2. Academic Validation
  3. Semisynthesis, Antiplasmodial Activity, and Mechanism of Action Studies of Isocoumarin Derivatives

Semisynthesis, Antiplasmodial Activity, and Mechanism of Action Studies of Isocoumarin Derivatives

  • J Nat Prod. 2021 May 28;84(5):1434-1441. doi: 10.1021/acs.jnatprod.0c01032.
Lorena Coronado 1,  Xue-Qing Zhang 2 3 4,  Doriana Dorta 1,  Nerea Escala 1 5,  Laura M Pineda 1,  Michelle G Ng 1,  Esther Del Olmo 5,  Chang-Yun Wang 2 3,  Yu-Cheng Gu 6,  Chang-Lun Shao 2 3,  Carmenza Spadafora 1
Affiliations

Affiliations

  • 1 Center of Cellular and Molecular Biology of Diseases, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, City of Knowledge, Clayton, Apartado 0816-02852, Panama.
  • 2 Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.
  • 3 Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266200, People's Republic of China.
  • 4 Hubei Key Laboratory of Natural Product Research and Development (China Three Gorges University), College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, People's Republic of China.
  • 5 Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, s/n, E-37007 Salamanca, Spain.
  • 6 Syngenta Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
PMID: 33979168 DOI: 10.1021/acs.jnatprod.0c01032
Abstract

In this study, eight natural isocoumarins (1-8) were isolated from a marine-derived Exserohilum sp. fungus. To explore their structure-activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a-1n, 2a, 3a-3c, 4a-4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC50 values of 1.1, 0.8, 0.4, and 2.6 μM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC50/IC50 = 675), high selectivity, and a notable drug-like profile.

Figures