1. Semisynthesis, Antiplasmodial Activity, and Mechanism of Action Studies of Isocoumarin Derivatives
- Author
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Yu-Cheng Gu, Chang-Lun Shao, Nerea Escala, Laura M. Pineda, Esther del Olmo, Chang-Yun Wang, Carmenza Spadafora, Michelle Ng, Lorena M. Coronado, Doriana Dorta, and Xue-Qing Zhang
- Subjects
Hemeproteins ,Aquatic Organisms ,China ,Stereochemistry ,Isocoumarins ,Plasmodium falciparum ,Pharmaceutical Science ,01 natural sciences ,DNA gyrase ,Analytical Chemistry ,chemistry.chemical_compound ,Antimalarials ,Structure-Activity Relationship ,Ascomycota ,Drug Discovery ,Chlorocebus aethiops ,Side chain ,medicine ,Animals ,Topoisomerase II Inhibitors ,Vero Cells ,Pharmacology ,Membrane Potential, Mitochondrial ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Hemozoin ,Organic Chemistry ,Anthozoa ,Semisynthesis ,0104 chemical sciences ,Isocoumarin ,010404 medicinal & biomolecular chemistry ,Complementary and alternative medicine ,Mechanism of action ,Polymerization ,DNA Gyrase ,Molecular Medicine ,medicine.symptom ,Reactive Oxygen Species - 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.
- Published
- 2021