Coumarins inhibit η-class carbonic anhydrase from Plasmodium falciparum

Abstract

Coumarins were discovered to act as inhibitors of α-carbonic anhydrases (CAs, EC 4.2.1.1) after undergoing hydrolysis mediated by the esterase activity of the enzyme to the corresponding 2-hydroxycinnamic acids. Other classes of CAs among the eight currently known do not possess esterase activity or this activity was poorly investigated. Hence, we decided to look at the potential of coumarins as inhibitors of the η-CA from the malaria-producing protozoan Plasmodium falciparum , PfaCA. A panel of simple coumarins incorporating hydroxyl, amino, ketone or carboxylic acid ester moieties in various positions of the ring system acted as low to medium micromolar PfaCA inhibitors, whereas their affinities for the cytosolic off-target human isoforms hCA I and II were in a much higher range. Thus, we confirm that η-CAs possess esterase activity and that coumarins effectively inhibit this enzyme. Elaboration of the simple coumarin scaffolds investigated here may probably lead to more effective PfaCA inhibitors.

Future antimalarials fromArtemisia? A rationale for natural product mining against drug-refractoryPlasmodiumstages

“…158 To our knowledge, scopolin, eleutheroside B1 and 4-methylesculetin have not been evaluated against Plasmodium parasites. Mechanistically, coumarins are general Natural Product Reports Review inhibitors of the P. falciparum h-carbonic anhydrase, 159 but none of the above-mentioned compounds seems to have been tested yet against this parasite target.…”

Natural products reverse cancer multidrug resistance

“…This review examines the scientific advances on using natural products to treat tumors with MDR. We discuss the mechanisms of action of various kinds of natural products, including as flavonoids ( Vissenaekens et al, 2022 ), alkaloids ( Liu C. et al, 2019 ), terpenoids ( Kuang et al, 2021 ), polyphenols ( Luca et al, 2020 ), and coumarins ( Xiaokaiti and Li, 2020 ; Giovannuzzi et al, 2022 ).…”

“…This review examines the scientific advances on using natural products to treat tumors with MDR. We discuss the mechanisms of action of various kinds of natural products, including as flavonoids (Vissenaekens et al, 2022), alkaloids (Liu C. et al, 2019), terpenoids (Kuang et al, 2021), polyphenols (Luca et al, 2020), and coumarins (Xiaokaiti and Li, 2020;Giovannuzzi et al, 2022). drug targets, increasing DNA damage repair, MDR-related factors or signaling pathways, non-coding RNA (ncRNA)-mediated multidrug resistance, and autophagy and tumor microenvironment effects.…”

Novel Insights on Human Carbonic Anhydrase Inhibitors Based on Coumalic Acid: Design, Synthesis, Molecular Modeling Investigation, and Biological Studies

“…However, this quite simple reaction slowly occurs in physiological conditions, requiring the aid of an enzyme that strongly accelerates it. Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes involved in the catalysis of this reaction, and currently eight diverse genetic CA families ( α -, β -, γ -, δ -, ζ -, η -, θ -, and i -CAs) have been reported [ 4 , 5 , 6 , 7 , 8 ]. The fifteen human carbonic anhydrase isoforms (hCAs) belong to the α -family and cover a pivotal role in a multitude of physiological functions such as respiration, transport of carbon dioxide between metabolizing tissues and lungs, pH homeostasis, electrolyte secretion in various tissues/organs, as well as biosynthetic reactions [ 9 ].…”