoona Akhter; Devanna Nayakanti; Halmuthur M S Kumar; Vandana Kumari; Kailash Pandey; Syed Shafi

doi:10.1002/ardp.201800192

Anti-proliferative and anti-malarial activities of spiroisoxazoline analogues of artemisinin

Arch Pharm (Weinheim). 2018 Dec 10:e1800192. doi: 10.1002/ardp.201800192. Online ahead of print.

Authors

Surya Pratap¹, Fatima Naaz², Srinivas Reddy^{3

4}, Kunal K Jha⁵, Kalicharan Sharma², Dinakar Sahal⁶, Mymoona Akhter², Devanna Nayakanti¹, Halmuthur M S Kumar³, Vandana Kumari⁷, Kailash Pandey^{7

8}, Syed Shafi⁹

Affiliations

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.

PMID: 30537298
DOI: 10.1002/ardp.201800192

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 IC₅₀ = 4.04 μM when compared to 5-fluorouracil (IC₅₀ = 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 IC₅₀ = 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.